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WO2025179161A1 - Protein degrading compounds - Google Patents

Protein degrading compounds

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Publication number
WO2025179161A1
WO2025179161A1 PCT/US2025/016822 US2025016822W WO2025179161A1 WO 2025179161 A1 WO2025179161 A1 WO 2025179161A1 US 2025016822 W US2025016822 W US 2025016822W WO 2025179161 A1 WO2025179161 A1 WO 2025179161A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
pharmaceutically acceptable
acceptable salt
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/016822
Other languages
French (fr)
Inventor
Qinyi DU
Weilin Xie
Patrick W. Papa
Veronique Plantevin-Krenitsky
Paul J. Krenitsky
Frank Mercurio
Derek MENDY
Michael P. HAUGHEY
Jan Elsner
John Sapienza
Brandon Whitefield
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innovo Therapeutics Inc
Original Assignee
Innovo Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Innovo Therapeutics Inc filed Critical Innovo Therapeutics Inc
Publication of WO2025179161A1 publication Critical patent/WO2025179161A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Cereblon is a key component of one E3 ubiquitin ligase complex and is thus an attractive target for molecular glues. Cereblon is reprogrammed by compounds such as thalidomide, lenalidomide and pomalidomide (imids) to induce degradation of neosubstrate proteins, including IKZF1 (Ikaros) and IKAF3 (Aiolos) (see, e.g., Charlinski et al. Cancers, 2021, 13, 4666). Thus, molecular glues that bind cereblon allow for ubiquination of target proteins, which are then degraded by the proteasome.
  • Casein kinase 1 ⁇ (“CK1 ⁇ ”) is a protein of the CK1 protein family that regulates signaling pathways related to membrane trafficking, cell cycle progression, chromosome segregation, apoptosis, autophagy, cell metabolism, and differentiation in development, circadian rhythm, and the immune response as well as neurodegeneration and cancer (see, e.g., Jiang et al., Cell Commun. Signaling 2018, 16, 23; Spinello et al., Int. J. Mol. Sci.2021, 22, 3716).
  • CK1 ⁇ is an attractive therapeutic target for a variety of indications and uses, including oncology, immuno-oncology, and autoimmune disorders.
  • CK1 ⁇ is required for BCR- (via BTK) and TCR-induced activation of the Card11/BCL10/MALT1 (CBM) complex (see, e.g., Gehring et al., Cell Reports 2019, 29, 873-888; Bidere et al., Nature 2009, 458, 7234; Yin et al. Cell. Mol. Life Sci.2022, 79, 112).
  • CBM Card11/BCL10/MALT1
  • Activation of CBM has been implicated in the progression of a variety of lymphoid malignancies, including non- Hodgkin lymphoma (NHL) (see, e.g., Bedsaul et al. Front.
  • NHL non- Hodgkin lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • ABC DLBCL ABC DLBCL
  • MALT mucosa- associated lymphoid tissue
  • MCL mantle cell lymphoma
  • ATLL adult T-cell leukemia/lymphoma
  • Sezary syndrome see, e.g., Juilland et al., Curr. Opin. Hemat.2016, 23(4), 402-409.
  • CK1 ⁇ has been shown to sustain B-cell signaling in MCL (see, e.g., Manni et al., Front. Oncol.2021, 11, Article 733848), while MALT1 inhibition has been shown to be an effective strategy in treatment of both na ⁇ ve and ibrutinib-resistant chronic lymphocytic leukemia (CLL) (see, e.g., Saba et al., Cancer Res. 2017, 77(24), 7038-7048).
  • CLL chronic lymphocytic leukemia
  • CK1 ⁇ Loss of CK1 ⁇ by siRNA or a kinase inhibitor has also been shown to result in stabilization of the tumor suppressor p53 and inhibition of cell cycle progression (see, e.g., Huart et al., J. Biol. Chem.2009, 284(47), 32384-32394). Briefly, CK1 ⁇ binds MDM2, which is the p53 E3 ubiquitin ligase (see, e.g., Wu et al. Mol. Cell. Biol.2012, 32(23), 4821- 4832).
  • Binding of the CK1 ⁇ -MDM2 active complex to p53 promotes degradation of p53 which prevents expression of the cell cycle progression inhibitor p21 (see, e.g., Kocik et al., 2 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Cancers 2019, 11, 1014).
  • degradation of CK1 ⁇ stabilizes p53 and induces growth arrest (see, e.g., Huart et al., PLoS One 2012, 7(8), e43391). Elevation of p53 activity has been shown to have an antiproliferative and proapoptotic effect in MCL (see, e.g., Tabe et al., Clin.
  • GSPT1 is a translation termination factor that is currently being explored as a therapeutic target for the treatment of acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • Recent studies have identified molecular glues that degrade GSPT1 without degrading CK1 ⁇ (see, e.g., Powell et al., ACS Chem. Biol.2020, 15, 2722 ⁇ 2730) or that degrade GSPT1 without degrading IKZF1 (Ikaros) (see, e.g., Nishiguchi et al., J. Med. Chem.2021, 64, 7296-7311).
  • molecular glues that degrade CK1 ⁇ or CK1 ⁇ /GSPT1.
  • Such molecular glues provide therapeutic options for treatment of a variety of proliferative diseases, including cancer and autoimmune diseases.
  • SUMMARY [0009] Provided herein are compounds and compositions that degrade CK1 ⁇ or CK1 ⁇ /GSPT1.
  • the compounds are molecular glues that bind an E3 ubiquitin ligase and CK1 ⁇ .
  • the compounds are molecular glues that bind cereblon and CK1 ⁇ .
  • a compound of Formula IV or a pharmaceutically acceptable salt thereof; wherein the variables Ring A and E are as defined elsewhere herein for Formula IV; with the proviso that the compound is not 3-(1-oxo-6-(pyrazolo[1,5-a]pyrimidin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1-ethyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-imid
  • halo(C1- C 4 )alkyl is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.
  • heterocyclyl means, unless otherwise stated, a monovalent monocyclic or multicyclic ring system that is saturated or partially unsaturated (but at least one ring is not aromatic) wherein one or more of the ring atoms is a heteroatom independently selected from O, S(O)0-2, and N, and the remaining ring atoms are carbon atoms.
  • the heterocyclyl comprises one or two heteroatom(s) that are oxygen.
  • sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • LUPRON DEPOTTM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • poly-D-(-)-3-hydroxybutyric acid examples include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • Organic adds include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water-soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat.
  • the suspension is a suspension of microparticles or nanoparticles.
  • the emulsion is an emulsion of microparticles or nanoparticles.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol.
  • the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include 73 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA.
  • the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations. [0300] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
  • bases examples include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono, di and triglycerides of fatty acids. Combinations of the various bases may be used.
  • Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams.
  • Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. F.
  • Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos.4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 76 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • the active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step.
  • the percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject.
  • G. TARGETED FORMULATIONS The compounds provided herein, or pharmaceutically acceptable salts thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non- limiting examples of targeting methods, see, e.g., U.S. Pat.
  • liposomal suspensions including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No.4,522,811.
  • the compounds or pharmaceutically acceptable salts can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable salt thereof provided herein, which is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein.
  • the articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day.
  • the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, 80 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.
  • the recommended daily dose range of the compound provided herein, or a derivative thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, in one embodiment given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day.
  • Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.
  • the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day.
  • the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day.
  • the dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day.
  • the compound can be administered in an amount of about 25 mg/day.
  • the compound can be administered in an amount of about 10 mg/day. In a particular embodiment, the compound can be administered in an amount of about 5 mg/day. In a particular embodiment, the compound can be administered in an amount of about 4 mg/day. In a particular embodiment, the compound can be administered in an amount of about 3 mg/day.
  • the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 to about 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.
  • the administered dose can also be expressed in units other than mg/kg/day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm).
  • a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m 2 /day.
  • the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 ⁇ M, about 0.002 to about 200 ⁇ M, about 0.005 to about 100 ⁇ M, about 0.01 to about 50 ⁇ M, from about 1 to about 50 ⁇ M, about 0.02 to about 25 ⁇ M, from about 0.05 to about 20 ⁇ M, from about 0.1 to about 20 ⁇ M, from about 0.5 to about 20 ⁇ M, or from about 1 to about 20 ⁇ M.
  • the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.
  • plasma concentration at steady state is the concentration reached after a period of administration of a compound provided herein, or a derivative thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.
  • the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL.
  • AUC area under the curve
  • the compound provided herein, or a derivative thereof may be administered by oral, parenteral (e.g., 82 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • parenteral e.g., 82 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108
  • PCT intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • the compound provided herein, or a derivative thereof may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration. [0340] In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered parenterally. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously.
  • the compound provided herein, or a derivative thereof can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time.
  • the compound can be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
  • stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement.
  • Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
  • the compound provided herein, or a derivative thereof can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID).
  • the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug).
  • the term “daily” is intended to mean that a therapeutic compound, such as the compound provided herein, or a derivative thereof, is administered once or more than once each day, for example, for a period of time.
  • the term “continuous” is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound provided herein or a derivative thereof is 83 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • cycling as used herein is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.
  • the frequency of administration is in the range of about a daily dose to about a monthly dose.
  • administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks.
  • the compound provided herein, or a derivative thereof is administered once a day.
  • the compound provided herein, or a derivative thereof is administered twice a day.
  • the compound provided herein, or a derivative thereof is administered three times a day.
  • the compound provided herein, or a derivative thereof is administered four times a day.
  • the compound provided herein, or a derivative thereof is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 4 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 5 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 6 days.
  • the compound provided herein, or a derivative thereof is administered once per day for one week. In another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for two weeks. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for three weeks. In still another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for four weeks.
  • VI. METHODS OF TREATMENT [0345] Provided is a method of degrading CK1 ⁇ in a cell by contacting the cell with a compound or composition provided herein. In another embodiment, provided is a method of 84 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • CK1 ⁇ is required for TCR- and BCR- regulated activation of the CBM complex (see, e.g., Gehring et al., Cell Reports 2019, 29, 873-888; Bidere et al., Nature 2009, 458, 7234; Yin et al. Cell. Mol. Life Sci.2022, 79, 112).
  • the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome, (MDS) (including 5q-MDS), colon cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell lymphoma or mantle cell lymphoma (MCL).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome, including 5q-MDS
  • colon cancer acute lymphoblastic leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome, including 5q-MDS
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • the cancer is a B-cell lymphoma.
  • the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).
  • the DLBCL is ABC DLBCL.
  • the cancer is a BTK inhibitor resistant cancer.
  • the BTK inhibitor resistant cancer is ibrutinib resistant cancer.
  • the ibrutinib resistant cancer is ABC DLBCL.
  • the BTK inhibitor resistant cancer is acalabrutinib resistant cancer.
  • the BTK inhibitor resistant cancer is zanubrutinib resistant cancer.
  • the BTK inhibitor resistant cancer is resistant to one or more of pirtobrutinib, spebrutinib, evobrutinib, olmutinib, tirabrutinib, elsubrutinib (ABBV-105), tolebrutinib (SAR 442168), fenebrutinib, vacabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068 or DTRMWXHA-12. 85 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • the BTK inhibitor resistant cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia or chronic graft-versus-host disease.
  • CLL chronic lymphocytic leukemia
  • FL follicular lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • SLL small lymphocytic lymphoma
  • Waldenstrom macroglobulinemia or chronic graft-versus-host disease.
  • CK1 ⁇ and GSPT1 in another embodiment, provided is a method of degrading CK1 ⁇ and GSPT1 in a subject by administering to the subject a compound or composition provided herein.
  • loss of CK1 ⁇ activity results in stabilization of p53 and inhibition of cell cycle progression. See, e.g., Huart et al., J. Biol. Chem.2009, 284(47), 32384-32394.
  • CK1 ⁇ and MDM2 form a complex that regulates p53 and E2F-1 protein stability.
  • the CK1 ⁇ -MDM2 complex promotes degradation of p53, which in turn prevents expression of p53 targets, such as p21 (an inhibitor of cell cycle progression).
  • GSPT1 degraders have shown efficacy in clinical trials against acute myeloid leukemia (AML). Degradation of CK1 ⁇ (providing elevated p53), along with GSPT1 degradation leads to an improved therapeutic window and safety profile. [0354] It is also known in the art that GSPT1 is implicated in a variety of cancers, including AML, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, stomach cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testis cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, hepatocellular carcinoma and gastric cancer.
  • AML glioma
  • thyroid cancer lung cancer, colorectal cancer, head and neck cancer
  • stomach cancer liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testis cancer, breast cancer, cervical cancer, endometrial cancer, ova
  • WO 2022/066835 WO 2022/029138, WO 2021/069705, WO 2018/169777, WO 2019/173224, WO 2019/241271, WO 2021/086830, WO 2022/007659, WO 2022/066835 and WO 2022/073469.
  • a method of treating AML in a subject by administering to the subject a compound or composition provided herein.
  • a method of treating a solid tumor in a subject by administering to the subject a compound or composition provided herein.
  • the solid tumor is breast cancer.
  • CK1 ⁇ is required for activation of Card11/BCL10/MALT1 (CBM) complex. It is known in the art that inhibition of MALT1 ameliorates autoimmune pathogenesis. See, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320. Degradation of CK1 ⁇ leads to inhibition of CBM activation and MALT1 signaling. 87 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0357] Thus, in another embodiment, provided is a method of treating a subject having an autoimmune disorder by administering to the subject a compound or composition provided herein.
  • the compound provided herein, or a derivative thereof is administered orally or intravenously
  • the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • the compound provided herein, or a derivative thereof, and a second therapy are administered by the same mode of administration, orally or by IV.
  • Condition 2 To a vial containing a solution of 0015_A001 (66.6 mg, 0.15 mmol, 1.00 eq) and 0015_Bi (0.15 mmol, 1.00 eq) in Dioxane (1.20 mL) was added K 3 PO 4 (450 ⁇ mol, 3.00 eq, 1.50 M in H2O), Pd-118 (0.015 ⁇ mol, 0.10 eq) under protection of N2. The mixture was stirred at 120 °C for 2 hrs under microwave condition. Spot checked by LCMS. The reaction mixture was diluted with H 2 O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3).
  • the reaction mixture was diluted with 150 mL of Dichloromethane and washed with water (3 x 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the title compound (20.0 g, 72.3 mmol, 88.3% yield) as brown oil, which was used in the next step directly without further purification.
  • 2-(3,3-Difluorocyclobutyl)-N-(2,2-dimethoxyethyl)-N-methylacetimidamide A mixture of 2-(3,3-difluorocyclobutyl)acetonitrile (6.88 g, 52.4 mmol, 1.25 eq), 2,2- dimethoxy-N-methyl-ethanamine (5.00 g, 41.9 mmol, 5.39 mL, 1.00 eq), CuCl (5.19 g, 52.4 mmol, 1.25 mL, 1.25 eq) was stirred at 85 °C for 12 h under N2 atmosphere.
  • 2-Cyclopropyl-1-phenyl-1H-imidazole To a solution of 2-cyclopropyl-1H- imidazole (5.00 g, 46.2 mmol, 1.00 eq) in MeOH (150 mL) was added phenylboronic acid (4.79 g, 39.3 mmol, 0.85 eq) and Cu2O (331 mg, 2.31 mmol, 236 ⁇ L, 0.05 eq) under O2. The mixture was stirred at 25 °C for 24 h under O 2 . The mixture was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, 103 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • 2-Bromo-4-isobutyl-1-phenyl-1H-imidazole To a solution of 4-isobutyl-1- phenyl-imidazole (550 mg, 2.73 mmol, 1.00 eq) in THF (6 mL) was added dropwise n-BuLi (2.5 M, 1.26 mL, 1.15 eq) at -78 °C under N2. The reaction mixture was stirred for additional 0.5 h, then 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (745 mg, 2.87 mmol, 1.05 eq) was added dropwise at -78 °C. Then the reaction mixture was stirred at 25 °C for 12 h.
  • 2-Methyl-1-phenyl-1H-imidazole To a solution of 2-methyl-1H-imidazole (5.00 g, 60.9 mmol, 1.00 eq) in MeOH (150 mL) was added phenylboronic acid (6.31 g, 51.7 mmol, 0.85 eq) and Cu2O (435 mg, 3.04 mmol, 311 ⁇ L, 0.05 eq) under air. The mixture was stirred at 25 °C for 12 h under air. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue.
  • phenylboronic acid 6.31 g, 51.7 mmol, 0.85 eq
  • Cu2O 435 mg, 3.04 mmol, 311 ⁇ L, 0.05 eq
  • the residue 1 was purified by preparative- HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 ⁇ m) and gradient of 14% - 44% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (120 mg, 271 ⁇ mol, 39.1% yield, 100% purity in HPLC at 220 nm) as a white solid.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 11.0 (s, 1H), 8.07 (s, 1H), 7.64 (d, J 8.0 Hz, 113 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • 2-Cyclopropyl-N-(2,2-dimethoxyethyl)acetimidamide To a mixture of 2,2- dimethoxyethanamine (5.00 g, 47.5 mmol, 5.18 mL, 1.00 eq) and CuCl (5.89 g, 59.4 mmol, 1.42 mL, 1.25 eq) was added 2-cyclopropylacetonitrile (4.82 g, 59.45 mmol, 5.49 mL, 1.25 eq). The reaction mixture was stirred at 85 °C for 12 h under N2. The mixture was diluted with MeOH (100 mL) and cooled to 0 °C.
  • the mixture was stirred at 25 °C for 12 h under O 2 .
  • the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (3 x 20.0 mL) to collect the organic layers.
  • the organic layers was concentrated under reduced pressure to get a residue.
  • the residue was purified by Preparative-HPLC using a Welch Ultimate C18 (150 mm x 25 mm x 5 ⁇ m) and gradiente of 10 - 40% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (39.3 mg, 88.9 ⁇ mol, 33.3% yield, 99.6% purity in HPLC at 220 nm) as a white solid.
  • 5-Bromo-2-ethyl-1-phenyl-1H-imidazole To a solution of 2-ethyl-1-phenyl- 1H-imidazole (1.78 g, 10.0 mmol, 1.00 eq) in ACN (18.0 mL) was added a solution of NBS (1.88 g, 10.5 mmol, 1.05 eq) in ACN (9.00 mL) at 0 °C, then the mixture was stirred at 25 °C for 2 h. It was poured into water (50.0 mL) and extracted with ethyl acetate (3 x 40.0 mL) to collect the organic layers.
  • A.2,2,2-Trifluoro-1-(1-methyl-1H-imidazol-2-yl)ethan-1-ol To a solution of 1- methyl-1H-imidazole-2-carbaldehyde (5.00 g, 45.4 mmol, 1.00 eq) in THF (100 mL) was added trimethyl(trifluoromethyl)silane (8.00 g, 56.2 mmol, 1.24 eq) and CsF (10.3 g, 68.1 mmol, 1.50 eq) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum.
  • the mixture was stirred at 100 °C for 16 h under N 2 .
  • the mixture was poured water (100 mL) and extracted with Ethyl acetate(3 x 100 mL) to collect the organic layers, The organic layer were washed with brine (3 x 100 mL), dried over Na2SO4, filtered and the filtrate was concentrate under vacuum at 45 °C to get a residue.
  • the mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C.
  • reaction mixture was stirred at -70°C for 1 h, after that a solution of NBS (250 mg, 963 ⁇ mol, 1.10 eq) in THF (1.00 mL) was added to the reaction mixture at -70 °C under N2.
  • the mixture was stirred at 20°C for 3 h under N2.
  • the reaction mixture was quenched by addition H 2 O 5.00 mL at 0°C under N2 and extracted with ethyl acetate 10.0 mL (3 x 10.0 mL).
  • the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the title compound was pre-purified by column chromatography followed by preparative- HPLC using a Welch Ultimate C18 (150 mm x 25 mm 5 ⁇ m) and gradient of 6 - 36% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min to give the title compound (72.0 mg, 149 ⁇ mol, 45.8% yield, 97.6% purity in HPLC at 220 nm) as a white solid.
  • reaction mixture was poured into saturated NH4Cl aqueous solution (30.0 mL), then was extracted with ethyl acetate (3 x 30.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated in vacuum to give a residue.
  • 1,4-Dimethyl-1H-imidazole To a solution of 4-methyl-1H-imidazole (10.0 g, 121 mmol, 1.00 eq) in acetone (120 mL) was added K2CO3 (25.2 g, 182 mmol, 1.50 eq) at 25 °C, then a solution CH 3 I (20.7 g, 146mmol, 9.10 mL, 1.20 eq) in acetone (10.0 mL) was slowly dropwise to the mixture at 25 °C, then the mixture was stirred at 25 °C for 5 h. The mixture was poured into H2O (200 mL) and extracted with ethyl acetate (2 x 200 mL).
  • 1,4-Dimethyl-5-phenyl-1H-imidazole To a solution of 1,4-dimethyl-1H- imidazole (600 mg, 6.22 mmol, 1.00 eq) ) in DMF (12.0 mL) was added bromobenzene (2.93 g, 18.6 mmol, 1.97 mL, 3.00 eq), K2CO3 (1.72 g, 12.4 mmol, 2.00 eq), Pd(OAc)2 (139 mg, 622 ⁇ mol, 0.10 eq) and P(Oxole) (144 mg, 622 ⁇ mol, 0.10 eq) at 25 °C under N 2 . The mixture was stirred at 100 °C for 16 h under N2.
  • the crude product was purified by column chromatography followed by preparative-HPLC using a Phenomenex Luna C18 (250 x 70mm, 10 ⁇ m) and gradient of 30 - 60% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min to give the title compound (128 mg, 310 ⁇ mol, 24.6% yield, 98.2% purity in HPLC at 220 nm) as a white solid.
  • reaction mixture was stirred at 25 °C for 12 h.
  • the reaction mixture was quenched with saturated NH4Cl solution (20.0 mL) at 0 °C under N 2 .
  • the mixture was extracted with ethyl acetate (3 x 8.00 mL) to collect the organic layers.
  • the combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue.
  • 1-Methyl-5-phenyl-4-(tetrahydropyran-4-ylidenemethyl)imidazole To a solution of 4-bromo-1-methyl-5-phenyl-imidazole (500 mg, 2.11 mmol, 1.00 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added 4,4,5,5-tetramethyl-2-(tetrahydropyran-4- ylidenemethyl)-1,3,2-dioxaborolane (945 mg, 4.22 mmol, 2.00 eq), K 3 PO 4 (1.34 g, 6.33 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (137 mg, 211 ⁇ mol, 0.10 eq).
  • 1-Methyl-5-phenyl-4-(tetrahydropyran-4-ylmethyl)imidazole To a solution of 1-methyl-5-phenyl-4-(tetrahydropyran-4-ylidenemethyl)imidazole (490 mg, 1.93 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (205 mg, 10.0% purity) under Ar2 atmosphere. The suspension was degassed and purged with H 2 for 3 times. The mixture was stirred under H2 (20 Psi) at 25 °C for 8 h.
  • Methyl 6-chloro-4-methylnicotinate To a solution of 6-chloro-4-methyl- pyridine-3-carboxylic acid (5.00 g, 29.1 mmol, 1.00 eq) in SOCl2 (40.9 g, 344 mmol, 25.0 mL, 11.8 eq) was addded DMF (213 mg, 2.91 mmol, 224 ⁇ L, 0.10 eq) at 25 °C under N 2 . The mixture was stirred at 25 °C for 4 h. The dropwised slowly MeOH (15.8 g, 494 mmol, 20.0 mL, 16.9 eq) to the mixture. The mixture was stirred at 10 min.
  • Methyl 4-(bromomethyl)-6-chloronicotinate To a solution of methyl 6- chloro-4-methyl-pyridine-3-carboxylate (3.70 g, 19.9 mmol, 1.00 eq) in CCl4 (37.0 mL) was addded NBS (3.90 g, 21.9 mmol, 1.10 eq) and AIBN (654 mg, 3.99 mmol, 0.20 eq) at 25 °C under N 2 . The mixture was stirred at 80 °C for 16 h. The mixture was poured into H 2 O (100 mL) and extracted with DCM (3 x 100 mL).
  • the mixture was concentrated under vacuum at 45 °C to get residue.
  • the residue 1 was purified by preparative-HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 ⁇ m) and gradient of 27% - 57% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (59.9 mg, 137 ⁇ mol, 40.8% yield, 100% purity in HPLC at 220 nm) as a white solid.
  • Methyl 2-(bromomethyl)-6-chloronicotinate A mixture of methyl 6-chloro- 2-methylnicotinate (1.00 g, 5.39 mmol, 1.00 eq) and AIBN (176 mg, 1.08 mmol, 0.20 eq) in CCl4 (5.00 mL) was degassed and purged with N2 for 3 times, and then was added NBS (767 mg, 4.31 mmol, 0.80 eq) the mixture was stirred at 80°C for 12 h under N2 atmosphere. After the reaction was completed, the solids were filtered off and the filtrate was concentrated under vacuum to give crude product.
  • 3-(2-Chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione A mixture of methyl 2-(bromomethyl)-6-chloronicotinate (100 mg, 378 ⁇ mol, 1.00 eq) in DMF (2 mL) and then was added 3-aminopiperidine-2,6-dione (58.1 mg, 353 ⁇ mol, 3.00 eq, HCl), DIEA (97.7 mg, 756 ⁇ mol, 131 ⁇ L, 2.00 eq) was degassed and purged 145 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • the crude product was purified by preparative-HPLC using a Welch Xtimate C18 150 x 25 mm x 5 ⁇ m) and gradiente of 24 - 54% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give title compound (40.5 mg, 91.8 ⁇ mol, 25.6% yield, 99.0% purity in HPLC at 220 nm) as a white solid.
  • the reaction mixture was poured into H2O (100 mL) and extracted with Dichloromethane (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated.
  • the crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25 mm x 5 ⁇ m) and gradiente of 1 - 31% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (300 mg, 1.17 mmol, 21.0% yield, 99.8% purity in HPLC at 220 nm) as light yellow oil.
  • the mixture was stirred at 100 °C for 3 h under N 2 .
  • the reaction mixture was concentrated under reduced pressure to get a residue at 45 °C.
  • the residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 11% - 41% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (102 mg, 205 ⁇ mol, 34.2% yield, 99.4% purity in HPLC at 220 nm) was obtained as white solid.
  • the combined organic layers was washed with brine (30.0 mL) and dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated under reduced pressure to get a residue.
  • the crude product was purified by Preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 ⁇ m) and gradiente of 40 - 70% 149 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) to give the title compound (75.0 mg, 285 ⁇ mol, 33.6% yield, 100% purity in LCMS at 220 nm) as a colorless oil.
  • Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate To a solution of tetrahydro-2H-pyran-4-ol (5.00 g, 48.9 mmol, 4.89 mL, 1.00 eq) in DCM (30.0 mL) was added TEA (7.43 g, 73.4 mmol, 10.2 mL, 1.50 eq) at 25°C. The mixture was stirred at 0 °C. Then TosCl (10.2 g, 53.8 mmol, 1.10 eq) in DCM (20.0 mL) was added to the mixture. The mixture was stirred at 25 °C for 12 h.
  • the reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (2 x 50.0 mL) to get the organic layers, the organic layers was washed with brine (20.0 mL) and dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C.
  • the residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 ⁇ m) and gradient of 42-72% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 30 mL/min) to get the solution.
  • the aqueous layer was extracted with DCM (3 x 100 mL).
  • the organic layer was washed with saturated Na2SO3 solution (100 mL).
  • the aqueous layer was checked with starch potassium iodide paper.
  • the organic layer was dried over MgSO 4 and concentrated.
  • 3-Bromo-5-isobutyl-4-phenyl-4H-1,2,4-triazole A mixture of 3-isobutyl-4- phenyl-1,2,4-triazole (500 mg, 2.48 mmol, 1 eq), NBS (574.81 mg, 3.23 mmol, 1.3 eq) in ACN (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred 159 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT at 25 °C for 12 h under N 2 atmosphere. The reaction mixture was poured into ice-H 2 O (10 mL).
  • the reaction mixture was cooled to 25 °C and filtered. The filtrate was concentrated.
  • the crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25mm x 5um) and gradient of 17%- 47% acetonitrile in water containing 0.05% TFA over 19 min at a flow rate of 25 mL/min to give the title compound (39.89 mg, 89.94 ⁇ mol, 8.40% yield, 98.9% purity in HPLC at 220 nm) as a white solid.
  • the aqueous layer was extracted with DCM (3 x 100 mL).
  • the organic layer was washed with saturated Na 2 SO 3 solution (100 mL).
  • the aqueous layer was checked with starch potassium iodide paper.
  • the organic layer was dried over MgSO4 and concentrated.
  • 3-Bromo-5-isobutyl-4-phenyl-4H-1,2,4-triazole A mixture of 3-isobutyl-4- phenyl-1,2,4-triazole (500 mg, 2.48 mmol, 1 eq), NBS (574.81 mg, 3.23 mmol, 1.3 eq) in ACN (10 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was poured into ice-H2O (10 mL). The aqueous layer was extracted DCM (3 x 20 mL).
  • the crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25mm x 5um) and gradient of 17%- 47% acetonitrile in water containing 0.05% TFA over 19 min at a flow rate of 25 mL/min to give the title compound (39.89 mg, 89.94 ⁇ mol, 8.40% yield, 98.9% purity in HPLC at 220 nm) as a white solid.
  • the mixture was stirred at 80 °C for 3 h under N2.
  • the reaction mixture was concentrated under reduced pressure to get a residue at 45 °C.
  • the residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 18% - 48% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (26.0 mg, 51.6 ⁇ mol, 8.76% yield, 99.8% purity in HPLC at 220 nm) was obtained as white solid.
  • the mixture was stirred at 100 °C for 3 h under N2.
  • the reaction mixture was concentrated under reduced pressure to get a residue at 45 °C.
  • the residue was purified by preparative-HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 35% - 65% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (94.8 mg, 204 ⁇ mol, 37.3% yield, 98.2% purity in HPLC at 220 nm) was obtained as white solid.
  • 2-(6-(Trimethylstannyl)pyridin-3-yl)propan-2-ol To a solution of 2-(6- bromopyridin-3-yl)propan-2-ol (500 mg, 2.31 mmol, 1.00 eq) and Me 6 Sn 2 (1.32 g, 4.03 mmol, 835 ⁇ L, 1.74 eq) in dioxane (10.0 mL) was added Pd(PPh 3 ) 4 (267 mg, 231 ⁇ mol, 0.10 eq) under N2. The reaction mixture was stirred at 100 °C for 16 h under N2to give the title 171 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • the mixture was concentrated under vacuum at 45 °C to get a residue.
  • the residue was purified by SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm,10um), mobile phase: [CO 2 -i- PrOH(0.1%NH3H2O)], B%:25%, isocratic elution mode) to give the title compound (300 mg, 932 ⁇ mol, 16.1% yield, 99.5% purity in LCMS at 220 nm) as a yellow solid.
  • 3-Bromo-1-(2,2-difluoropropyl)-5-methyl-4-phenyl-1H-pyrazole To a solution of 3-bromo-5-methyl-4-phenyl-1H-pyrazole (1.50 g, 6.33 mmol, 1.00 eq) and 2,2- difluoropropan-1-ol (729 mg, 7.59 mmol, 1.20 eq) in toluene (15.0 mL) was added 2- (tributyl-phosphanylidene)acetonitrile (2.29 g, 9.49 mmol, 1.50 eq) at 25 °C under N 2 . Then the mixture was stirred at 100 °C for 16 h.
  • reaction mixture was diluted with water (50.0 mL) and extracted with DCM (2 x 50.0 mL) to get the organic layers, the organic layers was dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C.
  • the reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 45 °C.
  • 3-Bromo-5-methyl-4-phenyl-1H-pyrazole To a solution of phenylboronic acid (9.70 g, 79.5 mmol, 0.90 eq) in dioxane (300 mL) and H2O (120 mL) was added 3-bromo-4- iodo-5-methyl-1H-pyrazole (26.0 g, 88.3 mmol, 1.00 eq), RuPhos Pd G3 (3.70 g, 4.42 mmol, 0.05 eq), K 3 PO 4 (37.5 g, 176 mmol, 2.00 eq) and RuPhos (4.12 g, 8.84 mmol, 0.1 eq) at 25 °C under N2.
  • 2-(3-Bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)-1-morpholinoethan-1-one To a solution of 2-chloro-1-morpholino-ethanone (345 mg, 2.11 mmol, 1.00 eq) and 3- bromo-5-methyl-4-phenyl-1Hpyrazole (500 mg, 2.11 mmol, 1.00 eq) in DMF (10.0 mL) was added K 2 CO 3 (582 mg, 4.22 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 80 °C for 12 h.
  • the mixture was stirred for 3 h at 100 °C under N 2 .
  • the mixture was filtered and the filtrate was concentrated under reduced pressure to get a residue.
  • the residue was purified using 177 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • the reaction mixture was stirred at 90 °C for 12 h under N 2 .
  • the reaction mixture was added to aq. NH 4 Cl (200 mL).
  • the reaction mixture was extracted with ethyl acetate (3 x 200 mL).
  • the combined organic layers were washed with aq.KF (2 x 100 mL), dried over Na 2 SO 4 , filter and concentrated to give resiude.
  • the reaction mixture was poured into saturated Na2SO3 aqueous solution (100 mL) and extracted with ethyl acetate (3 x 60.0 mL). The combined organic layer was washed with brine (2 x 30.0 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative-HPLC (using a Welch Ultimate C18 (250 x 50mm x 10 ⁇ m) and gradient of 10 - 40% acetonitrile in water containing 0.05% TFA over 5 min at a flow rate of 100 mL/min) to give the title compound (240 mg, 688 ⁇ mol, 22.0% yield) as a white solid.
  • the reaction mixture was poured into H2O (20.0 mL), extracted with Ethyl acetate (3 x 10.0 mL); the organic layer was washed with Na2SO3 (4 x 25.0 mL), dried over Na 2 SO 4 and the filtrate was concentrated in vacuum to give residue.
  • the crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 40 mm x 10 ⁇ m) and gradient of 24 - 54% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min give the title compound (310 mg, 828 ⁇ mol, 46.1% yield, 98.7% purity LCMS at 220 nm) as a white solid.
  • the mixture was stirred at 80 °C for 3 h under N2.
  • the reaction mixture was concentrated under reduced pressure to get a residue at 45 °C.
  • the residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 7 um) and gradient of 24% - 54% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (37.1 mg, 83.4 ⁇ mol, 22.8% yield, 98.2% purity in HPLC at 220 nm) was obtained as white solid.
  • the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (2 x 10.0 mL) to get the organic layers, the organic layers was washed with saturated solution of Na 2 SO 3 (15.0 mL) and dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C.
  • 1-Isobutyl-5-phenyl-triazole To a solution of 4-phenyl-1H-triazole (2.00 g, 13.7 mmol, 1.00 eq) in DMF (20.0 mL) was added 1-bromo-2-methyl-propane (2.83 g, 20.6 mmol, 2.25 mL, 1.50 eq) and K2CO3 (3.81 g, 27.5 mmol, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • reaction liquid is filtered to collect the filtrate and concentrate.
  • Water (20.0 mL) was added to the residue.
  • the resulting mixture was extracted with dichloromethane (3 x 20.0 mL).
  • the combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (2.20 g, crude) as a black brown oil.
  • the reaction mixture was concentrated directly in vacuum to give residue.
  • the crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25 mm x 7 ⁇ m) and gradiente of 0 - 30% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (117 mg, 254 ⁇ mol, 45.3% yield, 100% purity in HPLC at 220 nm) as a light yellow solid.
  • tert-Butyl 5-amino-4-(5-(1-methyl-2-(((1-methyl-1H-pyrazol-4- yl)amino)methyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 ⁇ mol, 1.00 eq) and 1-methyl-1H- pyrazol-4-amine (14.6 mg, 150 ⁇ mol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 ⁇ L, 300 ⁇ mol, 3.00 eq) under protection of N 2 .
  • tert-butyl 5-amino-4-(5-(1-methyl-2-((((S)-1-methylpyrrolidin-3-yl) amino)methyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 ⁇ mol, 1.00 eq) and (3S)-1- methylpyrrolidin-3-amine (15.0 mg, 150 ⁇ mol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 ⁇ L, 300 ⁇ mol, 3.00 eq) under protection of N 2 .
  • tert-Butyl 5-amino-4-(5-(2-((imidazo[1,2-a]pyridin-3-ylamino)methyl)-1- methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 ⁇ mol, 1.00 eq) and imidazo[1,2- a]pyridin-3-amine (19.9 mg, 150 ⁇ mol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 ⁇ L, 300 ⁇ mol, 3.00 eq) under protection of N2.
  • tert-Butyl 5-amino-4-(5-(2-((isoquinolin-6-ylamino)methyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate (44.7 mg, 100 ⁇ mol, 1.00 eq) and isoquinolin-6-amine (21.6 mg, 150 ⁇ mol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 ⁇ L, 300 ⁇ mol, 3.00 eq) under protection of N2.
  • tert-Butyl 5-amino-4-(5-(2-((isoquinolin-5-ylamino)methyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate (44.7 mg, 100 ⁇ mol, 1.00 eq) and isoquinolin-5-amine (21.6 mg, 150 ⁇ mol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 ⁇ L, 300 ⁇ mol, 3.00 eq) under protection of N2.
  • tert-Butyl 5-amino-4-(5-(2-((2,3-dihydro-1H-imidazo[1,2-a]imidazol-1- yl)methyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 ⁇ mol, 1.00 eq) and 1H,2H,3H- imidazo[1,2-a][1,3]diazole (16.4 mg, 150 ⁇ mol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 ⁇ L, 300 ⁇ mol, 3.00 eq) under protection of
  • Step 2 To a vial containing a solution of 0018_Bi_1 ( ⁇ 300 ⁇ mol, 1.00 eq) in DMF (3.00 mL) was added NCS (19.5 mg, 150 ⁇ mol, 0.50 eq), the mixture was stirred at 30 °C, after 15 minutes, then NCS (99.7 mg, 750 ⁇ mol, 2.50 eq) was added. The resulting mixture was stirred at 30 °C for 2.75 hrs. Spot checked by LCMS. The reaction mixture was diluted with H 2 O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3).
  • Step 3 To a vial containing a solution of 0018_Bi_2 ( ⁇ 200 ⁇ mol, 1.00 eq) in DMSO (4.00 mL) was added 0018_A001 (53.6 mg, 200 ⁇ mol, 1.00 eq). The mixture was 200 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT stirred at 50 °C for 16 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product.
  • Step 4 for Boc compounds: To a vial containing a solution of 0018_Bi_Boc ( ⁇ 100 ⁇ mol, 1.00 eq) in HCl ⁇ Dioxane (2 M) (2.00 mL). The mixture was stirred at 30 °C for 3 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 201 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 202 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.
  • 1-Benzyl-N-hydroxypiperidine-4-carbimidoyl chloride To a solution of 1- benzylpiperidine-4-carbaldehyde oxime (crude, ⁇ 300 ⁇ mol, 1.00 eq) in DMF (3.00 mL) was added NCS (19.9 mg, 150 ⁇ mol, 0.50 eq), the mixture was stirred at 30 °C for 15 minutes, then NCS (99.7 mg, 750 ⁇ mol, 2.50 eq) was added. The mixture was stirred at 30 °C for 2.75 hrs. The reaction mixture was diluted with H2O (3.00 mL) and extracted with ethyl acetate (6.00 mL * 3).
  • Step 2 To a vial containing a solution of 0020_A001_1 ( ⁇ 0.15 mmol, 1.00 eq) in DMF (1.50 mL) was added NCS (9.98 mg, 0.075 mmol, 0.50 eq). The mixture was stirred at 30 °C for 15 mins. Then NCS (49.9 mg, 0.375 mmol, 2.50 eq). The mixture was stirred at 30 °C for 2.75 hrs. Spot checked by LCMS. The reaction mixture was diluted with H2O (1.00 mL) and extracted with ethyl acetate (2.00 mL x 3), dried over Na 2 SO 4 , filtered, and concentrated to give crude intermediates used for next step.
  • Step 3 To a vial containing a solution of 0020_A001_2 ( ⁇ 0.15 mmol, 1.00 eq) and 0020_Bi (0.30 mmol, 2.00 eq) in DMF (1.50 mL) was added NaHCO3 (126 mg, 1.50 mmol, 10.00 eq). The mixture was stirred at 30 °C for 16 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 204 1103861084 ⁇ 1 ⁇ AMERICAS ATTY DKT.

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Abstract

Provided herein are compounds that act as molecular glues, inducing degradation of CK1α or CK1α/GSPT1, and pharmaceutically acceptable derivatives thereof. Also provided are pharmaceutical compositions containing the compounds and methods of using the compounds for treating a subject with a proliferative disease.

Description

ATTY DKT. NO.129824.00006 INVO 108 PCT PROTEIN DEGRADING COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to, and the benefit of, U.S. Provisional Patent Application No.63/556,304 filed February 21, 2024, the entirety of which is incorporated by reference for all purposes. FIELD [0002] Provided herein are compounds and compositions for degrading CK1α protein or for degrading both CK1α and GSPT1 proteins. The compounds and compositions are useful in treatment of proliferative diseases, including cancer and autoimmune disorders. BACKGROUND [0003] Recently, extensive research has been directed at the discovery of compounds that bind two different proteins, without necessarily inhibiting the function of either protein. Such compounds have been dubbed “molecular glues.” Of particular interest are molecular glues that, upon contact with their targeted proteins, result in degradation of one of the proteins. This strategy has proven useful for modulation of the activity of proteins that to date have been deemed “undruggable.” [0004] For example, certain molecular glues bind to an E3 ubiquitin ligase. E3 ubiquitin ligases specifically ubiquinate a substrate protein which is then degraded by the proteasome. Cereblon is a key component of one E3 ubiquitin ligase complex and is thus an attractive target for molecular glues. Cereblon is reprogrammed by compounds such as thalidomide, lenalidomide and pomalidomide (imids) to induce degradation of neosubstrate proteins, including IKZF1 (Ikaros) and IKAF3 (Aiolos) (see, e.g., Charlinski et al. Cancers, 2021, 13, 4666). Thus, molecular glues that bind cereblon allow for ubiquination of target proteins, which are then degraded by the proteasome. There has been extensive research in the field of cereblon binding compounds, with many such compounds having been discovered (see, e.g., WO 2022/066835, WO 2020/118098, WO 2021/041664, WO 2019/078522, WO 2021/188537, WO 2021/105334, WO 2022/144416, WO 2021/143816, WO 2022/017365, WO 2022/146151, WO 2022/148358, WO 2021/147889, WO 2021/143822, WO 2020/181232, WO 2019/043214, WO 2020/263832, WO 2020/006233, WO 2015/200795, WO 2019/043217, WO 2019/204354, U.S. Patent Publication Nos. US 2022/0062248, US 2019/0017998, 2020/0206201, 2020/0155690, 2021/0009559, 2018/0215731, 2021/0177825, 1 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2019/0076541, 2021/0403454, 2021/0284624, 2021/0032245, 2020/0207764, 2022/0112211, 2019/0233433, 2020/0207733). [0005] Casein kinase 1α (“CK1α”) is a protein of the CK1 protein family that regulates signaling pathways related to membrane trafficking, cell cycle progression, chromosome segregation, apoptosis, autophagy, cell metabolism, and differentiation in development, circadian rhythm, and the immune response as well as neurodegeneration and cancer (see, e.g., Jiang et al., Cell Commun. Signaling 2018, 16, 23; Spinello et al., Int. J. Mol. Sci.2021, 22, 3716). Thus, CK1α is an attractive therapeutic target for a variety of indications and uses, including oncology, immuno-oncology, and autoimmune disorders. Mechanistically, CK1α is required for BCR- (via BTK) and TCR-induced activation of the Card11/BCL10/MALT1 (CBM) complex (see, e.g., Gehring et al., Cell Reports 2019, 29, 873-888; Bidere et al., Nature 2009, 458, 7234; Yin et al. Cell. Mol. Life Sci.2022, 79, 112). Activation of CBM has been implicated in the progression of a variety of lymphoid malignancies, including non- Hodgkin lymphoma (NHL) (see, e.g., Bedsaul et al. Front. Onc.2018, 9, Article 2105), diffuse large B-cell lymphoma (DLBCL) including ABC DLBCL (see, e.g., Thys et al., Front. Onc.2018, 8, Article 498; Bidere et al., Nature 2009, 458(7234), 92-96), mucosa- associated lymphoid tissue (MALT) lymphomas, mantle cell lymphoma (MCL), adult T-cell leukemia/lymphoma (ATLL) and Sezary syndrome (see, e.g., Juilland et al., Curr. Opin. Hemat.2016, 23(4), 402-409). Specifically, CK1α has been shown to sustain B-cell signaling in MCL (see, e.g., Manni et al., Front. Oncol.2021, 11, Article 733848), while MALT1 inhibition has been shown to be an effective strategy in treatment of both naïve and ibrutinib-resistant chronic lymphocytic leukemia (CLL) (see, e.g., Saba et al., Cancer Res. 2017, 77(24), 7038-7048). In immuno-oncology, regulation of the CBM complex has been shown to cause regulatory T-cells to prime tumors for immune checkpoint therapy (see, e.g., Di Pilato et al., Nature 2019, 570(7759), 112-116), while MALT1 activity has been implicated in T-cell immunosuppression (see, e.g., Rosenbaum et al., Nat. Commun.2019, 10(1), 2352). Inhibition of MALT1 has also been shown to ameliorate autoimmune pathogenesis (see, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320). [0006] Loss of CK1α by siRNA or a kinase inhibitor has also been shown to result in stabilization of the tumor suppressor p53 and inhibition of cell cycle progression (see, e.g., Huart et al., J. Biol. Chem.2009, 284(47), 32384-32394). Briefly, CK1α binds MDM2, which is the p53 E3 ubiquitin ligase (see, e.g., Wu et al. Mol. Cell. Biol.2012, 32(23), 4821- 4832). Binding of the CK1α-MDM2 active complex to p53 promotes degradation of p53 which prevents expression of the cell cycle progression inhibitor p21 (see, e.g., Kocik et al., 2 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Cancers 2019, 11, 1014). Thus, degradation of CK1α stabilizes p53 and induces growth arrest (see, e.g., Huart et al., PLoS One 2012, 7(8), e43391). Elevation of p53 activity has been shown to have an antiproliferative and proapoptotic effect in MCL (see, e.g., Tabe et al., Clin. Cancer Res.2009, 15(3), 933-942; Liang et al., Mod. Pathol.2010, 23(3), 389-91). [0007] GSPT1 is a translation termination factor that is currently being explored as a therapeutic target for the treatment of acute myeloid leukemia (AML). Recent studies have identified molecular glues that degrade GSPT1 without degrading CK1α (see, e.g., Powell et al., ACS Chem. Biol.2020, 15, 2722−2730) or that degrade GSPT1 without degrading IKZF1 (Ikaros) (see, e.g., Nishiguchi et al., J. Med. Chem.2021, 64, 7296-7311). [0008] Thus, there is a need for molecular glues that degrade CK1α or CK1α/GSPT1. Such molecular glues provide therapeutic options for treatment of a variety of proliferative diseases, including cancer and autoimmune diseases. SUMMARY [0009] Provided herein are compounds and compositions that degrade CK1α or CK1α/GSPT1. In one embodiment, the compounds are molecular glues that bind an E3 ubiquitin ligase and CK1α. In another embodiment, the compounds are molecular glues that bind cereblon and CK1α. [0010] In one embodiment, provided herein is a compound of Formula I or I’: or a pharmaceutically acceptable salt thereof; wherein Ar, R, and E are as defined elsewhere herein for Formula I or I’; with the proviso that the compound is not 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3-(1-oxo-5-(5-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3-(1-oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(5-(2-ethyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3-(5-(2-isobutyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(2-isopropyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-cyclopropyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; or 3 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 3-(5-(2-(difluoromethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione. [0011] In one embodiment, provided herein is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein Het and E are as defined elsewhere herein for Formula II; with the proviso that the compound is not 3-(5-(3-methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(1-oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6- dione; or 3-(1-oxo-5-(3-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione. [0012] In one embodiment, provided herein is a compound of Formula III: or a pharmaceutically acceptable salt thereof; wherein Ar, R, and E are as defined elsewhere herein for Formula III; with the proviso that the compound is not 3-(1-oxo-5-(4-phenyl-4H-1,2,4-triazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; or 3-(5-(1-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione. [0013] In one embodiment, provided herein is a compound of Formula IV: or a pharmaceutically acceptable salt thereof; wherein the variables Ring A and E are as defined elsewhere herein for Formula IV; with the proviso that the compound is not 3-(1-oxo-6-(pyrazolo[1,5-a]pyrimidin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1-ethyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; or 4 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 3-(6-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione. [0014] In one embodiment, provided herein is a compound of Formula V: or a pharmaceutically acceptable salt thereof; wherein Ar, E, X11, X12, X13, and X14 are as defined elsewhere herein for Formula V. [0015] In another embodiment, the compounds provided herein are selected from the compounds of the Examples. [0016] In another embodiment, the compounds are for use in the compositions and methods provided herein. [0017] In another embodiment, provided are pharmaceutical compositions containing a compound provided herein and a pharmaceutically acceptable carrier. [0018] In another embodiment, provided is a compound or a pharmaceutically acceptable salt thereof, of any of Examples 1-476. [0019] In another embodiment, provided are methods of degrading CK1α or CK1α/GSPT1 using a compound or composition provided herein. The methods provided herein include methods of treatment of CK1α or CK1α/GSPT1 mediated diseases. In one embodiment, the CK1α disease is a B-cell lymphoma or a BTK inhibitor resistant cancer. In another embodiment, the CK1α/GSPT1 disease is AML or breast cancer. In another embodiment, the CK1α degraders provided herein are used in combination with a checkpoint inhibitor, including a CTLA-4, PD-1 or PD-L1 inhibitor, such as anti-CTLA-4, anti-PD-1 or anti-PD- L1 antibodies, in the treatment of cancer. DETAILED DESCRIPTION I. DEFINITIONS [0020] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. [0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in 5 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0022] The singular forms “a,” “an,” and “the” include plural references, unless the context clearly dictates otherwise. [0023] As used herein “subject” is an animal, such as a mammal, including human, such as a patient. [0024] As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behavior of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities. [0025] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates or hydrates thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are 6 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules. [0026] As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating CK1α or CK1α/GSPT1 mediated diseases. [0027] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or pharmaceutical composition. [0028] As used herein, and unless otherwise indicated, the terms “manage,” “managing” and “management” encompass preventing the recurrence of the specified disease or disorder in a subject who has already suffered from the disease or disorder, and/or lengthening the time that a subject who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a subject responds to the disease or disorder. [0029] As used herein, the DC50 refers to an amount, concentration or dosage of a particular test compound that achieves 50% of a maximal response in an assay that measures such response. [0030] Where moieties are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical moieties that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0031] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain saturated hydrocarbon radical, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. [0032] The term “alkenyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain hydrocarbon radical having one or more carbon-carbon double bonds, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). 7 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Examples of alkenyl groups include, but are not limited to, vinyl (i.e., ethenyl), 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and the higher homologs and isomers. [0033] The term “alkynyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Examples of alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers. [0034] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, including those groups having 10 or fewer carbon atoms. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having six or fewer carbon atoms. [0035] The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. [0036] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, consisting of a heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may have an alkyl substituent to fulfill valency and/or may optionally be quaternized. The heteroatom(s) O, N, P, Si and S may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2- CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, - CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-. For alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula – C(O)2R'- represents both –C(O)2R'- and –R'C(O)2-. [0037] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and 8 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT “heteroalkyl,” respectively, including bicyclic, tricyclic and bridged bicyclic groups. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornanyl, bicyclo[2.2.2]octanyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1,2,5,6-tetrahydropyrid-1-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, morpholin-4-yl, morpholin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien- 2-yl, tetrahydrothien-3-yl, piperazin-1-yl, piperazin-2-yl, azabicyclo[2.2.2]octan-1-yl, azabicyclo[2.2.2]octan-2-yl, and the like. [0038] The term “cycloalkenyl,” means, unless otherwise stated, a cyclic version of “alkenyl” as defined herein. [0039] The term “heterocycloalkenyl” means, unless otherwise saturated, heterocycloalkyl as defined herein and further having one or more carbon-carbon double bonds. [0040] The terms “halo,” by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1- C4)alkyl” is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like. [0041] The term “heterocyclyl,” means, unless otherwise stated, a monovalent monocyclic or multicyclic ring system that is saturated or partially unsaturated (but at least one ring is not aromatic) wherein one or more of the ring atoms is a heteroatom independently selected from O, S(O)0-2, and N, and the remaining ring atoms are carbon atoms. In some or any embodiments, the heterocyclyl comprises one or two heteroatom(s) that are oxygen. In some or any embodiments, the heterocyclyl comprises one or two heteroatom(s) that are nitrogen. In some or any embodiments, the heterocyclyl comprises one heteroatom that is oxygen and a second heteroatom that is nitrogen. In some or any embodiments, the heterocyclyl has from 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some or any embodiments, the heterocyclyl is a monocyclic or bicyclic ring system. In some or any embodiments, the heterocyclyl is a bridged or non-bridged, a spirocyclic or not spirocyclic, and/or a fused or not fused multicyclic group. [0042] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (in one embodiment from 1 to 3 rings) which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups that contain from one to four heteroatoms selected from N, O, and S in the 9 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT ring(s), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituent moieties for aryl and heteroaryl ring systems may be selected from the group of acceptable substituent moieties described herein. The term “heteroarylium” refers to a heteroaryl group that is positively charged on one or more of the heteroatoms. [0043] The term “cycloalkylalkyl” means, unless otherwise stated, an alkyl group as defined herein substituted with a cycloalkyl group as defined here. [0044] The term “heterocycloalkylalkyl” means, unless otherwise stated, an alkyl group as defined herein substituted with a heterocycloalkyl group as defined here. [0045] The term “oxo” as used herein means an oxygen atom that is double bonded to a carbon atom. [0046] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and “heteroaryl”) are meant to include both substituted and unsubstituted forms of the indicated radical. Non- limiting examples of substituent moieties for each type of radical are provided below. When a substituent is substituted with “one or more” groups, the substituent can be substituted with one to four substituents, one to three substituents, or one to two substituents. In one embodiment, “one or more” substituent refers to one substituent. In one embodiment, “one or more” substituent refers to two substituents. In one embodiment, “one or more” substituent refers to three substituents. [0047] Substituent moieties for alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are, in one embodiment, selected from, deuterium, -OR', =O, =NR', =N-OR', -NR'R", -SR', halo, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR- C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', - NRSO2NR'R'', -CN and –NO2 in a number ranging from zero to the number of hydrogen atoms in such radical. In one embodiment, substituent moieties for cycloalkyl, 10 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups also include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. R', R", R"' and R"" each in one embodiment independently are hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1- 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituent moieties, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and –CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). [0048] Substituent moieties for aryl and heteroaryl groups are, in one embodiment, selected from deuterium, halo, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl, -OR', -NR'R", -SR', - SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR- C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN and –NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of hydrogens on the aromatic ring system; and where R', R", R"' and R"" are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. [0049] Two of the substituent moieties on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -Q'-C(O)-(CRR')q-Q''-, wherein Q' and Q'' are independently –NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring 11 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently –CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula –(CRR')s-X'-(CR''R''')d-, where s and d are independently integers of from 0 to 3, and X' is –O-, -NR'-, -S-, -S(O)-, -S(O)2-, or –S(O)2NR'-. The substituent moieties R, R', R" and R'" are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0050] As used herein, the term “heteroatom” or “ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0051] As used herein, a prodrug is a compound that upon in vivo administration is metabolized, or otherwise undergoes chemical changes under physiological conditions, by one or more steps or processes or otherwise converted to a biologically, pharmaceutically or therapeutically active form of the compound. Additionally, prodrugs can be converted to a biologically, pharmaceutically or therapeutically active form of the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. [0052] Certain compounds provided herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds provided herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. [0053] Certain compounds provided herein possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present disclosure. The compounds provided herein do not include those which are known in the art to be too unstable to synthesize and/or isolate. [0054] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the 12 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds provided herein, whether radioactive or not, are encompassed within the scope of the present disclosure. II. COMPOUNDS Compounds of Formula I, I’, and II [0055] In one embodiment, the compound of Formula I or I’ is: or a pharmaceutically acceptable salt thereof, wherein: X and Ar are selected from (i) or (ii): (i) X is O; and Ar is alkyl, heteroaryl, phenyl fused to a heterocyclyl ring, cycloalkyl, indanyl, phenyl, or heterocycloalkyl; or (ii) X is S; and Ar is aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl or a 5-7 membered heterocycloalkenyl; wherein the alkyl, heteroaryl, phenyl fused to a heterocyclyl ring, cycloalkyl, indanyl, phenyl, phenylalkyl, heterocycloalkyl (alone or as part of another group), aryl, C5- 7cycloalkyl, C5-7cycloalkenyl, 5-7 membered heterocyclyl, and 5-7 membered heterocycloalkenyl, each of Ar, are each optionally substituted; E is according to any one of the following formulae: , wherein R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and 13 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein R5-R7 are each independently H or alkyl; and R is H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted; with the proviso that the compound is not 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3-(1-oxo-5-(5-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3-(1-oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(5-(2-ethyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3-(5-(2-isobutyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(2-isopropyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-cyclopropyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; or 3-(5-(2-(difluoromethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione. [0056] In one embodiment of Formula I and I’, (i) X is O; and Ar is alkyl, heteroaryl, is phenyl fused to a heterocyclyl ring, cycloalkyl, indanyl, phenyl, phenylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or (ii) X is S and Ar is aryl; wherein the alkyl of Ar is optionally substituted with heterocycloalkyl or phenyl; the aryl, heteroaryl, phenyl fused to a heterocyclyl ring, and phenyl, each of Ar, is substituted with 1, 2, or 3 R8; and each R8 is independently selected from H; halo; OR’ where R’ is H, alkyl, or haloalkyl; -CN; alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo and OR’ where R’ is H, alkyl, or haloalkyl; -C(O)R' where R’ is alkyl; -CONR'R" where R’ and R” are independently H or alkyl or R’ and R” together with the nitrogen to which they are attached form heterocycloalkyl (optionally substituted with alkyl); cycloalkyl; 2-oxo-1,2-dihydropyridin-1-yl; heterocycloalkyl (optionally substituted with alkyl); heteroaryl; or phenyl; 14 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT the cycloalkyl of Ar is optionally substituted with 1, 2, or 3 groups independently selected from halo; OR’ where R’ is alkyl; and alkyl optionally substituted with 1, 2, or 3 halo; the heterocycloalkyl of Ar, is optionally substituted with alkyl optionally substituted with 1, 2, or 3 groups halo which are independently selected; benzyl; or -C(O)R’ where R’ is alkyl; and the alkyl of R is optionally substituted with 1, 2, or 3 halo which are independently selected or substituted with cycloalkyl or heterocycloalkyl; wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo; wherein the heterocycloalkyl is optionally substituted with 1 or 2 alkyl which are independently selected; or a pharmaceutically acceptable salt thereof. [0057] In one embodiment of Formula I, including any of the foregoing, the compound is of Formula Ia: or a pharmaceutically acceptable salt thereof; wherein: Ar is phenyl substituted with 1, 2, or 3 R8; and R is independently alkyl, cycloalkyl or heterocycloalkyl; where the alkyl of R is optionally substituted with OR’ where R’ is alkyl or with 1, 2, or 3 halo groups. [0058] In one embodiment of Formula Ia, Ar is phenyl substituted with 1, 2, or 3 R8 and R is independently methyl, isopropyl, tert-butyl, trifluoromethyl, methoxymethyl, cyclopropyl or 4-pyranyl; or R is C1-C3 alkyl or cyclopropyl; or a pharmaceutically acceptable salt thereof. [0059] In one embodiment of Formula I, including any of the foregoing, the compound is of Formula Ib: or a pharmaceutically acceptable salt thereof; wherein: Ar is heteroaryl or is phenyl fused to a heterocyclyl ring; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl wherein the alkyl is optionally substituted with 1, 2, or 3 halo which are independently selected. 15 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0060] In one embodiment of Formula Ib, Ar is heteroaryl and R is independently H or alkyl wherein the alkyl is optionally substituted with 1, 2, or 3 halo which are independently selected; or a pharmaceutically acceptable salt thereof. [0061] In one embodiment of Formula Ib, including any of the foregoing, Ar is thienyl, pyridyl, pyrrolyl, pyrazolyl, indolyl, benzofuryl, pyridopyrazolyl, benzimidazolyl or indazolyl and R is independently H, methyl, difluoromethyl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. [0062] In one embodiment of Formula Ib, including any of the foregoing, Ar is: R is independently H, methyl, difluoromethyl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. [0063] In one embodiment of Formula Ib, Ar is phenyl fused to a heterocyclyl ring; and R is independently H or, alkyl, or haloalkyl; or a pharmaceutically acceptable salt thereof. 16 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0064] In one embodiment of Formula Ib, including any of the foregoing, Ar is: R is independently H, methyl, difluoromethyl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. [0065] In one embodiment of Formula Ib, the compound is or a pharmaceutically acceptable derivative thereof, wherein i) Ar is phenyl and is substituted with at least one R8 that is not H; or ii) Ar is phenyl substituted with 1, 2, or 3 R8 and R is alkyl substituted with cycloalkyl where the cycloalkyl is optionally substituted with one or two halo; or iii) Ar is phenyl substituted with1, 2, or 3 R8 and R is alkyl substituted with heterocycloalkyl where the heterocycloalkyl is optionally substituted with one or two alkyl; iv) Ar is phenyl substituted with1, 2, or 3 R8 and when and Z1-Z3 are each CR4, then at least one R4 is not H (preferably at least one R4 is halo). [0066] In one embodiment of Formula Ib, including any of the foregoing, at least one R8 is heterocycloalkyl (in some embodiments, piperazinyl, morpholinyl, methyl-substituted piperidinyl) where the heterocycloalkyl is optionally substituted with alkyl); -CONR'R" where R’ and R” are independently H or alkyl or R’ and R” together with the nitrogen to which they are attached form heterocycloalkyl (in some embodiments, pyrrolidinyl) where the heterocycloalkyl is optionally substituted with alkyl); 2-oxo-1,2- dihydropyridin-1-yl; heteroaryl (in some embodiments, pyrazolyl); OR’ where R’ is H or alkyl optionally substituted with 1, 2, or 3 halo which are independently selected (in some embodiments, methoxy, -OCHF2); halo (fluoro, chloro); -CN; or alkyl optionally substituted with OR’ where R’ is alkyl; or a pharmaceutically acceptable salt thereof. 17 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0067] In one embodiment of Formula Ib, the compound is or a pharmaceutically acceptable derivative thereof, wherein Ar is cycloalkyl (in some embodiments, cyclopentyl, cyclohexyl), heterocycloalkyl (in some embodiments, piperidinyl, pyranyl, furanyl, tetrahydro-2H-thiopyranyl), or alkyl optionally substituted with heterocycloalkyl (in some embodiments, isopropyl, piperidinyl); and the cycloalkyl of Ar is optionally substituted with 1, 2, or 3 groups independently selected from halo; OR’ where R’ is alkyl; and alkyl optionally substituted with 1, 2, or 3 halo; and the heterocycloalkyl of Ar, is optionally substituted with alkyl optionally substituted with 1, 2, or 3 groups halo which are independently selected; benzyl; or -C(O)R’ where R’ is alkyl. [0068] In one embodiment, the compound of Formula II is: or a pharmaceutically acceptable salt thereof, wherein: E is according to any one of the following formulae: R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 18 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Het is heteroaryl; alkyl; OR’ where R’ is alkyl; cycloalkyl optionally substituted with 1 or 2 groups independently selected from halo; heterocycloalkyl optionally substituted with benzyl; heterocycloalkylalkyl; or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, and heteroaryl are each optionally substituted; with the proviso that the compound is not 3-(5-(3-methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(1-oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6- dione; or 3-(1-oxo-5-(3-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione. [0069] In one embodiment of Formula II: the alkyl of Het is optionally substituted with 1, 2, or 3 groups independently selected from halo; OR’ where R’ is H or alkyl; NR’R” where R’ and R” are independently H or alkyl or where R’ and R” together with the nitrogen to which they are attached form 4-, 5-, 6-, or 7-membered heterocycloalkyl; -CO2R’ where R’ is alkyl; and -NR"C(O)R' where R” is H and R’ is alkyl; and the aryl and heteroaryl of Het are substituted with 1, 2, or 3 R9; where each R9 is independently H; halo; -CN; alkyl optionally substituted with 1, 2, or 3 halo which are independently selected; OR’ where R’ is H or alkyl; -CO2R’ where R’ is alkyl; or heterocycloalkyl (optionally substituted with alkyl); or a pharmaceutically acceptable salt thereof. [0070] In one embodiment of Formula II, including any of the foregoing, Het is pyridyl, thiazolyl or pyrazinyl; or a pharmaceutically acceptable salt thereof. [0071] In one embodiment of Formula II, including any of the foregoing, Het is pyridyl; or a pharmaceutically acceptable salt thereof. [0072] In one embodiment of Formula II, including any of the foregoing, Het is 2-pyridyl; or a pharmaceutically acceptable salt thereof. [0073] In one embodiment of Formula II, including any of the foregoing, Het is 4-thiazolyl, 5-methyl-2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro-2-pyridyl, 6-methoxy-2-pyridyl, 2-pyrazinyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl or 5-methoxy-2-pyridyl; or a pharmaceutically acceptable salt thereof. 19 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0074] In one embodiment of Formula II, including any of the foregoing, Het is 5-methyl- 2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro-2-pyridyl, 6- methoxy-2-pyridyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl or 5-methoxy- 2-pyridyl; or a pharmaceutically acceptable salt thereof. [0075] In one embodiment of Formula I, I’, Ia, Ib, or II, including any of the foregoing, E is pharmaceutically acceptable salt thereof. [0076] In one embodiment of Formula I, I’, Ia, Ib, or II, including any of the foregoing, A has the structure: pharmaceutically acceptable salt thereof. [0077] In one embodiment of Formula I, I’, Ia, Ib, or II, including any of the foregoing, E is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0078] In one embodiment of Formula I, I’, Ia, Ib, or II, including any of the foregoing, E is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In a further embodiment, R5 is H; or a pharmaceutically acceptable salt thereof. 20 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0079] In one embodiment of Formula I, Ia, or Ib, including any of the foregoing, the compound optionally wherein R5 is H; or a pharmaceutically acceptable salt thereof. [0080] In one embodiment of Formula II, including any of the foregoing, the compound is optionally wherein R5 is H; or a pharmaceutically acceptable salt thereof. [0081] In one embodiment of Formula I or Ia, including any of the foregoing, the compound pharmaceutically acceptable salt thereof. [0082] In one embodiment of Formula I or Ib, including any of the foregoing, the compound optionally wherein R5 is H; or a pharmaceutically acceptable salt thereof. Compounds of Formula P-I and P-II [0083] In one embodiment, the compound of Formula I is a compound of Formula P-I: or a pharmaceutically acceptable derivative thereof; and the use of the compound in compositions and methods provided herein; wherein the variables Ar, E, X and R are as defined elsewhere herein. 21 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0084] In another embodiment, the compound of Formula II is a compound of Formula P- II: or a pharmaceutically acceptable derivative thereof; and the use of the compound in compositions and methods provided herein; wherein Het and E are as defined elsewhere herein. [0085] In one embodiment, provided herein is a compound of Formula P-I: or a pharmaceutically acceptable derivative thereof, wherein: X and Ar are selected from (i) or (ii): (i) X is S; and Ar is aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl or a 5-7 membered heterocycloalkenyl; or (ii) X is O; and Ar is heteroaryl or is phenyl fused to a heterocyclyl ring; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl. [0086] In one embodiment, the compound of Formula P-I is not 3-(1-oxo-5-(5- phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione. [0087] In another embodiment, X is S and the compound is of Formula P-Ia: or a pharmaceutically acceptable derivative thereof, wherein: Ar is aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl or a 5-7 membered heterocycloalkenyl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl. [0088] In another embodiment, the compound is of Formula P-Ia, wherein: Ar is aryl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently alkyl, cycloalkyl or heterocyclyl. 22 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0089] In another embodiment, the compound is of Formula P-Ia, wherein: Ar is phenyl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently methyl, isopropyl, tert-butyl, trifluoromethyl, methoxymethyl, cyclopropyl or 4-pyranyl. [0090] In another embodiment, X is O is of Formula P-Ib: or a pharmaceutically acceptable derivative thereof, wherein: Ar is heteroaryl, or is phenyl fused to a heterocyclyl ring; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl. [0091] In another embodiment, the compound is of Formula P-Ib, wherein: Ar is heteroaryl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or alkyl. [0092] In another embodiment, the compound is of Formula P-Ib, wherein: Ar is thienyl, pyridyl, pyrrolyl, pyrazolyl, indolyl, benzofuryl, pyridopyrazolyl, benzimidazolyl or indazolyl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or methyl. [0093] In another embodiment, the compound is of Formula P-Ib, wherein: Ar is: 23 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or methyl. [0094] In another embodiment, the compound is of Formula P-Ib, wherein: Ar is phenyl fused to a heterocyclyl ring; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or alkyl. [0095] In another embodiment, the compound is of Formula P-Ib, wherein: Ar is: E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or methyl. [0096] In another embodiment, the compound is of Formula P-II: or a pharmaceutically acceptable derivative thereof, wherein: E is a moiety that binds to an E3 ubiquitin ligase; and Het is heteroaryl. [0097] In another embodiment, the compound is of Formula P-II, wherein Het is pyridyl, thiazolyl or pyrazinyl. In another embodiment, Het is pyridyl. In another embodiment, Het is 2-pyridyl. [0098] In another embodiment, the compound is of Formula P-II, wherein Het is 4- thiazolyl, 5-methyl-2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro- 2-pyridyl, 6-methoxy-2-pyridyl, 2-pyrazinyl, 4-methoxycarbonyl-2-pyridyl, 6- trifluoromethyl-2-pyridyl or 5-methoxy-2-pyridyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II, wherein Het is 5- methyl-2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro-2-pyridyl, 6- methoxy-2-pyridyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl or 5-methoxy- 2-pyridyl. 24 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Non-limiting embodiment of Formula P-I and P-II include: [0099] Provided in embodiment 1 is a compound of Formula P-I: or a pharmaceutically acceptable derivative thereof, wherein: X and Ar are selected from (i) or (ii): (i) X is S; and Ar is aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl or a 5-7 membered heterocycloalkenyl; or (ii) X is O; and Ar is heteroaryl or is phenyl fused to a heterocyclyl ring; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl; with the proviso that the compound is not 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione. [0100] In embodiment 2, provided is the compound of embodiment 1 has according to Formula P-Ia: . [0101] In embodiment 3, provided is the compound of embodiment 2, wherein: Ar is aryl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently alkyl, cycloalkyl or heterocyclyl. [0102] In embodiment 4, provided is the compound of embodiment 2 or embodiment 3, wherein: Ar is phenyl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently methyl, isopropyl, tert-butyl, trifluoromethyl, methoxymethyl, cyclopropyl or 4-pyranyl. [0103] In embodiment 5, provided is the compound of embodiment 1 that has Formula P- Ib: 25 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT or a pharmaceutically acceptable derivative thereof, wherein: Ar is heteroaryl, or is phenyl fused to a heterocyclyl ring; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl. [0104] In embodiment 6, provided is the compound of embodiment 5, wherein: Ar is heteroaryl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or alkyl. [0105] In embodiment 7, provided is the compound of embodiment 5 or embodiment 6, wherein: Ar is thienyl, pyridyl, pyrrolyl, pyrazolyl, indolyl, benzofuryl, pyridopyrazolyl, benzimidazolyl or indazolyl; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or methyl. [0106] In embodiment 8, provided is the compound of any one of embodiments 5-7, wherein: Ar is: E is a moiety that binds to an E3 ubiquitin ligase; and 26 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT R is independently H or methyl. [0107] In embodiment 9, provided is the compound of embodiment 5, wherein: Ar is phenyl fused to a heterocyclyl ring; E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or alkyl. [0108] In embodiment 10, provided is the compound of embodiment 9, wherein: Ar is: E is a moiety that binds to an E3 ubiquitin ligase; and R is independently H or methyl. [0109] In embodiment 11, provided is a compound of Formula II: or a pharmaceutically acceptable derivative thereof, wherein: E is a moiety that binds to an E3 ubiquitin ligase; and Het is heteroaryl. [0110] In embodiment 12, provided is the compound of embodiment 11, wherein Het is pyridyl, thiazolyl or pyrazinyl. [0111] In embodiment 13, provided is the compound of embodiment 11 or claim 12, wherein Het is pyridyl. [0112] In embodiment 14, provided is the compound of any one of embodiments 11-13, wherein Het is 2-pyridyl. [0113] In embodiment 15, provided is the compound of embodiment 11 or embodiment 12, wherein Het is 4-thiazolyl, 5-methyl-2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2- pyridyl, 3-fluoro-2-pyridyl, 6-methoxy-2-pyridyl, 2-pyrazinyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl or 5-methoxy-2-pyridyl. [0114] In embodiment 16, provided is the compound of any one of embodiments 11-15, wherein Het is 5-methyl-2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3- 27 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT fluoro-2-pyridyl, 6-methoxy-2-pyridyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2- pyridyl or 5-methoxy-2-pyridyl. [0115] In embodiment 17, provided is the compound of any one of embodiments 1-16, wherein E has one of the following formulae: , wherein A is a cyclic amide or cyclic imide or a derivative thereof; R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0116] In embodiment 18, provided is the compound of any one of embodiments 1-17, wherein A has the structure: wherein R5-R7 are each independently H or alkyl. [0117] In embodiment 19, provided is the compound of any one of embodiments 1-18, wherein A has the structure: . [0118] In embodiment 20, provided is the compound of any one of embodiments 1-16, wherein E is selected from: 28 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT wherein R5 is H or alkyl. [0119] In embodiment 21, provided is the compound of any one of embodiments 1-16, wherein E has the structure: wherein R5 is H or alkyl. [0120] In embodiment 22, provided is the compound of embodiment 21, wherein R5 is H. [0121] In embodiment 23, provided is the compound of embodiment 1 that has the structure: . [0122] In embodiment 24, provided is the compound of embodiment 11 that has the structure: . [0123] In embodiment 25, provided is the compound of embodiment 1 that has the structure: 29 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT . [0124] In embodiment 26, provided is the compound of embodiment 1 that has the structure: . [0125] In embodiment 27, provided is the compound of embodiment 1 that has the structure: . [0126] In embodiment 28, provided is the compound of embodiment 11 that has the structure: . [0127] In embodiment 29, provided is the compound of any one of embodiments 1-28, wherein each and any alkyl, alkenyl, alkynyl, aryl, heteroaryl, C5-7cycloalkyl, C5- 7cycloalkenyl, 5-7 membered heterocyclyl, 5-7 membered heterocycloalkenyl, phenyl fused to a heterocyclyl ring, cycloalkyl, and heterocyclyl are independently unsubstituted or substituted where nonlimiting examples of substituent moieties for each type of radical are provided below: Substituent moieties for alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are, in one embodiment, selected from, deuterium, -OR', =O, =NR', =N-OR', -NR'R", -SR', halo, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', 30 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NRSO2NR'R'', -CN and –NO2 in a number ranging from zero to the number of hydrogen atoms in such radical. In one embodiment, substituent moieties for cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups also include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. R', R", R"' and R"" each in one embodiment independently are hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1- 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituent moieties, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and –CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). Substituent moieties for aryl and heteroaryl groups are, in one embodiment, selected from deuterium, halo, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN and –NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of hydrogens on the aromatic ring system; and where R', R", R"' and R"" are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. 31 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Two of the substituent moieties on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -Q'-C(O)-(CRR')q-Q''-, wherein Q' and Q'' are independently –NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently –CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula –(CRR')s-X'-(CR''R''')d-, where s and d are independently integers of from 0 to 3, and X' is –O-, -NR'-, -S-, -S(O)-, -S(O)2-, or –S(O)2NR'-. The substituent moieties R, R', R" and R'" are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0128] In embodiment 30, provided is a compound or a pharmaceutically acceptable salt thereof, of any of Examples 1-312. [0129] In embodiment 31, provided is a pharmaceutical composition, comprising the compound of any one of embodiments 1-30 and a pharmaceutically acceptable carrier. [0130] In embodiment 32, provided is a method of degrading CK1α in a cell or a subject, comprising contacting the cell with or administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the composition of embodiment 31. [0131] In embodiment 33, provided is a method of degrading CK1α in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0132] In embodiment 34, provided is a method of inhibiting Card11/BCL10/MALT1 (CBM) complex activation in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0133] In embodiment 35, provided is a method of regulating cellular proliferation in a subject, comprising administering to the subject the compound or a pharmaceutically 32 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0134] In embodiment 36, provided is a method of treating a subject having a proliferative disease, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0135] In embodiment 37, provided is a method of treating a subject having cancer, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0136] In embodiment 38, provided is the method of embodiment 37, wherein the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome, (MDS) (including 5q-MDS), colon cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell lymphoma or mantle cell lymphoma (MCL). [0137] In embodiment 39, provided is the method of embodiment 37 or embodiment 38, wherein the cancer is a B-cell lymphoma. [0138] In embodiment 40, provided is the method of embodiment 38 or embodiment 39, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL). [0139] In embodiment 41, provided is the method of embodiment 40, wherein the DLBCL is ABC DLBCL. [0140] In embodiment 42, provided is the method of embodiment 37, wherein the cancer is a BTK inhibitor resistant cancer. [0141] In embodiment 43, provided is the method of embodiment 42, wherein the BTK inhibitor resistant cancer is ibrutinib resistant cancer. [0142] In embodiment 44, provided is the method of embodiment 43, wherein the ibrutinib resistant cancer is ABC DLBCL. [0143] In embodiment 45, provided is the method of embodiment 42, wherein BTK inhibitor resistant cancer is resistant to one or more of acalabrutinib, zanubrutinib, pirtobrutinib, spebrutinib, evobrutinib, olmutinib, tirabrutinib, elsubrutinib (ABBV-105), tolebrutinib (SAR 442168), fenebrutinib, vacabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068 or DTRMWXHA-12. [0144] In embodiment 46, provided is the method of embodiment 42, wherein the BTK inhibitor resistant cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), 33 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia or chronic graft-versus-host disease. [0145] In embodiment 47, provided is a method of degrading CK1α and GSPT1 in a cell, comprising contacting the cell with the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0146] In embodiment 48, provided is a method of degrading CK1α and GSPT1 in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0147] In embodiment 49, provided is a method of treating AML, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, stomach cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testis cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, hepatocellular carcinoma, a lympoma, or gastric cancer in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0148] In embodiment 50, provided is a method of treating a subject having an autoimmune disorder, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0149] In embodiment 51, provided is the method of embodiment 50, wherein the autoimmune disorder is Addison disease, Celiac disease - sprue (gluten-sensitive enteropathy), dermatomyositis, Graves’ disease, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus or type I diabetes. [0150] In embodiment 52, provided is the method of embodiment 50 or 51, further comprising administering to the subject a second active agent. [0151] In embodiment 53, provided is the method of embodiment 52, wherein the second active agent is a checkpoint inhibitor, such as an anti-CTLA-4, an anti-PD-1 or anti-PD-L1 antibody. [0152] In embodiment 54, provided is the method of embodiment 52 or 53, wherein the second active agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tramelimumab, or a combination thereof. 34 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0153] In embodiment 55, provided is the method of embodiment 36, wherein the proliferative disease to be treated is melanoma including unresectable or metastatic melanoma, BRAF 600 mutation positive, and melanoma with lymph node involvement; non- small cell lung cancer including metastatic non-small cell lung cancer; renal cell carcinoma; Hodgkin lymphoma including relapsed/refractory Hodgkin lymphoma; squamous cell carcinoma of the head and neck including metastatic disease; urothelial carcinoma including metastatic disease; colorectal cancer including metastatic disease; or hepatocellular carcinoma. [0154] In embodiment 56, provided is a method of treating a RAS-driven cancer in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. [0155] In embodiment 57, provided is the method of embodiment 56, wherein the RAS- driven cancer is a RAS-mutant cancer. [0156] In embodiment 58, provided is the method of embodiment 56, wherein the RAS- driven cancer is a KRASG12D-driven cancer. [0157] In embodiment 59, provided is the method of any one of embodiments 56-58, wherein the RAS-driven cancer is lung cancer, head and neck cancer, pancreatic cancer, breast cancer, colorectal cancer, gastrointestinal cancer, melanoma, myeloid cancer, bladder cancer, cervical cancer, ovarian cancer or uterine cancer. [0158] In embodiment 60, provided is a method of preventing acquired resistance to erlotinib in EGFR-mutant non-small cell lung cancer in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1-30 or the pharmaceutical composition of embodiment 31. Compounds of Formula III [0159] In one embodiment, the compound of Formula III is: or a pharmaceutically acceptable salt thereof, wherein: Ar is optionally substituted aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl, a 5-7 membered heterocycloalkenyl, or phenyl fused to a heterocyclyl ring; wherein the aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 35 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT membered heterocyclyl, a 5-7 membered heterocycloalkenyl, or phenyl fused to a heterocyclyl ring, each of Ar, are each optionally substituted; R is H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl; E is according to any one of the following formulae: wherein R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein R5-R7 are each independently H or alkyl; and R is H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted; with the proviso that the compound is not 3-(1-oxo-5-(4-phenyl-4H-1,2,4-triazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; or 3-(5-(1-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione. 36 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0160] In one embodiment, the compound of Formula a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula pharmaceutically acceptable salt thereof. [0161] In one embodiment of Formula III, including any of the foregoing, Ar is aryl, heteroaryl, C5-7cycloalkyl, or phenyl fused to a heterocyclyl ring and R is H, optionally substituted alkyl, or cycloalkyl; or a pharmaceutically acceptable salt thereof. [0162] In one embodiment of Formula III, including any of the foregoing, Ar is aryl, heteroaryl, C5-7cycloalkyl, or phenyl fused to a heterocyclyl ring and R is H, optionally substituted alkyl, or cycloalkyl; wherein the aryl of Ar is optionally substituted with 1, 2, or 3 R8a wherein R8a is independently selected from OR’ where R’ is H, alkyl, or haloalkyl; alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo and OR’ where R’ is H, alkyl, or haloalkyl; -NR’R” where R’ and R” are independently H or alkyl; and halo; and the alkyl of R is optionally substituted with 1, 2, or 3 halo; or a pharmaceutically acceptable salt thereof. [0163] In one embodiment of Formula III, including any of the foregoing, Ar is phenyl optionally substituted with 1 R8a selected from OR’ where R’ is H or alkyl; alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo; -NH2; and halo; or a pharmaceutically acceptable salt thereof. [0164] In one embodiment of Formula III, including any of the foregoing, Ar is phenyl optionally substituted with 1 R8a selected from OR’ where R’ is H or alkyl; alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo; -NH2; and halo; and R is alkyl optionally substituted with 1, 2, or 3 fluoro groups; or a pharmaceutically acceptable salt thereof. [0165] In one embodiment of Formula III, including any of the foregoing, Ar is pyridyl, benzothiazolyl, benzofuranyl, indolyl, or cyclohexyl; or a pharmaceutically acceptable salt thereof. 37 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0166] In one embodiment of Formula III, including any of the foregoing, Ar is , [0167] In one embodiment of Formula III, including any of the foregoing, R is alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo; or a pharmaceutically acceptable salt thereof. [0168] In one embodiment of Formula III, including any of the foregoing, R is unsubstituted alkyl or alkyl substituted with 1, 2, or 3 fluoro; or a pharmaceutically acceptable salt thereof. [0169] In one embodiment of Formula III, including any of the foregoing, R is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH(CH3)2; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula III, including any of the foregoing, R is -CHF2, -CF3, or -CH2CF3. In one embodiment of Formula III, including any of the foregoing, R is cyclobutyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula III, including any of the foregoing, R is H; or a pharmaceutically acceptable salt thereof. [0170] In one embodiment of Formula III, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. 38 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0171] In one embodiment of Formula III, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0172] In one embodiment of Formula III, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0173] In one embodiment of Formula III, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. Compounds of Formula IV [0174] In one embodiment, the compound of Formula IV is: or a pharmaceutically acceptable salt thereof; wherein: X2, X3, X4, X5, X6, and X7 are independently selected from CR10 and N; X1 is O, NR11 or C(R10)2; 39 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT wherein (a) at least two of X3-X6 are CR10; (b) when X1 is C(R10)2, X2 is N and when X2 is CR10, X1 is O or NR11; and (c) when X7 is CR10, X2 is N and when X2 is CR10, X7 is N; R9 is alkyl, halo, or aryl; R10 is independently selected from H, alkyl, alkoxy, and aryl; R11 is H, alkyl, or aryl wherein the aryl is optionally substituted with alkoxy or amino; n is 1 or 2; E is according to any one of the following formulae: , wherein R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein R5-R7 are each independently H or alkyl; with the proviso that the compound is not 3-(1-oxo-6-(pyrazolo[1,5-a]pyrimidin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1-ethyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; or 40 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 3-(6-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione. [0175] In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A is of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A is ; or a pharmaceutically acceptable salt thereof. [0176] In one embodiment of Formula IV, including any of the foregoing, X3-X6 are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, one of X3-X6 is N and the others are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X3 is N and X4-X6 are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X4 is N and X3 and X5-X6 are CH; or a 41 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X5 is N and X3-X4 and X6 are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X6 is N and X3- X5 are CH. ; or a pharmaceutically acceptable salt thereof [0177] In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A is pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A is [0178] In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring 42 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. [0179] In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt thereof. 43 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0181] In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring of Formula IV is Ring pharmaceutically acceptable salt thereof. [0182] In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring 44 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. [0183] In one embodiment of Formula IV is Ring A is ; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring pharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A is pharmaceutically acceptable salt 45 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT pharmaceutically acceptable salt thereof. [0185] In one embodiment of Formula IV, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compound wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0186] In one embodiment of Formula IV, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compound is 46 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0187] In one embodiment of Formula IV, including any of the foregoing, the compound is acceptable salt thereof. [0188] In one embodiment of Formula IV, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0189] In one embodiment of Formula IV, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. [0190] In one embodiment of Formula IV, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compound wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of 47 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT the foregoing, the compound wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compound wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. Compounds of Formula V [0191] In one embodiment, the compound of Formula V is: or a pharmaceutically acceptable salt thereof; wherein: X11, X12, and X13 are each independently CR, CRx, N, NR, or NRx; X14 is N or C; wherein when X14 is N, exactly one of X11, X12, and X13 is N, NR, or NRx and when X14 is C, exactly two of X11, X12, and X13 are N, NR, or NRx; and wherein when Ar is aryl or heteroaryl, at least one of one of X11, X12, and X13 must be CRx or NRx; Ar is aryl; heteroaryl optionally substituted with one or more alkyl groups; C0-C4- alkylene-NH-heterocyclyl wherein the heterocyclyl is optionally substituted with one or more alkyl groups which are independently selected; or C0-C4-alkylene-NH-heteroaryl wherein the heteroaryl is optionally substituted with one or more alkyl groups which are independently selected; 48 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT each Rx is independently cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected; heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups which are independently selected; aryl optionally substituted with one or more groups selected from alkyl, halo, or alkyloxy which are independently selected; or, C0-C4-alkylene-C(O)- heterocyclyl; and each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. [0192] In one embodiment, the compound of Formula V is selected from: , pharmaceutically acceptable salt thereof. [0193] In one embodiment of the compound of Formula V, including any of the foregoing, Ar is aryl; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of Formula V, including any of the foregoing, Ar is phenyl; or a pharmaceutically acceptable salt thereof. [0194] In one embodiment of the compound of Formula V, including any of the foregoing, Ar is C0-C4-alkylene-NH-heterocyclyl wherein the heterocyclyl is optionally substituted with one or more alkyl groups which are independently selected; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of Formula V, including any of the foregoing, Ar is CH2-NH-heterocyclalkyl wherein the heterocycloalkyl is optionally substituted with one or more alkyl groups which are independently selected; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of Formula V, including any of the foregoing, Ar is CH2-NH-heterocyclalkyl wherein the heterocycloalkyl is optionally substituted with one alkyl group; or a pharmaceutically acceptable salt thereof. [0195] In one embodiment of the compound of Formula V, including any of the foregoing, Ar is C0-C4-alkylene-NH-heteroaryl wherein the heteroaryl is optionally substituted with one 49 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT or more alkyl groups which are independently selected; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of Formula V, including any of the foregoing, Ar is CH2-NH-heteroaryl wherein the heteroaryl is optionally substituted with one or more alkyl groups which are independently selected; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of Formula V, including any of the foregoing, Ar is CH2-NH-heteroaryl wherein the heteroaryl is optionally substituted with one alkyl group; or a pharmaceutically acceptable salt thereof. [0196] In one embodiment of the compound of Formula V, including any of the foregoing, the compound is ; Ar is C0-C4-alkylene-NH-heterocyclyl wherein the heterocyclyl is optionally substituted with one or more alkyl groups which are independently selected or C0-C4-alkylene-NH-heteroaryl wherein the heteroaryl is optionally substituted with one or more alkyl groups which are independently selected; and R is unsubstituted alkyl. In a further embodiment, R is methyl; or a pharmaceutically acceptable salt thereof. [0197] In one embodiment of the compound of Formula V, including any of the foregoing, [0198] In one embodiment of Formula V, including any of the foregoing, Rx is cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is cycloalkylalkyl wherein the cycloalkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is cycloalkylalkyl wherein the alkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, 50 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT including any of the foregoing, Rx is cycloalkylalkyl optionally substituted with two halo groups which are independently selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is cycloalkylalkyl optionally substituted with two fluoro; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0199] In one embodiment of Formula V, including any of the foregoing, Rx is cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected and Ar is aryl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected and Ar is phenyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0200] In one embodiment, the compound of Formula V is selected from: , , and ; Rx is cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected; Ar is aryl; and R is unsubstituted alkyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0201] In one embodiment, the compound of Formula V is selected from: , cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected; Ar is phenyl; and R is methyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0202] In one embodiment of Formula V, including any of the foregoing, Rx is -CH2- cyclopropyl or -CH2-cyclobutyl wherein the -CH2- portion or the cyclopropyl or cyclobutyl portion is optionally substituted with one or more halo groups which are independently 51 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is -CH2- cyclopropyl or -CH2-cyclobutyl wherein the -CH2- portion or the cyclopropyl or cyclobutyl portion is optionally substituted with two halo groups; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0203] In one embodiment of Formula V, including any of the foregoing, Rx is unsubstituted -CH2-cyclopropyl or -CH2-cyclobutyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0204] In one embodiment of Formula V, including any of the foregoing, ; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0205] In one embodiment of Formula V, including any of the foregoing, Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups and wherein the heterocycloalkyl is a 4- to 7-membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more C1-C3alkyl groups and wherein the heterocycloalkyl is a 4- to 7-membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is unsubstituted heterocycloalkylalkyl wherein the heterocycloalkyl is a 4- to 7-membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one C1-C3alkyl group and wherein the 52 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT heterocycloalkyl is a 4- to 7-membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0206] In one embodiment of Formula V, including any of the foregoing, Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups and Ar is aryl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups and Ar is phenyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0207] In one embodiment, the compound of Formula V is selected from: , heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups; Ar is aryl; and R is unsubstituted alkyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0208] In one embodiment, the compound of Formula V is selected from: , heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups; Ar is phenyl; and R is methyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 53 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0209] In one embodiment of Formula V, including any of the foregoing, optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0210] In one embodiment of Formula V, including any of the foregoing, Rx is aryl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is unsubstituted aryl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is aryl optionally substituted with one or more groups selected from methyl, Cl, F, and methoxy; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is aryl substituted with one alkyl group; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is aryl substituted with two alkyl groups; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is aryl substituted with one alkoxy group. In one embodiment of Formula V, including any of the foregoing, Rx is aryl substituted with one halo group; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is aryl substituted with one halo group wherein the halo group is Cl or F; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0211] In one embodiment of Formula V, including any of the foregoing, Rx is phenyl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0212] In one embodiment of Formula V, including any of the foregoing, Rx is aryl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar is aryl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is phenyl 54 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar is phenyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0213] In one embodiment of Formula V, including any of the foregoing, Rx is aryl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar is heteroaryl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is phenyl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar is a pyrazole optionally substituted with one or more alkyl groups; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0214] In one embodiment of Formula V, including any of the foregoing, Rx is phenyl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar ; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0215] In one embodiment, the compound of Formula V is selected from: , aryl; Ar is aryl; and R is alkyl or cycloalkyl wherein alkyl is optionally substituted with 1, 2, or 3 halo; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0216] In one embodiment, the compound of Formula V is selected from: , phenyl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy; Ar is phenyl; and R is methyl, cyclopropyl, cyclobutyl, or CF3; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 55 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0217] In one embodiment of Formula V, including any of the foregoing, Rx is , pharmaceutically acceptable salt thereof. [0218] In one embodiment of Formula V, including any of the foregoing, Rx is C(O)- heterocycloalkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is C1-C3-C(O)-heterocycloalkyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is C2-C(O)-heterocycloalkyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0219] In one embodiment of Formula V, including any of the foregoing, Rx is C0-C4- C(O)-heterocyclyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is C0-C4-C(O)- heterocyclyl wherein the heterocyclyl is a 4- to 7-membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is C0-C4-C(O)- heterocyclyl wherein the heterocyclyl is a 4- to 7- membered ring comprising at least one heteroatom selected from O and N and the alkyl is C1- C3alkyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0220] In one embodiment of Formula V, including any of the foregoing, Rx is C0-C4-C(O)- heterocyclyl and Ar is aryl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rx is C0-C4-C(O)-heterocyclyl and Ar is phenyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 56 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0221] In one embodiment, the compound of Formula V is selected from: heterocyclyl; Ar is aryl; and R is unsubstituted alkyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0222] In one embodiment, the compound of Formula V is selected from: heterocyclyl; Ar is phenyl; and R is methyl; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. [0223] In one embodiment of Formula V, including any of the foregoing, Rx is optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. E3 Ubiquitin ligase Binding Moiety (E) [0224] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E is a moiety that binds to cereblon. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E contains an imide, amide, thioamide or thioimide derived moiety. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E contains a phthalimido group or an analog or derivative thereof. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E contains a phthalimido-glutarimide group or an analog or derivative thereof. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E contains a thalidomide, lenalidomide or pomalidomide moiety, or an analog or derivative thereof. 57 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0225] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E has one of the following formulae: , where A is a cyclic amide or cyclic imide or a derivative thereof; R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or halo. In one embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z1-Z4 are each independently N or CR4, where each R4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In one embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), at most two of Z1-Z4 are N. [0226] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E is wherein at least one of Z1-Z3 is CR4 wherein R4 is halo, and preferably fluoro. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E is [0227] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z1 and R1, together with the atoms to which they are attached, form a fused phenyl ring; R2 is absent; and E has the formula: 58 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT where A is a cyclic amide or cyclic imide or a derivative thereof; and Z2 and Z3 are each independently N or CR4, where each R4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0228] In one embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), A is a cyclic imide having the structure: where R5 is H or alkyl; R6 and R7 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl; and m is an integer from 1-4. [0229] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5 is H or lower alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5 is H or methyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5 is H. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5 is methyl. [0230] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R6 and R7 are each independently H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R6 and R7 are each independently H or methyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R6 and R7 both H. [0231] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), m is 1, 2 or 3. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), m is 2 or 3. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), m is 2. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), m is 3. [0232] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), A has the structure: where R5-R7 are selected as described elsewhere herein. [0233] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), A has the structure: 59 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT where R5 is selected as described elsewhere herein. [0234] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), A has one of the following structures with the absolute stereochemistry shown: . [0235] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R1 and R2 are each independently H, alkyl, alkenyl or alkynyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R1 and R2 are each independently H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R1 and R2 are each independently H or methyl. In another embodiment of Formula (I), (II), (P-I), (P- II), (III), (IV), or (V), R1 and R2 are each H. [0236] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R3 is H, alkyl, alkenyl or alkynyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R3 is H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P- II), (III), (IV), or (V), R3 is H or methyl. In another embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), R3 is H. [0237] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R4 is H, alkyl, alkenyl or alkynyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R4 is H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P- II), (III), (IV), or (V), R4 is H or methyl. In another embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), R4 is H. [0238] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Y1 is S and Y2 is CR3. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Y1 is S and Y2 is CH. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Y1 is CR3 and Y2 is S. In another embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), Y1 is CH and Y2 is S. [0239] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z1 is N and Z2-Z4 are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z1 is N and Z2-Z4 are CH. 60 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0240] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z2 is N and Z1, Z3 and Z4 are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z2 is N and Z1, Z3 and Z4 are CH. [0241] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z3 is N and Z1, Z2 and Z4 are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z3 is N and Z1, Z2 and Z4 are CH. [0242] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z4 is N and Z1-Z3 are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z4 is N and Z1-Z3 are CH. [0243] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E is an imide. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E is selected from: , where R5 is as defined elsewhere herein. [0244] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E has the structure: where R5 is as defined elsewhere herein. In another embodiment, E is selected from: [0245] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compounds provided herein have the structure: 61 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT where R5, Ar, X and R are as defined elsewhere herein. [0246] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compounds provided herein have the structure: where R5 and Het are as defined elsewhere herein. [0247] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compounds provided herein have the structure: where Ar, X and R are as defined elsewhere herein. [0248] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compounds provided herein have the structure: where Ar and R are as defined elsewhere herein. [0249] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compounds provided herein have the structure: where Ar and R are as defined elsewhere herein. [0250] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compounds provided herein have the structure: where Het is as defined elsewhere herein. 62 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0251] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), the compound is selected from the Examples disclosed herein. [0252] some, a compound provided herein is used in the compositions and methods provided herein. III. SYNTHESIS OF THE COMPOUNDS [0253] The compounds provided herein may be synthesized using standard methods well known to those of skill in the art starting with commercially available starting materials. In one embodiment, the compound provided herein is synthesized according to one of the methods shown in the Examples starting with know compounds. IV. PHARMACEUTICAL COMPOSITIONS [0254] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of compounds provided herein and a pharmaceutically acceptable carrier, diluent or excipient. [0255] The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999). [0256] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts is (are) mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and/or progression of a disease or disorder disclosed herein. [0257] Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. [0258] In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also 63 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. [0259] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans. In some embodiments, the active compound is administered in a method to achieve a therapeutically effective concentration of the drug. In some embodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen J T, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389/fonC.2014.00105) is used to determine the therapeutic concentration and safety profile of the active compound in specific subjects or subject populations. [0260] The concentration of active compound in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of a disease or disorder disclosed herein. [0261] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/mL to about 50-100 µg/mL. In one embodiment, the pharmaceutical compositions provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and in certain embodiments, from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form. [0262] The active ingredient may be administered at once or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be 64 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. [0263] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue distribution, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art. [0264] The compositions are intended to be administered by a suitable route, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, dermal, transdermal, buccal, rectal, topical, local, nasal or inhalation. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. [0265] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material. [0266] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, 65 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. [0267] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. [0268] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically therapeutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging. [0269] Sustained-release preparations can also be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for 66 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions. [0270] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium croscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% 100% active ingredient, in certain embodiments, about 0.185% or about 75-95%. [0271] The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings. [0272] The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases related to oxidative stress. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein. 67 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0273] Lactose-free compositions provided herein can contain excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate. [0274] Further encompassed are anhydrous pharmaceutical compositions and dosage forms containing a compound provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp.379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations. [0275] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. [0276] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs. A. ORAL DOSAGE FORMS [0277] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. 68 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0278] In certain embodiments, the formulations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent. [0279] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water-soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. [0280] If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. [0281] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. 69 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0282] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable salt thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included. [0283] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [0284] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil in-water or water in oil. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. [0285] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a 70 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms. [0286] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic adds include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation. [0287] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration. [0288] Alternatively, liquid or semi solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, 71 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates. [0289] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal. [0290] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. B. INJECTABLES, SOLUTIONS AND EMULSIONS [0291] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow release or sustained release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate 72 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. [0292] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous. [0293] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. [0294] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances. [0295] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include 73 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. [0296] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the subject or animal as is known in the art. [0297] The unit dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. [0298] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. [0299] Injectables are designed for local and systemic administration. Typically, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, such as more than 1% w/w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations. [0300] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. 74 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT C. LYOPHILIZED POWDERS [0301] Also provided herein are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels. [0302] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable salt thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (including but not limited to 10-1000 mg or 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature. [0303] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, about 5- 35 mg, or about 9-30 mg of lyophilized powder, is added per mL of sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined. D. TOPICAL ADMINISTRATION [0304] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. [0305] The compounds or pharmaceutically acceptable salts thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert 75 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT carrier such as lactose. In such a case, the particles of the formulation will have diameters of less than 50 microns or less than 10 microns. [0306] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. [0307] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7, with appropriate salts. E. COMPOSITIONS FOR OTHER ROUTES OF ADMINISTRATION [0308] Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein. [0309] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono, di and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams. [0310] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. F. SUSTAINED RELEASE COMPOSITIONS [0311] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos.4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 76 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. [0312] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. In one embodiment, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. In certain embodiments, advantages of controlled- release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. [0313] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. [0314] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138 (1984). 77 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0315] In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. G. TARGETED FORMULATIONS [0316] The compounds provided herein, or pharmaceutically acceptable salts thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non- limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. [0317] In one embodiment, the antibody-based delivery system is an antibody-drug conjugate (“ADC”), e.g., as described in Hamilton G S, Biologicals, 2015 September, 43(5):318-32; Kim E G and Kim K M, Biomol. Ther. (Seoul), 2015 November, 23(6):493- 509; and Peters C and Brown S, Biosci. Rep., 2015 Jun.12, 35(4) pii: e00225, each of which is incorporated herein by reference. 78 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0318] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. H. ARTICLES OF MANUFACTURE [0319] The compounds or pharmaceutically acceptable salts can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable salt thereof provided herein, which is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein. [0320] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated. [0321] In certain embodiments, provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [0322] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers 79 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein. [0323] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle- less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients. [0324] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. V. DOSING [0325] The compounds and pharmaceutical compositions provided herein may be dosed in certain therapeutically or prophylactically effective amounts, certain time intervals, certain dosage forms, and certain dosage administration methods as described below. [0326] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day. [0327] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, 80 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day. [0328] In one embodiment, the recommended daily dose range of the compound provided herein, or a derivative thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, in one embodiment given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day. [0329] In a specific embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In a specific embodiment, the compound can be administered in an amount of about 25 mg/day. In a particular embodiment, the compound can be administered in an amount of about 10 mg/day. In a particular embodiment, the compound can be administered in an amount of about 5 mg/day. In a particular embodiment, the compound can be administered in an amount of about 4 mg/day. In a particular embodiment, the compound can be administered in an amount of about 3 mg/day. [0330] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 to about 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day. [0331] The administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m2/day. 81 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0332] In certain embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM. [0333] In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM. [0334] As used herein, the term “plasma concentration at steady state” is the concentration reached after a period of administration of a compound provided herein, or a derivative thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound. [0335] In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 50 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM. [0336] In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.01 to about 25 µM, from about 0.01 to about 20 µM, from about 0.02 to about 20 µM, from about 0.02 to about 20 µM, or from about 0.01 to about 20 µM. [0337] In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL. [0338] The methods provided herein encompass treating a patient regardless of subject's age, although some diseases or disorders are more common in certain age groups. [0339] Depending on the disease to be treated and the subject's condition, the compound provided herein, or a derivative thereof, may be administered by oral, parenteral (e.g., 82 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound provided herein, or a derivative thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration. [0340] In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered parenterally. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. [0341] The compound provided herein, or a derivative thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities. [0342] The compound provided herein, or a derivative thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term “daily” is intended to mean that a therapeutic compound, such as the compound provided herein, or a derivative thereof, is administered once or more than once each day, for example, for a period of time. The term “continuous” is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound provided herein or a derivative thereof is 83 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term “cycling” as used herein is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days. [0343] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once a day. In another embodiment, the compound provided herein, or a derivative thereof, is administered twice a day. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered three times a day. In still another embodiment, the compound provided herein, or a derivative thereof, is administered four times a day. [0344] In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 4 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 5 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 6 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for one week. In another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for two weeks. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for three weeks. In still another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for four weeks. VI. METHODS OF TREATMENT [0345] Provided is a method of degrading CK1α in a cell by contacting the cell with a compound or composition provided herein. In another embodiment, provided is a method of 84 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT degrading CK1α in a subject by administering to the subject a compound or composition provided herein. [0346] In another embodiment, provided is a method of inhibiting Card11/BCL10/MALT1 (CBM) complex activation. It is known in the art that CK1α is required for TCR- and BCR- regulated activation of the CBM complex (see, e.g., Gehring et al., Cell Reports 2019, 29, 873-888; Bidere et al., Nature 2009, 458, 7234; Yin et al. Cell. Mol. Life Sci.2022, 79, 112). Activation of the CBM complex leads to IL-2 induction, JNK signaling, and canonical NF- κB pathway signaling, and ultimately to cellular proliferation. Thus, degradation of CK1α leads to CBM complex inhibition and regulation of cellular proliferation. [0347] Thus, in one embodiment, provided is a method of treating a subject having a proliferative disease by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating a subject having cancer by administering to the subject a compound or composition provided herein. [0348] In one embodiment, the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome, (MDS) (including 5q-MDS), colon cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell lymphoma or mantle cell lymphoma (MCL). See, e.g., Manni et al., Front. Oncol.2021, 11, Article 733848; Tabe et al., Clin. Cancer Res.2009, 15(3), 933-942; Liang et al., Mod. Pathol.2010, 23(3), 389-91; Gehring et al., Cell Reports 2019, 29, 873-888; Bidere et al., Nature 2009, 458, 7234; Di Pilato et al., Nature 2019, 570(7759), 112-116; Rosenbaum et al., Nat. Commun.2019, 10(1), 2352; Saba et al., Cancer Res.2017, 77(24), 7038-7048. [0349] In one embodiment, the cancer is a B-cell lymphoma. In another embodiment, the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL). In another embodiment, the DLBCL is ABC DLBCL. [0350] In another embodiment, the cancer is a BTK inhibitor resistant cancer. In one embodiment, the BTK inhibitor resistant cancer is ibrutinib resistant cancer. In another embodiment, the ibrutinib resistant cancer is ABC DLBCL. [0351] In another embodiment, the BTK inhibitor resistant cancer is acalabrutinib resistant cancer. In one embodiment, the BTK inhibitor resistant cancer is zanubrutinib resistant cancer. In one embodiment, the BTK inhibitor resistant cancer is resistant to one or more of pirtobrutinib, spebrutinib, evobrutinib, olmutinib, tirabrutinib, elsubrutinib (ABBV-105), tolebrutinib (SAR 442168), fenebrutinib, vacabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068 or DTRMWXHA-12. 85 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0352] In another embodiment, the BTK inhibitor resistant cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia or chronic graft-versus-host disease. [0353] In another embodiment, provided is a method of degrading CK1α and GSPT1 in a cell by contacting the cell with a compound or composition provided herein. In another embodiment, provided is a method of degrading CK1α and GSPT1 in a subject by administering to the subject a compound or composition provided herein. It is known in the art that loss of CK1α activity results in stabilization of p53 and inhibition of cell cycle progression. See, e.g., Huart et al., J. Biol. Chem.2009, 284(47), 32384-32394. CK1α and MDM2 form a complex that regulates p53 and E2F-1 protein stability. The CK1α-MDM2 complex promotes degradation of p53, which in turn prevents expression of p53 targets, such as p21 (an inhibitor of cell cycle progression). GSPT1 degraders have shown efficacy in clinical trials against acute myeloid leukemia (AML). Degradation of CK1α (providing elevated p53), along with GSPT1 degradation leads to an improved therapeutic window and safety profile. [0354] It is also known in the art that GSPT1 is implicated in a variety of cancers, including AML, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, stomach cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testis cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, hepatocellular carcinoma and gastric cancer. See, e.g., WO 2022/066835, WO 2022/029138, WO 2021/069705, WO 2018/169777, WO 2019/173224, WO 2019/241271, WO 2021/086830, WO 2022/007659, WO 2022/066835 and WO 2022/073469. [0355] Thus, in another embodiment, provided is a method of treating AML in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating a solid tumor in a subject by administering to the subject a compound or composition provided herein. In another embodiment, the solid tumor is breast cancer. In another embodiment, provided is a method of treating glioma in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating thyroid cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating lung cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a 86 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT method of treating colorectal cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating head and neck cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating stomach cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating liver cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating pancreatic cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating renal cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating urothelial cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating prostate cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating testis cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating cervical cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating endometrial cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating ovarian cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating melanoma in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating multiple myeloma in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating hepatocellular carcinoma in a subject by administering to the subject a compound or composition provided herein. In another embodiment, provided is a method of treating gastric cancer in a subject by administering to the subject a compound or composition provided herein. [0356] As discussed above, CK1α is required for activation of Card11/BCL10/MALT1 (CBM) complex. It is known in the art that inhibition of MALT1 ameliorates autoimmune pathogenesis. See, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320. Degradation of CK1α leads to inhibition of CBM activation and MALT1 signaling. 87 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0357] Thus, in another embodiment, provided is a method of treating a subject having an autoimmune disorder by administering to the subject a compound or composition provided herein. In one embodiment, the autoimmune disorder is Addison disease, Celiac disease - sprue (gluten-sensitive enteropathy), dermatomyositis, Graves’ disease, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus or type I diabetes. [0358] It is known in the art that CK1α plays a role in promoting RAS-driven cancers, for example by destabilizing forkhead box O (FOXO) 3A/4 tumor suppressors, regulating oncogenic RAS-induced autophagy and phosphorylating Fas-associated death domain (FADD). See, e.g., Zhang et al. Oncogene, 2018, 37, 363-376; Cheong et al. J. Clin. Invest. 2015, 125(4), 1401-1418; Bowman et al. Sci. Signal.2016, 8(361), ra9; Cheong et al. Mol. Cell. Onc.2016, 3(3), e1045117. Thus, in one embodiment, provided herein is a method of treating a RAS-driven cancer in a subject by administering to the subject a compound or composition provided herein. In another embodiment, the RAS-driven cancer is a RAS- mutant cancer. In another embodiment, the RAS-driven cancer is a KRASG12D-driven cancer. In another embodiment, the RAS-driven cancer is lung cancer, head and neck cancer, pancreatic cancer, breast cancer, colorectal cancer, gastrointestinal cancer, melanoma, myeloid cancer, bladder cancer, cervical cancer, ovarian cancer or uterine cancer. [0359] It is known in the art that inhibition of CK1α prevents acquired resistance to erlotinib in EGFR-mutant non-small cell lung cancer. See, e.g., Lantermann et al. Cancer Res.2015, 75(22), 4937-4948. Thus, in one embodiment, provided herein is a method of preventing acquired resistance to erlotinib in EGFR-mutant non-small cell lung cancer in a subject by administering to the subject a compound or composition provided herein. VII. COMBINATION THERAPY WITH A SECOND ACTIVE AGENT [0360] The compound provided herein, or a derivative thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of proliferative diseases, including cancer and autoimmune disorders. [0361] In one embodiment, provided herein is a method of treating, preventing, or managing a proliferative disease, comprising administering to a subject a compound provided herein, or a derivative thereof; in combination with one or more second active agents. [0362] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy 88 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (e.g., a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound provided herein, or a derivative thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein. [0363] Administration of the compound provided herein, or a derivative thereof and one or more second active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder being treated. [0364] The route of administration of the compound provided herein, or a derivative thereof, is independent of the route of administration of a second therapy. In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. Thus, in accordance with these embodiments, the compound provided herein, or a derivative thereof, is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the compound provided herein, or a derivative thereof, and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the compound provided herein, or a derivative thereof, is administered by one mode of administration, e.g., by IV, whereas the second agent is administered by another mode of administration, e.g., orally. [0365] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the 89 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT type of disease being treated or managed, the severity and stage of disease, and the amount of the compound provided herein, or a derivative thereof, and any optional additional active agents concurrently administered to the subject. [0366] One or more second active ingredients or agents can be used together with the compound provided herein, or a derivative thereof, in the methods and compositions provided herein. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). [0367] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly, therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins. [0368] It is known in the art that targeting the CBM complex causes regulatory T-cells to prime tumors for immune checkpoint therapy. It is also known that MALT1 activity is key for regulatory T-cell immunosuppression. Thus, in one embodiment, the second active agent is a checkpoint inhibitor, such as an anti-CTLA-4, an anti-PD-1 or anti-PD-L1 antibody. In another embodiment, the second active agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tramelimumab, or a combination thereof. In these embodiments, the proliferative disease to be treated is cancer, including melanoma including unresectable or metastatic melanoma, BRAF 600 mutation positive, and melanoma with lymph node involvement; non-small cell lung cancer including metastatic non-small cell lung cancer; renal cell carcinoma; Hodgkin lymphoma including relapsed/refractory Hodgkin lymphoma; squamous cell carcinoma of the head and neck including metastatic disease; urothelial carcinoma including metastatic disease; colorectal cancer including metastatic disease; or hepatocellular carcinoma. [0369] In one embodiment, the compound provided herein, or a derivative thereof, can be administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent, prior to, during, or after the use of conventional therapy. VIII. EXAMPLES [0370] The examples below are meant to illustrate certain embodiments provided herein, and not to limit the scope of this disclosure. 90 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 1-7 [0371] The compound of Examples 1-7 were prepared according to the following synthetic [0372] Experimental Procedure [0373] Step 1: Under N2, to a solution of 0014_A001 (47.6 mg, 0.10 mmol, 1.00 eq.) in Dioxane (1.00 mL) and K3PO4 (100 µL, 0.80 mmol, 2 M in H2O, 2.00 eq.) was added 0014_Bi (0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL) and extracted with EA (2.00 mL x 3), dried over Na2SO4, filtered and concentrated to give 0014_A001Bi_1 used for next step. [0374] Step 2: To a solution of 0014_A001Bi_1 (0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (0.80 mmol, 8.00 eq.). Then the mixture was stirred at 80 ℃ for 2 hrs. Spot checked by LCMS. The reaction mixture was filtered and purified by prep-HPLC to give desired product. 91 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 92 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 8-31 [0375] The compounds of Example 8-31 were prepared according to the following synthetic scheme: 93 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0376] Experimental Procedure [0377] Step 1: [0378] Condition 1: To a vial containing a solution of 0015_A001 (66.6 mg, 0.15 mmol, 1.00 eq) and 0015_Bi (0.15 mmol, 1.00 eq) in Dioxane (1.20 mL) was added K3PO4 (450 umol, 3.00 eq, 1.50 M in H2O), Pd-118 (0.015 µmol, 0.10 eq) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. Spot checked by LCMS. The reaction mixture was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediates used for next step. [0379] Condition 2: To a vial containing a solution of 0015_A001 (66.6 mg, 0.15 mmol, 1.00 eq) and 0015_Bi (0.15 mmol, 1.00 eq) in Dioxane (1.20 mL) was added K3PO4 (450 µmol, 3.00 eq, 1.50 M in H2O), Pd-118 (0.015 µmol, 0.10 eq) under protection of N2. The mixture was stirred at 120 °C for 2 hrs under microwave condition. Spot checked by LCMS. The reaction mixture was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediates used for next step. [0380] Condition 3: To a vial containing a solution of 0015_A001 (66.6 mg, 0.15 mmol, 1.00 eq) and 0015_Bi (0.15 mmol, 1.00 eq) in Dioxane (1.20 mL) was added K3PO4 (450 µmol, 3.00 eq, 1.50 M in H2O), CataCXiumA Pd G4 (0.015 µmol, 0.10 eq) under protection of N2. The mixture was stirred at 120 °C for 2 hrs under microwave condition. Spot checked by LCMS. The reaction mixture was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediates used for next step. [0381] Condition 4: To a vial containing a solution of 0015_A001 (66.6 mg, 0.15 mmol, 1.00 eq) and 0015_Bi (0.15 mmol, 1.00 eq) in DMA (1.20 mL) was added K3PO4 (450 µmol, 3.00 eq, 1.50 M in H2O), CataCXiumA Pd G4 (0.015 µmol, 0.10 eq) under protection of N2. The mixture was stirred at 120 °C for 2 hrs under microwave condition. Spot checked by LCMS. The reaction mixture was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediates used for next step. 94 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Step 2: To a vial containing a solution of 0015_A001Bi_1 (~0.15 mmol, 1.00 eq) in CH3CN (1.00 mL) was added TsOH.H2O (1.20 mmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. Spot checked by LCMS. The residue was concentrated under reduced pressure and purified by prep-HPLC to give final product. 95 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 96 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 97 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 98 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 32 [0382] Synthesis of 3-(5-(2-(cyclopropylmethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione [0383] A. 2-Cyclopropyl-N-(2,2-dimethoxyethyl)-N-methylacetimidamide: A mixture of 2-cyclopropylacetonitrile (10.0 g, 123 mmol, 1.00 eq), 2,2-dimethoxy-N-methylethan-1- amine (11.7 g, 98.6 mmol, 0.80 eq) and CuCl (15.2 g, 154 mmol, 1.25 eq) was stirred at 85 °C for 12 h to give the title compound (20.0 g, crude) as brown oil. (ESI+) m/z: 201.2 (M+H)+, (C10H20N2O2). [0384] B. 2-(Cyclopropylmethyl)-1-methyl-1H-imidazole: To mixture of 2- cyclopropyl-N-(2,2-dimethoxyethyl)-N-methylacetimidamide (20.0 g, 99.8 mmol, 1.00 eq) in MeOH (40.0 mL) was added HCl (12 M, 20.0 mL, 2.40 eq). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated in vacuum to give residue. To the reaction mixture was added 50% aq NaOH (10.0 g) at 0 °C, then added DCM (30.0 mL) and stirred at 20 °C for 5 min. The reaction mixture was filtered to give a solid, which was washed with dichloromethane: methanol = 10: 1 (2 x 15.0 mL) and dried in vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 90: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give the title compound (3.00 g, 22.0 mmol, 22.0% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.80 (s, 1H), 3.59 (s, 3H), 2.64 - 2.62 (m, 2H), 1.14 - 1.09 (m, 1H), 0.58 - 0.55 (m, 2H), 0.25 - 0.21 (m, 2H). (ESI+) m/z: 137.2 (M+H)+, (C8H12N2). [0385] C. 2-(Cyclopropylmethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2- (cyclopropylmethyl)-1-methyl-1H-imidazole (1.00 g, 7.34 mmol, 1.00 eq) and bromobenzene (3.46 g, 22.0 mmol, 3.00 eq) in DMF (20.0 mL) was added Pd(OAc)2 (164 mg, 734 μmol, 0.10 eq), P(oxole)3 (340 mg, 1.47 mmol, 0.20 eq) and K2CO3 (2.03 g, 14.6 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 80: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give the title compound (0.45 g, 2.12 mmol, 28.8% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.45 - 7.42 (m, 2H), 7.38 - 99 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.36 (m, 3H), 7.01 (s, 1H), 3.56 (s, 3H), 2.72 - 2.70 (m, 2H), 1.21 - 1.18 (m, 1H), 0.65 - 0.60 (m, 2H), 0.31 - 0.28 (m, 2H). (ESI+) m/z: 213.2 (M+H)+, (C14H16N2). [0386] D. 4-Bromo-2-(cyclopropylmethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-(cyclopropylmethyl)-1-methyl-5-phenyl-imidazole (0.45 g, 2.12 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (377 mg, 2.12 mmol, 1.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (5.00 mL), extracted with EtOAc (3 x 5.00 mL), dried over Na2SO4 and concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 20: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.50) to give the title compound (150 mg, 466 μmol, 75.4% yield) as colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 7.50 - 7.48 (m, 2H), 7.45 - 7.41 (m, 3H), 3.95 - 3.90 (m, 2H), 3.48 (s, 3H), 3.46 - 3.42 (m, 2H), 3.33 - 3.07 (m, 1H), 1.78 - 1.69 (m, 4H). (ESI+) m/z: 321.0 (M+H)+, (C15H17BrN2O). [0387] E. 3-(5-(2-(Cyclopropylmethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(cyclopropylmethyl)- 1-methyl-5-phenyl-imidazole (0.20 g, 686 μmol, 1.00 eq), 3-[1-oxo-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (508 mg, 1.37 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (57.4 mg, 68.6 μmol, 0.10 eq), K3PO4 (291 mg, 1.37 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 30: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.20) and preparative-HPLC (using a Welch Xtimate C18 (150 mm x 25 mm x 5 μm) and gradiente of 10-40% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (118 mg, 258 μmol, 37.6% yield, 99.2% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 - 7.69 (m, 1H), 7.58 - 7.54 (m, 4H), 7.49 - 7.46 (m, 2H), 7.45 - 7.42 (m, 1H), 5.12 - 5.07 (m, 1H), 4.43 - 4.25 (m, 2H), 3.57 (s, 3H), 3.10 - 3.01 (m, 2H), 2.97 - 2.80 (m, 1H), 2.61 - 2.56 (m, 1H), 2.39 - 2.35 (m, 1H), 2.03 - 1.99 (m, 1H), 1.26 - 1.24 (m, 1H), 0.63 - 0.59 (m, 2H), 0.43 - 0.41 (m, 2H). (ESI+) m/z: 455.2 (M+H)+, (C27H26N4O3). 100 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 33 [0388] Synthesis of 3-(5-(2-((3,3-difluorocyclobutyl)methyl)-1-methyl-5-phenyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [0389] A. (3,3-Difluorocyclobutyl)methyl 4-methylbenzenesulfonate: To a solution of (3,3-difluorocyclobutyl)methanol (10 g, 81.8 mmol, 1.00 eq) and pyridine (19.4 g, 245 mmol, 19.8 mL, 3.00 eq) in Dichloromethane (150 mL) was added TsCl (17.1 g, 90.0 mmol, 1.10 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was diluted with 150 mL of Dichloromethane and washed with water (3 x 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the title compound (20.0 g, 72.3 mmol, 88.3% yield) as brown oil, which was used in the next step directly without further purification.1H NMR: (400 MHz, DMSO-d6) δ 7.80 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.09 (d, J = 6.8 Hz, 2H), 2.66 - 2.54 (m, 2H), 2.47 - 2.44 (m, 1H), 2.42 (s, 3H), 2.36 - 2.23 (m, 2H). (ESI+) m/z: 277.0 (M+H)+, (C12H14F2O3S). [0390] B. 2-(3,3-Difluorocyclobutyl)acetonitrile: To a solution of (3,3- difluorocyclobutyl)methyl 4-methylbenzenesulfonate (20.0 g, 72.3 mmol, 1.00 eq) in DMSO (100 mL) was added NaCN (8.97 g, 183 mmol, 2.53 eq). The mixture was stirred at 85 °C for 3 h. After the reaction was completed, the mixture was cooled to 25 °C carefully poured into 300 mL crushed ice. The mixture was stirred for 30 mins and extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with brine (3 x 100ml), dried over Na2SO4 and concentrated in vacuum to give the title compound (8.50 g, crude) as brown oil, which was used in the next step directly without further purification.1H NMR: (400 MHz, CDCl3) δ 2.87 - 2.80 (m, 2H), 2.60 - 2.57 (m, 2H), 2.56 - 2.44 (m, 1H), 2.45 - 2.36 (m, 2H). (ESI+) m/z: 132.0 (M+H)+, (C6H7F2N). [0391] C. 2-(3,3-Difluorocyclobutyl)-N-(2,2-dimethoxyethyl)-N-methylacetimidamide: A mixture of 2-(3,3-difluorocyclobutyl)acetonitrile (6.88 g, 52.4 mmol, 1.25 eq), 2,2- dimethoxy-N-methyl-ethanamine (5.00 g, 41.9 mmol, 5.39 mL, 1.00 eq), CuCl (5.19 g, 52.4 mmol, 1.25 mL, 1.25 eq) was stirred at 85 °C for 12 h under N2 atmosphere. Then the reaction mixture was concentrated in vacuum to give the title compound (10.0 g, crude) as 101 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT brown oil, which was used in the next step directly without further purification. (ESI+) m/z: 251.0 (M+H)+, (C11H20N2O2F2). [0392] D. 2-((3,3-Difluorocyclobutyl)methyl)-1-methyl-1H-imidazole: To a solution of 2-(3,3-difluorocyclobutyl)-N-(2,2-dimethoxyethyl)-N-methyl-acetamidine (10.0 g, 39.95 mmol, 1.00 eq) in MeOH (50.0 mL) was added HCl (12 M, 10.0 mL, 3.00 eq). The mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated in vacuum to remove the solvent and the residue was diluted with 50.0 mL of water. Then the mixture was basified with 20.0 mL of saturated NaHCO3 solution to pH = 10 keeping the temperature below 20 °C.50.0 mL of EtOAc was added, and the mixture was stirred for 5 mins and filtered. The solid was washed with EtOAc (2 x 50.0 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1, Rf = 0.45 (Dichloromethane: Methanol = 5: 1)) to give the title compound (2.00 g, 10.4 mmol, 26.2% yield for two steps, 97.6% purity in LCMS at 220 nm) as brown oil. (ESI+) m/z: 187.1 (M+H)+, (C9H12N2F2). [0393] E. 2-((3,3-Difluorocyclobutyl)methyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-[(3,3-difluorocyclobutyl)methyl]-1-methyl-imidazole (1.00 g, 5.24 mmol, 1.00 eq) and bromobenzene (2.47 g, 15.7 mmol, 1.66 mL, 3.00 eq) in DMF (20.0 mL) was added Pd(OAc)2 (117 mg, 524 μmol, 0.10 eq), P(oxole)3 (243 mg, 1.05 mmol, 0.20 eq) and K2CO3 (1.45 g, 10.4 mmol, 2.00 eq). The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.40 (Dichloromethane: Methanol = 10: 1)) to give the title compound (600 mg, 1.80 mmol, 34.3% yield, 78.8% purity in LCMS at 220 nm) as yellow oil. (ESI+) m/z: 263.0 (M+H)+, (C15H16N2F2). [0394] F. 4-Bromo-2-((3,3-difluorocyclobutyl)methyl)-1-methyl-5-phenyl-1H- imidazole: To a solution of 2-[(3,3-difluorocyclobutyl)methyl]-1-methyl-5-phenyl- imidazole (600 mg, 1.80 mmol, 1.00 eq) in ACN (6.00 mL) was added NBS (336 mg, 1.89 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with 10.0 mL of H2O and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.40 (Petroleum ether: Ethyl acetate = 5: 1)) to give the title compound (350 mg, 932 μmol, 51.7% yield, 90.9% purity in 102 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT LCMS at 220 nm) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.53 - 7.47 (m, 2H), 7.46 - 7.39 (m, 3H), 3.44 (s, 3H), 2.91 (d, J = 7.2 Hz, 2H), 2.81 - 2.69 (m, 2H), 2.63 - 2.56 (m, 1H), 2.45 - 2.31 (m, 2H). (ESI+) m/z: 341.0 (M+H)+, (C15H15N2BrF2). [0395] G. 3-(5-(2-((3,3-Difluorocyclobutyl)methyl)-1-methyl-5-phenyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-[(3,3- difluorocyclobutyl)methyl]-1-methyl-5-phenyl-imidazole (350 mg, 932 μmol, 1.00 eq) and 3- [1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (863 mg, 2.33 mmol, 2.50 eq) in dioxane (7.00 mL) and H2O (0.35 mL) was added K3PO4 (593 mg, 2.80 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (155 mg, 186 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: EtOAc = 100: 1 to 1: 1, Rf = 0.50 (Dichloromethane: EtOAc = 0: 1)) and then by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 20 mm 10 μm) and gradient of 10 - 40% acetonitrile in water containing 0.5% FA over 15 min at a flow rate of 25.0 mL/min to give the title compound (227 mg, 450 μmol, 48.3% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.58 (s, 1H), 7.56 - 7.47 (m, 4H), 7.44 - 7.35 (m, 3H), 5.06 (dd, J = 13.2, 4.8 Hz, 1H), 4.27 (dd, J = 60.4, 17.2 Hz, 2H), 3.35 (s, 3H), 2.98 (d, J = 7.2 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.83 - 2.66 (m, 3H), 2.62 - 2.54 (m, 1H), 2.47 - 2.28 (m, 3H), 2.01 - 1.92 (m, 1H). (ESI+) m/z: 505.2 (M+H)+, (C28H26N4O3F2). EXAMPLE 34 [0396] Synthesis of 3-(5-(2-cyclopropyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0397] A. 2-Cyclopropyl-1-phenyl-1H-imidazole: To a solution of 2-cyclopropyl-1H- imidazole (5.00 g, 46.2 mmol, 1.00 eq) in MeOH (150 mL) was added phenylboronic acid (4.79 g, 39.3 mmol, 0.85 eq) and Cu2O (331 mg, 2.31 mmol, 236 μL, 0.05 eq) under O2. The mixture was stirred at 25 °C for 24 h under O2. The mixture was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, 103 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Dichloromethane/Methanol = 100/0 to 100/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.38) to give the title compound (1.50 g, 8.07 mmol, 17.5% yield, 99.1% purity in LCMS at 220 nm) as a light yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.78 (d, J = 1.2 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.39 – 7.31 (m, 3H), 6.99 (s, 1H), 2.30 – 2.93 (m, 1H), 1.32 (s, 2H), 1.31 (s, 2H). (ESI+) m/z: 185.1 (M+H)+, (C12H12N2) [0398] B. 5-Bromo-2-cyclopropyl-1-phenyl-1H-imidazole: To a solution of 2- cyclopropyl-1-phenyl-1H-imidazole (1.40 g, 7.53 mmol, 1.00 eq) in ACN (24.0 mL) was added NBS (1.41 g, 7.91 mmol, 1.05 eq) at 0°C under N2. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.38) to give the title compound (1.50 g, 8.07 mmol, 17.5% yield, 99.1% purity in LCMS at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.61 – 7.56 (m, 3H), 7.43 – 7.41 (m, 2H), 6.96 (s, 1H), 1.58 – 1.53 (m, 1H), 0.86 – 0.84 (m, 2H), 0.79 – 0.77 (m, 2H). (ESI+) m/z: 264.8 (M+H)+, (C12H11BrN2) [0399] C. 4,5-Dibromo-2-cyclopropyl-1-phenyl-1H-imidazole: To a solution of 5- bromo-2-cyclopropyl-1-phenyl-1H-imidazole (1.20 g, 4.56 mmol, 1.00 eq) in DMF (12.0 mL) was added NBS (2.5 M, 2.19 mL, 1.20 eq) at 0 °C. Then the mixture was stirred at 25°C for 1.5 h. The mixture was diluted with ethyl acetate (40.0 mL) and washed with 5% K2CO3 aqueous (40.0 mL), 10% Na2S2O3 aqueous (40.0 mL) The combined organic layer was washed with saturated NaCl aqueous (2 x 40.0 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1.10 g, crude) as a light brown solid. (ESI+) m/z: 342.8 (M+H)+, (C12H10Br2N2). [0400] D. 4-Bromo-2-cyclopropyl-1-phenyl-1H-imidazole: To a solution of 4,5- dibromo-2-cyclopropyl-1-phenyl-1H-imidazole (1.50 g, 4.39 mmol, 1.00 eq) in THF (30.0 mL) was added n-BuLi (2.5 M, 2.11 mL, 1.20 eq) dropwise under N2 at -70 °C. The mixture was stirred at -70 °C for 1 h under N2. The mixture was poured into NH4Cl aqueous (30.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layer was washed with saturated NaCl aqueous (2 x 30.0 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/0 to 100/20, TLC: Petroleum ether/Ethyl acetate = 5/1, Rf = 0.37) to give the title compound (450 mg, 1.63 mmol, 37.2% yield, 95.5% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CD3CN) δ 7.54 - 7.52 (m, 2H), 7.49 - 7.46 (m, 3H), 7.11 (s, 1H), 1.77 - 1.71 (m, 1H), 0.94 - 0.92 (m, 2H), 0.88 - 0.86 (m, 2H). (ESI+) m/z: 264.7 (M+H)+, (C12H11BrN2). 104 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0401] E. 3-(5-(2-Cyclopropyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-cyclopropyl-1-phenyl-1H-imidazole (200 mg, 726 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (537 mg, 1.45 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (308 mg, 1.45 mmol, 2.00 eq) and RuPhos-Pd-G3 (60.7 mg, 72.6 μmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 2.5 h. The mixture was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/3, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.36) to give a residue. The residue was purified by preparative-HPLC using a Welch ultimate C18 (150 mm x 25 mm x 5μm) and gradient of 10- 40% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (72.4 mg, 169 μmol, 23.3% yield, 99.7% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.00 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 - 7.64 (m, 4H), 7.58 - 7.57 (m, 1H), 5.13 (dd, J = 5.2 Hz, J = 13.2 Hz, 1H), 4.53 - 4.49 (m, 1H), 4.40 - 4.36 (m, 1H), 2.94 - 2.92 (m, 1H), 2.63 - 2.60 (m, 1H), 2.45 - 2.41 (m, 1H), 2.04 - 2.01 (m, 1H), 1.94 - 1.92 (m, 1H), 1.12 - 1.02 (m, 2H), 1.01 - 1.00 (m, 2H). (ESI+) m/z: 427.2 (M+H)+, (C25H22N4O3). EXAMPLE 35 [0402] Synthesis of 3-(5-(4-isobutyl-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0403] A. 1-Bromo-4-methyl-pentan-2-one: To a solution of 4-methylpentan-2-one (10.0 g, 99.8 mmol, 12.5 mL, 1.00 eq) in MeOH (60.0 mL) was added Br2 (15.9g, 99.8 mmol, 5.14 mL, 1.00 eq) slowly at -5 ℃. The mixture was stirred at -5 ℃ for 2 h. The mixture was poured into water (100 mL) and stirred at 25 °C for 12 h. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 80.0 mL) to collected organic layers. The organic layers was washed with water (100 mL) and saturated NaHCO3 solution (100 mL). The organic layers was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column 105 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 20/1, TLC:Petroleum ether/Ethyl acetate = 20/1, Rf = 0.39) to give the title compound (6.50 g, 36.3 mmol, 36.3% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 3.86 (s, 2H), 2.54 (d, J = 7.6 Hz, 2H), 2.21 - 2.15(m, 1H), 0.95 (d, J = 7.6 Hz, 6H). [0404] B. N,N,N-Triethyl-4-methyl-2-oxopentan-1-aminium bromide. To a solution of 1-bromo-4-methyl-pentan-2-one (6.00 g, 33.5 mmol, 1.00 eq) in EtOH (10.0 mL) was added TEA (4.36 g, 43.1 mmol, 6.00 mL, 1.29 eq) at 20 °C under N2. The mixture was stirred at 20 °C for 24 h. The mixture was concentrate under reduced pressure to get a residue. The crude product was triturated with ethyl acetate (20.0 mL) at 25 ℃ for 0.5 h to give the title compound (3.00 g, 14.9 mmol, 44.6% yield) as a white solid.1H NMR: (400 MHz, D2O) δ 4.34 (s, 2H), 3.55 - 3.49 (m, 6H),2.45(d, J = 6.8 Hz, 2H), 2.13 - 2.03(m, 1H),1.23 (t, J = 7.2 Hz, 9H), 0.89 (d, J = 7.6 Hz, 6H). [0405] C. 4-Isobutyl-1H-imidazole: A solution of triethyl-(4-methyl-2-oxo- pentyl)ammonium (3.00 g, 14.97 mmol, 1 eq) in formamide (12.0 mL) was stirred at 200 °C for 6 h. The mixture was poured into water (50.0 mL) and adjust to pH = 5 with 1N HCl. The mixture was extracted with ethyl acetate (2 x 20.0 mL) to collect the aqueous phase. The aqueous phase was adjust to pH = 8 with K2CO3. The mixture was extracted with ethyl acetate (20.0 mL x 2) to collect the organic layers. The combined organic layers was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC:Dichloromethane/Methanol = 10/1, Rf = 0.27) to give the title compound (900 mg, 6.72 mmol, 44.8% yield, 92.7% purity in LCMS) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.48 (s, 1H), 6.71 (s, 1H), 2.41(d, J= 6.8 Hz, 2H), 1.86 - 1.83(m, 1H), 0.86 (d, J = 6.4 Hz, 6H) (ESI+) m/z: 125.2 (M+H)+ (C7H12N2). [0406] D. 4-Isobutyl-1-phenyl-1H-imidazole: A stirred mixture of Pd2(dba)3 (43.7 mg, 47.7 μmol, 0.01 eq) and ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6- triisopropylphenyl)phenyl]phosphane (45.9 mg, 95.5 μmol, 0.02 eq) at 25 °C under N2. Then TOLUENE (3.75 mL) and dioxane (0.75 mL) was added to the mixture, the mixture was stirred at 120 °C for 10 min.2. A mixture was of 4-isobutyl-1H-imidazole (767 mg, 5.73 mmol, 1.2 eq) and K3PO4 (2.03 g, 9.55 mmol, 2.00 eq) was stirred at 25 °C under N2, then bromobenzene (750 mg, 4.78 mmol, 503 μL, 1.00 eq) was added to the mixture at 25 °C. Then the 2 was added to the 1 and stirred at 120 °C for 12 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL x 2) to collect the organic layers. The combined organic layers was dried over Na2SO4, filtered and the filtrate was 106 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT concentrated under reduced pressure to give a residue. The residue purified by column chromatography (SiO2, Dichloromethane/Methanol = 1/0 to 50/1, TLC:Dichloromethane/Methanol = 30/1, Rf = 0.39) to give the title compound (550 mg, 2.73 mmol, 57.2% yield, 99.% purity in LCMS) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.46 - 7.35 (m, 5H), 7.01 (s, 1H), 2.50(d, J= 7.2 Hz, 2H), 2.05 - 1.99(m, 1H), 0.97 (d, J = 6.8 Hz, 6H) (ESI+) m/z: 201.2 (M+H)+ (C13H16N2). [0407] E. 2-Bromo-4-isobutyl-1-phenyl-1H-imidazole: To a solution of 4-isobutyl-1- phenyl-imidazole (550 mg, 2.73 mmol, 1.00 eq) in THF (6 mL) was added dropwise n-BuLi (2.5 M, 1.26 mL, 1.15 eq) at -78 °C under N2. The reaction mixture was stirred for additional 0.5 h, then 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (745 mg, 2.87 mmol, 1.05 eq) was added dropwise at -78 °C. Then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 50.0 mL of saturated NH4Cl solution at 0 °C under N2. Then the mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 8/1, Rf = 0.47) to give the title compound (200 mg, 713 μmol, 26.1% yield, 99.6% purity in LCMS) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.49 - 7.45 (m, 3H), 7.38 - 7.36 (m, 2H), 6.88 (s, 1H), 2.45(d, J= 7.2 Hz, 2H), 2.04 - 1.97(m, 1H), 0.97 (d, J = 6.8 Hz, 6H) (ESI+) m/z: 280.8 (M+H)+ (C13H15BrN2). [0408] F. 3-(5-(4-Isobutyl-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 2-bromo-4-isobutyl-1-phenyl-imidazole (100 mg, 356 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine- 2,6-dione (264 mg, 713 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.100 mL) was added K3PO4 (151 mg, 713 μmol, 2.00 eq) and RuPhos Pd G3 (29.8 mg, 35.6 μmol, 0.100 eq) at 25 °C under N2. The mixture was stirred for 2 h at 100 °C under N2. The mixture was diluted with DCM (10.0 mL), filtered and the filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by Preparative-HPLC (using a Welch Ultimate C18 (150 mm x 25 mm x 5 μm) and gradiente of 14 - 44% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min) to afforrd the title compound (85.0 mg, 191.5 μmol, 53.6% yield, 99.7% purity in HPLC) as a white solid.1H NMR: (400 MHz, DMSO)δ 10.9 (s, 1H), 7.91 - 7.69 (m, 3H), 7.54 - 7.48 (m, 6H), 5.13 - 5.08 (m, 1H), 4.46 - 4.28 (m, 2H), 2.93 - 2.90 (m, 1H), 2.60 - 2.57 (m, 3H), 2.40 - 2.37 (m, 1H), 2.05 - 2.00 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H) (ESI+) m/z: 443.3 (M+H)+ (C26H26N4O3). 107 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 36 [0409] Synthesis of 3-(5-(2-(cyclobutylmethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0410] A. 2-Cyclobutylacetonitrile: To a solution of NaCN (5.11 g, 104 mmol, 1.55 eq) in DMSO (100 mL) was added bromomethylcyclobutane (10.0 g, 67.1 mmol, 7.54 mL, 1.00 eq) dropwise at 60 °C. The mixture was stirred at 75°C for 12 h. After the reaction was completed, the mixture was cooled to 25 °C and carefully poured into 300 mL crushed ice. The mixture was stirred for 0.5 h and then extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 ml), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give the title compound (10.0 g, crude) as white oil.1H NMR: (400 MHz, CDCl3) δ 2.64 - 2.56 (m, 1H), 2.38 (d, J = 6.4 Hz, 2H), 2.17 - 2.11 (m, 2H), 1.88 - 1.79 (m, 4H). (ESI+) m/z: 96.0 (M+H)+, (C6H9N). [0411] B. 2-Cyclobutyl-N-(2,2-dimethoxyethyl)-N-methylacetimidamide: To a mixture of 2-cyclobutylacetonitrile (4.50 g, 47.3 mmol, 1.25 eq) and 2,2-dimethoxy-N-methyl- ethanamine (4.51 g, 37.8 mmol, 4.86 mL, 1.00 eq) was added CuCl (4.68 g, 47.3 mmol, 1.25 eq) under N2. The mixture was stirred at 85 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (9.00 g, crude) as yellow oil. (ESI+) m/z: 215.1 (M+H)+, (C11H22N2O2). [0412] C. 2-(Cyclobutylmethyl)-1-methyl-1H-imidazole: To a solution of 2-cyclobutyl- N-(2,2-dimethoxyethyl)-N-methyl-acetamidine (9.00 g, 42.0 mmol, 1.00 eq) in MeOH (50.0 mL) was added HCl (12 M, 9.00 mL, 2.57 eq) under N2. The mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the mixture was adjusted to pH = 9 with Na2CO3 aqueous solution (20.0 mL). Then the mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give the title compound (1.00 g, 6.51 mmol, 15.5% yield, 97.8% purity in HPLC at 220 nm) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 6.90 (s, 1H), 6.76 (s, 1H), 3.55 (s, 3H), 2.75 (d, 108 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT J = 2.8 Hz, 3H), 2.68 - 2.60 (m, 2H), 2.41 (d, J = 6.4 Hz, 4H). (ESI+) m/z: 151.2 (M+H)+, (C9H14N2). [0413] D. Preparation of 2-(Cyclobutylmethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-(cyclobutylmethyl)-1-methyl-imidazole (1.00 g, 6.66 mmol, 1.00 eq) in DMF (20.0 mL) was added bromobenzene (3.14 g, 19.9 mmol, 2.10 mL, 3.00 eq), K2CO3 (1.84 g, 13.3 mmol, 2.00 eq), Pd(OAc)2 (149 mg, 665 μmol, 0.10 eq) and P(oxole)3 (309 mg, 1.33 mmol, 0.20 eq) under N2. The mixture was stirred at 100 °C for 12 h under N2. After the reaction was completed, the reaction mixture was poured into saturated NaCl aqueous solution (50.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.40 (Dichloromethane: Methanol = 10: 1)) to give the title compound (400 mg, 1.29 mmol, 19.3% yield, 72.9% purity in HPLC at 220 nm) as yellow oil. (ESI+) m/z: 227.3 (M+H)+, (C15H18N2). [0414] E. 4-Bromo-2-(cyclobutylmethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-(cyclobutylmethyl)-1-methyl-5-phenyl-imidazole (400 mg, 1.29 mmol, 1.00 eq) in ACN (3.00 mL) was added NBS (252 mg, 1.42 mmol, 1.10 eq) at 0 °C under N2.The mixture was stirred at 25 °C for 3 h. After the reaction was completed, the reaction mixture was poured into saturated NaCl aqueous solution (10.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layer was washed with brine (10.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.60) to give the title compound (60.0 mg, 175 μmol, 13.6% yield, 89.4% purity in HPLC at 220 nm) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.48 - 7.44 (m, 2H), 7.42 - 7.36 (m, 3H), 3.44 (s, 3H), 2.85 - 2.80 (m, 3H), 2.19 - 2.16 (m, 2H), 1.91 - 1.87 (m, 2H), 1.81 - 1.79 (m, 2H). (ESI+) m/z: 305.0 (M+H)+, (C15H17BrN2). [0415] F. 3-(5-(2-(Cyclobutylmethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(cyclobutylmethyl)-1- methyl-5-phenyl-imidazole (60.0 mg, 175 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl]piperidine-2,6-dione (162 mg, 439 μmol, 2.50 eq) , Ru-Phos-Pd-G3 (29.4 mg, 35.1 μmol, 0.20 eq) and K3PO4 (111 mg, 527 μmol, 3.00 eq) under N2.The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the 109 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.40) and by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 5 μm) and gradient of 18 - 48% acetonitrile in water containing 0.5% FA over 13 min at a flow rate of 25.0 mL/min to give the title compound (36.0 mg, 75.5 μmol, 43.8% yield, 98.1% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.58 - 7.54 (m, 4H), 7.48 - 7.46 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 5.08 (dd, J = 13.2, 4.8 Hz, 1H), 4.34 (dd, J = 54.0, 17.2 Hz, 2H), 3.54 (s, 3H), 3.16 (d, J = 7.2 Hz, 2H), 2.89 - 2.81 (m, 2H), 2.61 - 2.60 (m, 1H), 2.40 - 2.36 (m, 1H), 2.14 - 2.10 (m, 2H), 2.03 - 1.95 (m, 1H), 1.93 - 1.83 (m, 4H). (ESI+) m/z: 469.2 (M+H)+, (C28H28N4O3). EXAMPLE 37 [0416] Synthesis of 3-(5-(2-methyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0417] A. 2-Methyl-1-phenyl-1H-imidazole: To a solution of 2-methyl-1H-imidazole (5.00 g, 60.9 mmol, 1.00 eq) in MeOH (150 mL) was added phenylboronic acid (6.31 g, 51.7 mmol, 0.85 eq) and Cu2O (435 mg, 3.04 mmol, 311 μL, 0.05 eq) under air. The mixture was stirred at 25 °C for 12 h under air. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.50 (Dichloromethane: Methanol = 10: 1)) to give the title compound (4.50 g, 28.3 mmol, 46.6% yield, 99.8% purity in HPLC at 220 nm) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.48 - 7.39 (m, 3H), 7.28 - 7.25 (m, 2H), 7.01 - 6.97 (m, 2H), 2.33(s, 3H). (ESI+) m/z: 159.0 (M+H)+, (C10H10N2). [0418] B. 4,5-Dibromo-2-methyl-1-phenyl-1H-imidazole: To a solution of 2-methyl-1- phenyl-imidazole (1.00 g, 6.32 mmol, 1.00 eq) in DMF (10.0 mL) was added NBS (2.81 g, 15.8 mmol, 2.50 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction mixture was poured into saturated Na2SO3 aqueous solution (30.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum 110 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate = 3: 1)) to give the title compound (900 mg, 2.85 mmol, 45.0% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.63 - 7.57 (m, 3H), 7.45 - 7.42 (m, 2H), 2.15 (s, 3H). (ESI+) m/z: 314.9 (M+H)+, (C10H8Br2N2). [0419] C. 4-Bromo-2-methyl-1-phenyl-1H-imidazole: To a solution of 4,5-dibromo-2- methyl-1-phenyl-imidazole (900 mg, 2.85 mmol, 1.00 eq) in THF (10.0 mL) was added n- BuLi (2.5 M, 1.71 mL, 1.50 eq) at -75 °C under N2. The mixture was stirred at -75 °C for 2 h under N2. After the reaction was completed, the reaction mixture was poured into saturated NH4Cl aqueous solution (30.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.30) to give the title compound (300 mg, 1.17 mmol, 41.1% yield, 92.6% purity in HPLC at 220 nm) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.42 - 7.34 (m, 3H), 7.25 - 7.23 (m, 2H), 7.00 (s, 1H), 2.11 (s, 3H). (ESI+) m/z: 236.9 (M+H)+, (C10H9BrN2). [0420] D. 3-(5-(2-Methyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 4-bromo-2-methyl-1-phenyl-imidazole (200 mg, 781 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (722 mg, 1.95 mmol, 2.50 eq), Ru-Phos-Pd-G3 (65.3 mg, 78.1 μmol, 0.10 eq) and K3PO4 (165 mg, 781 μmol, 1.00 eq) under N2.The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.30) and by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 5 μm) and gradient of 5 - 35% acetonitrile in water containing 0.5% FA over 10 min at a flow rate of 25.0 mL/min to give the title compound (34.0 mg, 83.6 μmol, 10.7% yield, 98.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.68 - 7.63 (m, 5H), 5.15 (dd, J = 13.6, 7.2 Hz, 1H), 4.49 (dd, J = 54.8, 17.6 Hz, 2H), 2.97 - 2.90 (m, 1H), 2.64 - 2.59 (m, 1H), 2.53 (s, 3H), 2.43 - 2.41 (m, 1H), 2.05 - 2.02 (m, 1H). (ESI+) m/z: 401.1 (M+H)+, (C23H20N4O3). 111 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 38 [0421] Synthesis of 3-(5-(2-isobutyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0422] A. 2-Isobutyl-1H-imidazole: A solution of ethyl 3-methylbutanimidate (10.0 g, 60.3 mmol, 1.00 eq, HCl) and 2,2-dimethoxyethanamine (6.35 g, 60.3 mmol, 6.58 mL, 1.00 eq) in MeOH (10.0 mL) was stirred at 25 °C for 20 h.Then HCl (12.0 M, 23.3 mL, 4.63 eq) was addded to the mixture at 25 °C, the mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure to get a residue at 60 °C. Then poured into H2O (20.0 mL) and adjust to pH = 10 with 50% NaOH (5.50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 20/1, TLC: DCM/MeOH = 10/1, Rf = 0.30) to give the compound (3.00 g, 23.6 mmol, 39.1% yield, 97.9% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 6.84 (s, 2H), 2.44 (d, J = 7.2 Hz, 2H), 2.01 - 1.91 (m, 1H),0.856 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 125.3 (M+H)+, (C7H12N2). [0423] B. 2-Isobutyl-1-phenyl-1H-imidazole: To a solution of 2-isobutyl-1H-imidazole (1.50 g, 12.0 mmol, 1.00 eq) and phenylboronic acid (1.25 g, 10.2 mmol, 0.85 eq) in MeOH (45.0 mL) was addded Cu2O (86.4 mg, 603 μmol, 61.7 μL, 0.05 eq) at 25 °C under O2.The mixture was stirred at 25 °C for 16 h.The mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 20/1, TLC: DCM/MeOH = 10/1, Rf = 0.30) to give the compound (900 mg, 3.45 mmol, 28.5% yield, 76.7% purity in LCMS at 220 nm) as a colourless oil.1H NMR: (400 MHz, DMSO-d6) δ 7.55 - 7.51 (m, 2H), 7.48 - 7.44 (m, 1H), 7.40 - 7.37 (m, 2H), 7.22 (d, J = 1.2 Hz, 1H), 1.92 - 1.87 (m, 1H), 2.47 (d, J = 7.2 Hz, 2H), 1.92 - 1.83 (m, 1H), 0.77 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 201.2 (M+H)+, (C13H16N2). [0424] C. 4,5-Dibromo-2-isobutyl-1-phenyl-1H-imidazole: To a solution of 2-isobutyl- 1-phenyl-imidazole (900 mg, 3.45 mmol, 1.00 eq) in DMF (9.00 mL) was addded NBS (1.53 112 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT g, 8.62 mmol, 2.50 eq) dropwise at 0°C. The mixture was stirred at 25 °C for 2 h. The mixture was poured into 5% K2CO3 (5.00 mL ), 10% Na2S2O3 ( 10.0 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 30.0 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 50/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to give the title compound (560 mg, 1.56 mmol, 45.3% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.60 - 7.58 (m, 3H), 7.42 - 7.40 (m, 2H), 2.33 (d, J = 7.2 Hz, 2H), 1.86 - 1.79 (m, 1H), 0.77 (d, J = 6.4 Hz, 6H). (ESI+) m/z: 358.8 (M+H)+, (C13H14N2Br2). [0425] D. 4-Bromo-2-isobutyl-1-phenyl-1H-imidazole: To a solution of 4,5-dibromo-2- isobutyl-1-phenyl-imidazole (560 mg, 1.56 mmol, 1.00 eq) in THF (12.0 mL) was addded n- BuLi (2.50 M, 938 μL, 1.50 eq) at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. The mixture was poured into NH4Cl (aq, 20.0 mL ) extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 30.0 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 50/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to give the title compound (220 mg, 762 μmol, 48.7% yield, 96.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, CD3CN) δ 7.54 - 7.48 (m, 3H), 7.36 - 7.33 (m, 2H), 7.11 (s, 1H), 2.46 (d, J = 7.2 Hz, 2H), 1.94 - 1.86 (m, 1H),0.80 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 280.0 (M+H)+ (C13H15N2Br). [0426] E. 3-(5-(2-Isobutyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-isobutyl-1-phenyl-imidazole (200 mg, 692 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (641 mg, 1.73 mmol, 2.50 eq) in dioxane (4.00 mL) and H2O (0.200 mL) was added RuPhos - Pd - G3 (57.9 mg, 69.2 μmol, 0.10 eq) and K3PO4 (294 mg, 1.39 mmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 2 h. The mixture was filtered and the filtrate was to concentrated under vacuum at 45 °C to get residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 100/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to get residue 1. The residue 1 was purified by preparative- HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 14% - 44% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (120 mg, 271 μmol, 39.1% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.07 (s, 1H), 7.64 (d, J = 8.0 Hz, 113 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 6H), 7.60 - 7.54 (m, 5H), 7.46 (s, 1H), 7.27 - 7.20 (m, 1H), 5.10 - 5.05 (m, 1H), 4.40 - 4.22 (m, 2H), 2.97 - 2.88 (m, 1H), 2.71 (d, J = 6.8 Hz, 2H), 2.64 - 2.59 (m, 1H), 2.45 - 2.41 (m, 1H), 2.04 - 1.98 (m, 1H), 1.97 - 1.90 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H). (ESI+) m/z: 443.2 (M+H)+, (C26H26N4O3). EXAMPLE 39 [0427] Synthesis of 3-(5-(2-(cyclopropylmethyl)-1-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (INNO-0001611, Example 39): [0428] A. 2-Cyclopropyl-N-(2,2-dimethoxyethyl)acetimidamide: To a mixture of 2,2- dimethoxyethanamine (5.00 g, 47.5 mmol, 5.18 mL, 1.00 eq) and CuCl (5.89 g, 59.4 mmol, 1.42 mL, 1.25 eq) was added 2-cyclopropylacetonitrile (4.82 g, 59.45 mmol, 5.49 mL, 1.25 eq). The reaction mixture was stirred at 85 °C for 12 h under N2. The mixture was diluted with MeOH (100 mL) and cooled to 0 °C. Ethanethioamide (4.47g) was added to the mixture at 10 °C and stirred for 1 h at 45 °C. Filtered and the filtrate was concentrated under reduced pressure to give the title compound (9.00 g, Crude) as a black brown oil. (ESI+) m/z: 186.1 (M+H)+ (C9H18N2O2). [0429] B. 2-(Cyclopropylmethyl)-1H-imidazole: To a solution of 2-cyclopropyl-N-(2,2- dimethoxyethyl)acetamidine (9.00 g, 48.3 mmol, 1.00 eq) in MeOH (45.0 mL) was added HCl (12.0 M, 9.00 mL, 2.24 eq). The mixture was stirred at 65 °C for 4 h. The mixture was concentrated under reduced pressure to get a residue. The residue was adjust to pH = 10 with NaOH solution (50.0%, 10.0 mL) and filtered. The filtrate was diluted with water (200 mL) and extracted with DCM (3 x 100mL) to collected organic layers. The combined organic layers was dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.31) to give the title compound (700 mg, 5.63 mmol, 11.6% yield, 98.2% purity) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 6.98 (s, 2H), 2.70 (d, J = 6.8 Hz, 2H), 1.10 - 1.08 (m, 1H), 0.64 - 0.59 (m, 2H), 0.28 - 0.25 (m, 2H). (ESI+) m/z: 123.1 (M+H)+ (C7H10N2). 114 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0430] C. 2-(Cyclopropylmethyl)-1-phenyl-1H-imidazole: To a solution of 2- (cyclopropylmethyl)-1H-imidazole (650 mg, 5.22 mmol, 1.00 eq) in MeOH (6.00 mL) was added phenylboronic acid (637 mg, 5.22 mmol, 1.00 eq) and Cu2O (37.3 mg, 261 μmol, 26.7 μL, 0.05 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h under O2. The mixture was poured into water (50.0 mL) and extracted with ethyl acetate (3 x 20.0 mL) to collect the organic layers. The organic layers was concentrated under reduced pressure to get a residue. The crude product was Purified by column chromatography (SiO2, Dichloromethane/Methanol = 1/0 to 50/1, TLC:Dichloromethane/Methanol = 20/1, Rf = 0.52) to give the title compound (298 mg, 1.46 mmol, 27.8% yield, 96.9% purity in LCMS at 220 nm) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ7.50 - 7.45 (m, 3H), 7.30 - 7.27 (m, 2H), 7.09 (s, 1H), 7.00 (s, 1H), 2.59 (d, J = 6.8 Hz, 2H), 1.05 - 1.02 (m, 1H), 0.49 - 0.44 (m, 2H), 0.09 - 0.05 (m, 2H).. (ESI+) m/z: 199.0 (M+H)+, (C13H14N2). [0431] D. 4,5-Dibromo-2-(cyclopropylmethyl)-1-phenyl-1H-imidazole: To a solution of 2-(cyclopropylmethyl)-1-phenyl-imidazole (298 mg, 1.46 mmol, 1.00 eq) in DMF (3.00 mL) was added NBS (648 mg, 3.64 mmol, 2.50 eq) at 0 °C, then the mixture was stirred at 25 °C for 1.5 h. The mixture was diluted with ethyl acetate (10.0 mL) and washed with 5% K2CO3 (aq, 10.0 mL), 10% Na2S2O3 (aq, 20.0 mL). The combined organic layer was washed with saturated NaCl aqueous (2 x 30.0 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The crude product was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 9/1,Rf = 0.45) to give the title compound (150 mg, 409.07 μmol, 28.0% yield, 97.1% purity in LCMS at 220 nm) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ7.55 - 7.53 (m, 3H), 7.26 - 7.24 (m, 2H), 2.47 (d, J = 6.8 Hz, 2H), 0.90 - 0.88 (m, 1H), 0.45 - 0.40 (m, 2H), 0.02 - 0.01 (m, 2H). (ESI+) m/z: 354.9 (M+H)+, (C13H12N2Br2). [0432] E. 4-Bromo-2-(cyclopropylmethyl)-1-phenyl-1H-imidazole: To a solution of 4,5- dibromo-2-(cyclopropylmethyl)-1-phenyl-imidazole (150 mg, 409 μmol, 1.00 eq) in THF (2.00 mL) was added n-BuLi (2.50 M, 245 μL, 1.50 eq) dropwise under N2. The mixture was stirred at -70°C for 1 h under N2. The mixture was poured into NH4Cl (aq,10.0 mL) and extracted with Ethyl acetate (3 x 5.00mL). The combined organic layer was washed with saturated NaCl aqueous (10.0 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The crude product was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 8/1, Rf = 0.44) to give the title compound (74.0 mg, 266 μmol, Crude) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ7.52 - 7.50 (m, 3H), 7.37 - 7.36 (m, 2H), 7.13 (s, 1H), 2.50 (d, J = 6.8 Hz, 2H), 0.93 - 0.88 (m, 1H), 0.41 - 0.38 (m, 2H), 0.03 - 0.01 (m, 2H). (ESI+) m/z: 276.9 (M+H)+, (C13H13N2Br). 115 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0433] F. 3-(5-(2-(Cyclopropylmethyl)-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(cyclopropylmethyl)-1-phenyl- imidazole (74.0 mg, 266μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (197 mg, 533 μmol, 2.00 eq) in dioxane (2.00 mL) and water (0.100 mL) was added K3PO4 (113 mg, 533 μmol, 2.00 eq) and Ru Phos Pd G3 (22.3 mg, 26.7 μmol, 0.10 eq) at 25 °C under N2. The mixture was stirred for 2 h at 100 °C under N2. The mixture was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatorgraphy (SiO2, Dichloromethane/Methanol = 100/1 to 40/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.38) to get a residue. The residue was purified by Preparative-HPLC using a Welch Ultimate C18 (150 mm x 25 mm x 5 μm) and gradiente of 10 - 40% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (39.3 mg, 88.9 μmol, 33.3% yield, 99.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO)δ 11.0 (s, 1H), 8.25 - 8.23 (m, 1H), 8.07 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.66 - 7.63 (m, 5H), 5.13 - 5.08 (m, 1H), 4.46 - 4.28 (m, 2H), 2.93 - 2.91 (m, 1H), 2.74 - 2.72 (m, 2H), 2.63 - 2.59 (m, 1H), 2.45 - 2.43 (m, 1H), 2.05 - 2.00 (m, 1H), 0.99 - 0.93 (m, 1H), 0.44 - 0.40 (m, 2H), 0.11 - 0.08 (m, 2H). (ESI+) m/z: 441.2 (M+H)+ (C26H24N4O3). EXAMPLE 40 [0434] Synthesis of 3-(1-oxo-5-(5-phenyl-2-(trifluoromethyl)oxazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: [0435] A. 2,2,2-Trifluoro-N-(2-oxo-2-phenylethyl)acetamide: To a solution of 2-amino- 1-phenyl-ethanone (5.00 g, 29.1 mmol, 1.00 eq, HCl) and TFAA (10.4 g, 49.5 mmol, 6.88 mL, 1.70 eq) in THF (100 mL) was added TEA (5.90 g, 58.2 mmol, 8.11 mL, 2.00 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated in vacuum to give the title compound (5.00 g, 20.8 mmol, crude) as yellow solid. (ESI+) m/z: 231.9 (M+H)+, (C10H8F3NO2). 116 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0436] B. 5-Phenyl-2-(trifluoromethyl)oxazole: A mixture of 2,2,2-trifluoro-N-(2-oxo-2- phenylethyl)acetamide (5.00 g, 21.6 mmol, 1.00 eq) and H2SO4 (12 M, 9.01 mL, 5.00 eq) was stirred at 80 °C for 12 h. The reaction mixture was cooled down to 25 °C and poured into ice cold H2O (50.0 mL). The solution was neutralized with 28% aqueous ammonia (pH = 6) and extracted with ethyl acetate (3 x 100 mL). The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 50: 1; TLC, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.40) to give the title compound (0.80 g, 3.75 mmol, 17.3% yield) as red oil.1H NMR: (400 MHz, CDCl3) δ 7.71 - 7.69 (m, 2H), 7.49 - 7.43 (m, 4H). (ESI+) m/z: 214.3 (M+H)+, (C10H6F3NO). [0437] C. 4-Bromo-5-phenyl-2-(trifluoromethyl)oxazole: A mixture of 5-phenyl-2- (trifluoromethyl)oxazole (0.40 g, 1.88 mmol, 1.00 eq) and NBS (400 mg, 2.25 mmol, 1.20 eq) in ACN (10.0 mL) was stirred at 80 °C for 12 h. The reaction mixture was poured into H2O (10.0 mL), extracted with ethyl acetate (3 x 15.0 mL), dried over Na2SO4 and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 50: 1; TLC, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.60) to give the title compound (0.10 g, 342 μmol, 18.2% yield) as red oil.1H NMR: (400 MHz, CDCl3) δ 7.99 - 7.96 (m, 2H), 7.53 - 7.48 (m, 3H). (ESI+) m/z: 291.4 (M+H)+, (C10H5BrF3NO). [0438] D. 3-(1-Oxo-5-(5-phenyl-2-(trifluoromethyl)oxazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-5-phenyl-2-(trifluoromethyl)oxazole (0.10 g, 342 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (253 mg, 684 μmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (28.6 mg, 34.2 μmol, 0.10 eq), K3PO4 (145 mg, 684 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 20: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.40) and preparative-HPLC (using a Welch Xtimate C18 (150 mm x 25 mm x 10 μm) and gradient of 40 - 70% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (129 mg, 282 μmol, 82.5% yield, 99.8% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.88 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.55 - 7.52 (m, 3H), 5.15 - 5.11 (m, 1H), 4.52 - 4.35 (m, 2H), 117 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2.96 - 2.87 (m, 1H), 2.63 - 2.57 (m, 1H), 2.42 - 2.38 (m, 1H), 2.04 - 2.00 (m, 1H). (ESI+) m/z: 456.3 (M+H)+, (C23H16F3N3O4). EXAMPLE 41 [0439] Synthesis of 3-(5-(2-methyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0440] A. 2-Methyl-1-phenyl-1H-imidazole: To a solution of 2-methyl-1H-imidazole (5.00 g, 60.9 mmol, 1.00 eq) in MeOH (150 mL) was added phenylboronic acid (6.31 g, 51.7 mmol, 0.85 eq) ang Cu2O (435 mg, 3.04 mmol, 311 μL, 0.05 eq) under air. The mixture was stirred at 25 °C for 12 h under air. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.50 (Dichloromethane: Methanol = 10: 1)) to give the title compound (4.50 g, 28.3 mmol, 46.6% yield, 99.8% purity in HPLC at 220 nm) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.48 - 7.39 (m, 3H), 7.28 - 7.25 (m, 2H), 7.01 - 6.97 (m, 2H), 2.33(s, 3H). (ESI+) m/z: 159.0 (M+H)+, (C10H10N2). [0441] B. 5-Bromo-2-methyl-1-phenyl-1H-imidazole: To a solution of 2-methyl-1- phenyl-imidazole (2.00 g, 12.6 mmol, 1.00 eq) in ACN (20.0 mL) was added NBS (2.36 g, 13.2 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction mixture was poured into saturated NaCl aqueous solution (50.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.40 (Dichloromethane: Methanol = 10: 1)) to give the title compound (710 mg, 2.97 mmol, 23.5% yield, 99.3% purity in HPLC at 220 nm) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.54 - 7.51 (m, 3H), 7.25 - 7.22 (m, 2H), 7.00 (s, 1H), 2.26 (s, 3H). (ESI+) m/z: 236.9 (M+H)+, (C10H9BrN2). [0442] C. 3-(5-(2-Methyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 5-bromo-2-methyl-1-phenyl-imidazole (400 mg, 1.68 mmol, 1.00 118 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (1.55 g, 4.19 mmol, 2.50 eq), Ru-Phos-Pd-G3 (140 mg, 167 μmol, 0.10 eq) and K3PO4 (711 mg, 3.35 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.40 (Dichloromethane: Methanol = 10: 1)) and by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 5 μm) and gradient of 2 - 32% acetonitrile in water containing 0.5% FA over 14 min at a flow rate of 25.0 mL/min to give the title compound (82.8 mg, 206 μmol, 12.3% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 4.4 Hz, 3H), 7.54 - 7.51 (m, 2H), 7.45 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.32 (dd, J = 56.0, 17.6 Hz, 2H), 2.94 - 2.84 (m, 1H), 2.61 - 2.56 (m, 1H), 2.46 (s, 3H), 2.9 - 2.34 (m, 1H), 2.00 - 1.96 (m, 1H). (ESI+) m/z: 401.1 (M+H)+, (C23H20N4O3). EXAMPLE 42 [0443] Synthesis of 3-(5-(2-ethyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0444] A. 2-Ethyl-1-phenyl-1H-imidazole: To a solution of 2-ethyl-1H-imidazole (5.00 g, 52.0 mmol, 1.00 eq) in MeOH (150 mL) was added phenylboronic acid (5.39 g, 44.2 mmol, 0.85 eq) and Cu2O (372 mg, 2.60 mmol, 265 μL, 0.05 eq) at 25 °C under O2 (15 PSI), then the mixture was stirred at 25 °C for 16 h. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether /Ethyl acetate = 100/1 to 1/4, TLC: Petroleum ether /Ethyl acetate = 0/1, Rf = 0.44) to give the title compound (4.40 g, 24.6 mmol, 47.4% yield, 96.6% purity LCMS at 220 nm) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.48 - 7.30 (m, 3H), 7.29 - 7.27 (m, 2H), 7.05 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 1.2 Hz, 1H), 2.69 - 2.63 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H). (ESI+) m/z: 173.0 (M+H)+, (C11H12N2). 119 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0445] B. 5-Bromo-2-ethyl-1-phenyl-1H-imidazole: To a solution of 2-ethyl-1-phenyl- 1H-imidazole (1.78 g, 10.0 mmol, 1.00 eq) in ACN (18.0 mL) was added a solution of NBS (1.88 g, 10.5 mmol, 1.05 eq) in ACN (9.00 mL) at 0 °C, then the mixture was stirred at 25 °C for 2 h. It was poured into water (50.0 mL) and extracted with ethyl acetate (3 x 40.0 mL) to collect the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 50/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.38) to give the title compound (1.60 g, 6.31 mmol, 62.8% yield, 99.0% purity LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.60 - 7.55 (m, 3H), 7.38 - 7.36 (m, 2H), 7.02 (d, J = 5.2 Hz, 1H), 2.48 - 2.42 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H). (ESI+) m/z: 252.6 (M+H)+, (C11H11N2Br). [0446] C. 3-(5-(2-Ethyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 5-bromo-2-ethyl-1-phenyl-1H-imidazole (200 mg, 788 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (729 mg, 1.97 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (334 mg, 1.58 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (65.9 mg, 78.8 μmol, 0.100 eq) at 25 °C, then the mixture was stirred at 100 °C for 4 h under N2. It was filtered and the filter was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 33/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.36) to give a residue. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 8 - 38% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (50.7 mg, 121 μmol, 15.4% yield, 99.6% purity HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.00 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.59 - 7.56 (m, 3H), 7.53 - 7.51 (m, 2H), 7.43 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.08 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.39 - 4.21 (m, 2H), 2.89 - 2.87 (m, 1H), 2.76 - 2.72 (m, 2H), 2.60 - 2.56 (m, 1H), 2.42 - 2.32 (m, 1H), 1.99 - 1.96 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H). (ESI+) m/z: 415.2 (M+H)+, (C24H22N4O3). 120 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 43 [0447] Synthesis of 3-(5-(2-cyclopropyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0448] A. 5-Bromo-2-cyclopropyl-1-phenyl-1H-imidazole: To a solution of 2- cyclopropyl-1-phenyl-1H-imidazole (1.40 g, 7.53 mmol, 1.00 eq) in ACN (24.0 mL) was added NBS (1.41 g, 7.91 mmol, 1.05 eq) at 0°C under N2. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.38) to give the title compound (1.20 g, 4.54 mmol, 60.3% yield, 99.6% purity in LCMS at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.61 - 7.56 (m, 3H), 7.43 - 7.41 (m, 2H), 6.96 (s, 1H), 1.58 - 1.53 (m, 1H), 0.86 - 0.84 (m, 2H), 0.79 - 0.77 (m, 2H). (ESI+) m/z: 264.8 (M+H)+, (C12H11BrN2) [0449] B. 3-(5-(2-Cyclopropyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-2-cyclopropyl-1-phenyl-1H-imidazole (200 mg, 753 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (558 mg, 1.51 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (320 mg, 1.51 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (63.0 mg, 75.3 μmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 2.5 h under N2. The mixture was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/3, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.28) to give a residue. The residue was purified by preparative-HPLC using a Welch Ultimate C18 (150 mm x 25 mm x 5 μm) and gradient of 8-38% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (172 mg, 402 μmol, 53.4% yield, 99.5% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.97 (s, 1H), 7.66 - 7.64 (m, 1H), 7.61 - 7.56 (m, 5H), 7.43 (s, 1H), 7.25 - 7.23 (m, 1H), 5.01 - 5.06 (m, 1H), 4.01 - 4.36 (m, 1H), 4.26 - 4.22 (m, 1H), 2.94 - 2.85 (m, 1H), 2.63 - 2.58 (m, 1H), 2.39 - 2.35 (m, 1H), 2.01 - 1.96 (m, 1H), 1.90 - 1.85 (m, 1H), 1.19 - 1.13 (m, 2H), 1.09 - 1.03 (m, 2H). (ESI+) m/z: 427.0 (M+H)+, (C25H22N4O3). 121 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 44 [0450] Synthesis of 3-(5-(2-isopropyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0451] A. 3-(5-(2-Isopropyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-2-isopropyl-1-phenyl-1H-imidazole (200 mg, 754 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (698 mg, 1.89 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (320 mg, 1.51 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (63.0 mg, 75.4 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 96.5/3.5, TLC: DCM/MeOH = 10/1, Rf = 0.50) to get a residue. The residue was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 11-41% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (200 mg, 459 μmol, 60.8% yield, 98.4% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.15 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 (s, 5H), 7.45 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.10 (dd, J = 5.2 Hz, J = 13.6 Hz, 1H), 4.40 - 4.21 (m, 2H), 2.98 - 2.93 (m, 1H), 2.89 - 2.86 (m, 1H), 2.60 - 2.55 (m, 1H), 2.39 - 2.35 (m, 1H), 1.99 - 1.98 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 429.1 (M+H)+, (C25H24N4O3). EXAMPLE 45 [0452] Synthesis of 3-(5-(1-methyl-5-phenyl-2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: 122 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0453] A.2,2,2-Trifluoro-1-(1-methyl-1H-imidazol-2-yl)ethan-1-ol: To a solution of 1- methyl-1H-imidazole-2-carbaldehyde (5.00 g, 45.4 mmol, 1.00 eq) in THF (100 mL) was added trimethyl(trifluoromethyl)silane (8.00 g, 56.2 mmol, 1.24 eq) and CsF (10.3 g, 68.1 mmol, 1.50 eq) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 0/1, TLC: Petroleum ether/Ethyl acetate = 1/1, Rf = 0.20) to give the title compound (5.70 g, 28.8 mmol, 63.6% yield, 91.3% purity LCMS at 220 nm) as an off- white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.17 (s, 1H), 7.01 (d, J = 6.4 Hz, 1H), 6.86 (s, 1H), 5.37 - 5.31 (m, 1H), 3.69 (s, 3H). (ESI+) m/z: 181.0 (M+1)+, (C6H7F3N2O). [0454] B. 1-Methyl-2-(2,2,2-trifluoroethyl)-1H-imidazole: To a solution of 2,2,2- trifluoro-1-(1-methyl-1H-imidazol-2-yl)ethan-1-ol (5.70 g, 28.8 mmol, 1.00 eq) in THF (96.9 mL) was added PPh3 (9.09 g, 34.7 mmol, 1.20 eq), imidazole (2.36 g, 34.6 mmol, 1.20 eq) and I2 (4.40 g, 17.3 mmol, 3.49 mL, 0.600 eq) at 25 °C, then the mixture was stirred at 70 °C for 1 h. The reaction was quenched with saturated Na2SO3 solution (200 mL) at 0 °C and extracted with Ethyl acetate (3 x 150 mL) to collect the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 0/1, TLC: Petroleum ether/Ethyl acetate = 2/3, Rf = 0.21) to give the title compound (1.88 g, 11.3 mmol, 39.2% yield, 98.9% purity LCMS at 220 nm) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.85 (d, J = 1.2 Hz, 1H), 3.88 - 3.80 (m, 2H), 3.66 (s, 3H). (ESI+) m/z: 165.0 (M+H)+, (C6H7F3N2) [0455] C. 1-Methyl-5-phenyl-2-(2,2,2-trifluoroethyl)-1H-imidazole: To a solution of 1- methyl-2-(2,2,2-trifluoroethyl)-1H-imidazole (1.83 g, 11.2 mmol, 1.00 eq) in DMF (18.3 mL) was added bromobenzene (5.25 g, 33.5 mmol, 3.52 mL, 3.00 eq), K2CO3 (3.08 g, 22.3 mmol, 2.00 eq), Pd(OAc)2 (250 mg, 1.11 mmol, 0.10 eq) , P(oxole)3 (518 mg, 2.23 mmol, 0.20 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 16 h under N2. The mixture was poured water (100 mL) and extracted with Ethyl acetate(3 x 100 mL) to collect the organic layers, The organic layer were washed with brine (3 x 100 mL), dried over Na2SO4, filtered and the filtrate was concentrate under vacuum at 45 °C to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/0 to 1/1, TLC: Petroleum ether/Ethyl acetate = 1/1, Rf = 0.43) to give the title compound (440 mg, 1.78 mmol, 16.0% yield, 97.0% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 123 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT MHz, CD3CN) δ 7.50 – 7.41 (m, 5H), 7.00 (s, 1H), 3.76 (t, J = 10.4 Hz, 2H), 3.59 (s, 3H). (ESI+) m/z: 241.1 (M+H)+, (C12H11F3N2). [0456] D. 4-Bromo-1-methyl-5-phenyl-2-(2,2,2-trifluoroethyl)-1H-imidazole: To a solution of 1-methyl-5-phenyl-2-(2,2,2-trifluoroethyl)-1H-imidazole (380 mg, 1.53 mmol, 1.00 eq) in ACN (7.60 mL) was added NBS (287 mg, 1.61 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 15/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.30) to give the title compound (440 mg, 1.78 mmol, 15.9% yield, 97.0% purity in LCMS at 220 nm) as an off-white solid.1H NMR: (400 MHz, CD3CN) δ 7.52 - 7.42 (m, 5H), 3.78 - 3.70 (m, 2H), 3.49 (s, 3H). (ESI+) m/z: 320.0 (M+H)+, (C12H10BrF3N2). [0457] E. 3-(5-(1-Methyl-5-phenyl-2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-5-phenyl-2- (2,2,2-trifluoroethyl)-1H-imidazole (200 mg, 622 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (576 mg, 1.56 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (264 mg, 1.24 mmol, 2.00 eq) and RuPhos-Pd-G3 (52.1 mg, 62.2 μmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 3 h. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/0 to 1/1, TLC: Petroleum ether/Ethyl acetate = 1/1, Rf = 0.43) to give a residue. The residue was purified by preparative-HPLC (using a Welch ultimate C18 (150 mm x 25 mm x 10 μm) and gradient of 8-38% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (139 mg, 288 μmol, 46.3% yield, 100% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.60 (s, 1H), 7.54 - 7.51 (m, 4H), 7.43 - 7.41 (m, 3H), 5.09 - 5.04 (m, 1H), 4.38 - 4.31 (m, 1H), 4.23 - 4.19 (m, 1H), 4.09 - 4.01 (m, 2H), 3.44 (s, 3H), 2.90 - 2.86 (m, 1H), 2.60 - 2.56 (m, 1H), 2.37 - 2.33 (m, 1H), 1.98 - 1.96 (m, 1H). (ESI+) m/z: 483.2 (M+H)+, (C25H21F3N4O3). 124 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 46 [0458] Synthesis of 3-(5-(4-(difluoromethyl)-1-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0459] A. 4-(Difluoromethyl)-1-trityl-1H-imidazole: To a solution of 1-trityl-1H- imidazole-4-carbaldehyde (22.0 g, 65.0 mmol, 1.00 eq) in DCM (220 mL) was added BAST (28.8 g, 130 mmol, 28.5 mL, 2.00 eq) at 0 °C underN2. The mixture was stirred at 25 °C for 16 h under N2. The mixture was poured into water (500 mL) at 0 °C and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with saturated NaHCO3 aqueous (2 x 300 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 50/1 to 5/1, TLC: Petroleum ether/Ethyl acetate = 5/1, Rf = 0.42) to give the title compound (11.0 g, 30.5 mmol, 47.0% yield, 100% purity in LCMS at 220 nm) as an off- white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.45 – 7.39 (m, 9H), 7.25 (s, 1H), 7.11 – 7.09 (m, 6H), 7.01 – 6.74 (m, 1H). (ESI+) m/z: 383.0 (M+23)+, (C23H18F2N2) [0460] B. 4-(Difluoromethyl)-1H-imidazole: A solution of 4-(difluoromethyl)-1-trityl- 1H-imidazole (9.00 g, 25.0 mmol, 1.00 eq) in AcOH (47.0 g, 787 mmol, 45.0 mL, 31.5 eq) and HCl (12 M, 9.00 mL, 4.32 eq) was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filter cake was washed with H2O (2 x 30 mL). The filtrate was concentrated under vacuum to give a residue at 50 °C. The residue was freeze-drying to give a residue. The residue was dissolved with DCM (100 mL) and adjusted to pH = 7 with NaHCO3 solid. Filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.60 g, crude) as a white solid.1H NMR: (400 MHz, MeOD) δ 9.14 (s, 1H), 7.98 (s, 1H), 7.66 – 6.99 (m, 2H). (ESI+) m/z: 119.3 (M+H)+, (C4H4F2N2) [0461] C. 4-(Difluoromethyl)-1-phenyl-1H-imidazole: To a solution of 4- (difluoromethyl)-1H-imidazole (2.00 g, 16.9 mmol, 1.00 eq) in ACN (50.0 mL) was added Ph(OH)2 (2.07 g, 16.9 mmol, 1.00 eq), boric acid (1.05 g, 16.9 mmol, 1.00 eq) Cu(OAc)2 (3.08 g, 16.9 mmol, 1.00 eq) , 4A MS (2.00 g) at 25 °C. The mixture was stirred at 70 °C for 16 h under O2. The mixture was filtered and the filter cake was washed with DCM (2 x 30 mL). The filtrate was concentrated under vacuum to give a residue at 40 °C. The residue was 125 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/0 to 10/1, TLC: Petroleum ether/Ethyl acetate = 5/1, Rf = 0.26) to give the title compound (1.40 g, 13.4 mmol, 60.7% yield, 100% purity in LCMS at 220 nm) as an off-white solid.1H NMR: (400 MHz, CD3CN) δ 8.00 (s, 1H), 7.75 – 7.74 (m, 1H), 7.54 – 7.53 (m, 4H), 7.45 – 7.42 (m, 1H), 6.92 – 6.64 (m, 1H). (ESI+) m/z: 195.1 (M+H)+, (C10H8F2N2). [0462] D. 2-Bromo-4-(difluoromethyl)-1-phenyl-1H-imidazole: To a solution of 4- (difluoromethyl)-1-phenyl-1H-imidazole (700 mg, 3.60 mmol, 1.00 eq) in THF (7.00 mL) was added n-BuLi (2.5 M, 1.59 mL, 1.10 eq) dropwise at - 78 °C under N2. The mixture was stirred at -78 °C for 0.5 h, then a solution of 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (983 mg, 3.79 mmol, 1.05 eq) in THF (1.75 mL) was added dropwise at -78 °C. Then the mixture was stirred at 25 °C for 4 h under N2. The reaction mixture was quenched with 20.0 mL of saturated NH4Cl solution at 0 °C under N2. Then the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether/Ethyl acetate = 5/1, Rf = 0.35) to give the title compound (520 mg, 1.90 mmol, 52.7% yield, 99.7% purity in LCMS at 220 nm) as a colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 7.97 (t, J = 2.4 Hz, 1H), 7.59 – 7.57 (m, 3H), 7.54 – 7.51 (m, 2H), 7.08 – 6.81 (m, 1H). (ESI+) m/z: 273.0 (M+H)+, (C10H7BrF2N2). [0463] E. 3-(5-(4-(Difluoromethyl)-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-4-(difluoromethyl)-1-phenyl-1H- imidazole (200 mg, 730. μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (676 mg, 1.83 mmol, 2.50 eq) in dioxane (0.50 mL) and H2O (0.250 mL) was added K3PO4 (310 mg, 1.46 mmol, 2.00 eq) and RuPhos-Pd-G3 (61.1 mg, 73.0 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 100 °C for 3 h. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The mixture was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/3, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.26) to give a residue. The residue was purified by preparative-HPLC (using a Welch ultimate C18 (150 mm x 25 mm x 10 μm) and gradient of 23-53% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (122 mg, 279 μmol, 38.2% yield, 100% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.96 - 7.95 (m, 1H), 7.66 - 7.64 (m, 1H), 7.63 - 7.62 (m, 1H), 7.61 - 7.50 (m, 3H), 7.40 - 7.37 (m, 2H), 7.34 - 7.32 (m, 1H), 7.04 – 6.91 (m, 1H), 5.12 – 5.07 (m, 1H), 4.44 – 4.39 (m, 1H), 4.30 – 4.26 (m, 1H), 2.90 – 2.87 (m, 1H), 2.61 126 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT - 2.58 (m, 1H), 2.40 - 2.35 (m, 1H), 2.02 – 1.98 (m, 1H). (ESI+) m/z: 437.1 (M+H)+, (C23H18F2N4O3). EXAMPLE 47 [0464] Synthesis of 3-(5-(1-methyl-5-phenyl-4-(tetrahydrofuran-3-yl)-1H-imidazol-2- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0465] A. 4-(2,5-Dihydrofuran-3-yl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 4-bromo-1-methyl-5-phenyl-1H-imidazole (500 mg, 2.11 mmol, 1.00 eq) in dioxane (8.00 mL) and H2O (2.00 mL) was purged with N2 for 3 times and then added 2-(2,5-dihydrofuran- 3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (578 mg, 2.95 mmol, 1.40 eq), K3PO4 (1.34 g, 6.33 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (137 mg, 210 μmol, 0.10 eq) under N2.The mixture was stirred at 65°C for 16 h. After the reaction was completed, the reaction was diluted with H2O 10.0 mL and extracted with dichloromethane 20.0 mL (3 x 20.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.3) to give the title compound (357 mg, 1.41 mmol, 66.8% yield) was obtained as a brown oil. (ESI+) m/z: 227.1 (M+H)+, (C14H14N2O). [0466] B. 1-Methyl-5-phenyl-4-(tetrahydrofuran-3-yl)-1H-imidazole: To a solution of 4-(2,5-dihydrofuran-3-yl)-1-methyl-5-phenyl-1H-imidazole (350 mg, 1.55 mmol, 1.00 eq) in methanol (20.0 mL) was added Pd/C (82.3 mg, 10% purity) under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (20 psi) at 25°C for 16 h. After the reaction was completed, the mixture was filtered with 50.0 mL methanol and then concentrated under vacuum to give crude product. The residue was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 15:1, Rf = 0.33) to give the title compound (234 mg, 1.03 mmol, 66.2% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.28 - 7.26 (m, 2H), 7.26 - 7.22 (m, 2H), 7.10 - 7.07 (m, 2H), 3.86 - 3.81 (m, 1H), 3.79 (s, 1H), 3.69 - 3.67 (m, 1H), 3.62 - 3.60 (m, 1H), 3.31 (s, 3H), 3.15 - 3.13 (m, 1H), 2.10 - 1.68 127 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0467] C. 2-Bromo-1-methyl-5-phenyl-4-(tetrahydrofuran-3-yl)-1H-imidazole: A solution of 1-methyl-5-phenyl-4-(tetrahydrofuran-3-yl)-1H-imidazole (200 mg, 876 μmol, 1.00 eq) in THF (2.00 mL) cooled to -70°C, then n-BuLi (2.50 M, 385 μL, 1.10 eq) was dropwise to the mixture at -70°C under N2. Then the reaction mixture was stirred at -70°C for 1 h, after that a solution of NBS (250 mg, 963 μmol, 1.10 eq) in THF (1.00 mL) was added to the reaction mixture at -70 °C under N2. The mixture was stirred at 20°C for 3 h under N2. After the reaction was completed, the reaction mixture was quenched by addition H2O 5.00 mL at 0°C under N2 and extracted with ethyl acetate 10.0 mL (3 x 10.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 15:1, Rf = 0.63) to give the title compound (100 mg, 317 μmol, 36.2% yield) as a yellow oil. (ESI+) m/z: 308.9 (M+H)+, (C14H15N2BrO). [0468] D. 3-(5-(1-Methyl-5-phenyl-4-(tetrahydrofuran-3-yl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl) piperidine-2, 6-dione: A mixture of 2-bromo-1-methyl-5-phenyl-4- (tetrahydrofuran-3-yl)-1H-imidazole (100 mg, 325 μmol, 1.00 eq) in dioxane (4.00 mL) and H2O (0.20 mL). The mixture was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione (241 mg, 651 μmol, 2.00 eq) and K3PO4 (207 mg, 976 μmol, 3.00 eq) under N2, and then was added Ruphos-Pd-G3 (27.2 mg, 32.5 μmol, 0.10 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O 5.00 mL and extracted with ethyl acetate 10.0 mL (3 x 10.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 20:1) to give the title compound. The title compound was pre-purified by column chromatography followed by preparative- HPLC using a Welch Ultimate C18 (150 mm x 25 mm 5 μm) and gradient of 6 - 36% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min to give the title compound (72.0 mg, 149 μmol, 45.8% yield, 97.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.03 (s,1H), 8.07 (s, 1H), 7.99 - 7.94 (m, 2H), 7.62 - 7.55(m, 5H), 5.20 - 5.16 (m, 1H), 4.63 - 4.50 (m, 2H), 3.98 - 3.92 (m, 2H), 3.76 - 3.56(m, 3H), 3.59 (s, 3H), 2.94 - 2.65 (m, 1H), 2.61 (s, 1H), 2.45-2.43 (m, 1H), 2.14 - 2.12 (m, 1H), 2.10 - 2.07 (m, 2H). (ESI+) m/z: 471.2 (M+H)+, (C27H26N4O4). 128 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 48 [0469] Synthesis of 3-(5-(1-methyl-5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0470] A. 4-(3,6-Dihydro-2H-pyran-4-yl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 4-bromo-1-methyl-5-phenyl-1H-imidazole (1.00 g, 4.22 mmol, 1.00 eq), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.33 g, 6.33 mmol, 1.50 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added Pd(dtbpf)Cl2 (274 mg, 421 μmol, 0.10 eq), K3PO4 (2.69 g, 12.6 mmol, 3.00 eq) under N2. The reaction mixture was stirred at 65 °C for 16 h under N2. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0: 1; TLC, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.30) to give the title compound (0.70 g, 2.91 mmol, 69.0% yield) as yellow solid. (ESI+) m/z: 241.1 (M+H)+, (C15H16N2O). [0471] B. 1-Methyl-5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of 4-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-5-phenyl-1H-imidazole (0.70 g, 2.91 mmol, 1.00 eq) in MeOH (15.0 mL) was added Pd/C (70.0 mg, 10.0% purity) under N2. The reaction mixture was degassed and purged with N2 for 3 times, then degassed and purged with H2 for 3 times. The reaction mixture was warmed to 25 °C and stirred at 20 psi under H2 for 16 h. The reaction mixture was filtered through diatomite. The filtrate was concentrated in vacuum to give residue and purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 4: 1; TLC: Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.40) to give the title compound (0.60 g, 2.48 mmol, 85.0% yield) was obtained as colorless oil.1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.52 - 7.45 (m, 2H), 7.43 - 7.38 (m, 1H), 7.37 - 7.31 (m, 2H), 3.90 - 3.75 (m, 2H), 3.45 (s, 3H), 2.72 - 2.58(m 1H), 3.32 - 3.21(m, 2H), 1.91 - 1.71 (m, 2H), 1.57 - 1.41 (m, 2H). (ESI+) m/z: 243.14 (M+H)+, (C15H18N2O). [0472] C. 2-Bromo-1-methyl-5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of 1-methyl-5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (600 mg, 2.48 mmol, 1.00 eq) in DMF (10.0 mL), then NBS (467 mg, 2.62 mmol, 1.06 eq) in DMF (5.00 mL) was dropwise at 0 °C. The reaction was stirred at 25 °C for 1 h. The residue was 129 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT diluted with H2O (30.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (3 x 20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 4: 1; TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.50) to give the title compound (620 mg, 1.89 mmol, 76.1% yield, 97.7 % purity in LCMS at 220 nm) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.52 - 7.40 (m, 3H), 7.28 - 7.25 (m, 2H), 4.01 - 3.93 (m, 2H), 3.40 (s, 3H), 3.39 - 3.32 (m, 2H), 2.74 - 2.64 (m, 1H), 2.05 - 1.93 (m, 2H), 1.62 - 1.52 (m, 2H). (ESI+) m/z: 322.8 (M+H)+, (C15H17BrN2O). [0473] D. 3-(5-(1-Methyl-5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-5-phenyl-4- (tetrahydro-2H-pyran-4-yl)-1H-imidazole (300 mg, 934 μmol, 1.00 eq), 3-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (692 mg, 1.87 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-phos-Pd-G3 (78.1 mg, 93.4 μmol, 0.10 eq), K3PO4 (397 mg, 1.87 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 20: 1; TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.30) and preparative-HPLC (using a Welch Ultimate C18 (150 x 25mm x 5 μm) and gradient of 8 - 38% acetonitrile in water containing 0.05% TFA over 13 min at a flow rate of 25 mL/min) to give the title compound (223 mg, 459 μmol, 49.2% yield, 99.5% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.09 (s, 1H), 8.06 - 8.00 (m, 1H), 7.99 - 7.93 (m, 1H), 7.71 - 7.51 (m, 5H), 5.25 - 5.13 (m, 1H), 4.69 - 4.44 (m, 2H), 3.98 - 3.85 m, 2H), 3.58 (s, 3H), 3.35 - 3.30 (m, 2H), 3.02 - 2.84 (m, 2H), 2.68 - 2.59 (m, 1H), 2.48 - 2.43 (m, 1H), 2.12 - 2.00 (m, 1H), 1.97 - 1.83 (m, 2H), 1.77 - 1.63 (m, 2H), (ESI+) m/z: 485.2 (M+H)+, (C28H28N4O4). 130 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 49 [0474] Synthesis of 3-[5-[1-methyl-4-(1-methylpyrazol-4-yl)-5-phenyl-imidazol-2-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione: [0475] A. 1-Methyl-4-(1-methylpyrazol-4-yl)-5-phenyl-imidazole: To a solution of 4- bromo-1-methyl-5-phenyl-imidazole (500 mg, 2.11 mmol, 1.00 eq) in dioxane (10.0 mL) was added H2O (2.50 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (526 mg, 2.53 mmol, 1.20 eq), K3PO4 (1.34 g, 6.33 mmol, 3.00 eq) and Pd(dppf)2Cl2·CH2Cl2 (137 mg, 210 μmol, 0.10 eq). The mixture was stirred at 65 °C for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.43 (Dichloromethane: Methanol = 10: 1)) to give the title compound (496 mg, 1.81 mmol, 85.8% yield, 87.0% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.54 - 7.46 (m, 4H), 7.43 - 7.38 (m, 2H), 7.16 (s, 1H), 3.74 (s, 3H), 3.45 (s, 3H). (ESI+) m/z: 239.1 (M+H)+, (C14H14N4). [0476] B. 2-Bromo-1-methyl-4-(1-methylpyrazol-4-yl)-5-phenyl-imidazole: To a solution of 1-methyl-4-(1-methylpyrazol-4-yl)-5-phenyl-imidazole (450 mg, 1.64 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (321 mg, 1.81 mmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtare concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.35) to give the title compound (212 mg, 655 μmol, 39.8% yield, 98.0% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.50 - 7.45 (m, 3H), 7.37 (s, 1H), 7.35 - 7.31 (m, 2H), 7.23 (s, 1H), 3.77 (s, 3H), 3.39 (s, 3H). (ESI+) m/z: 317.0 (M+H)+, (C14H13BrN4). [0477] C. 3-[5-[1-Methyl-4-(1-methylpyrazol-4-yl)-5-phenyl-imidazol-2-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-4-(1- methylpyrazol-4-yl)-5-phenyl-imidazole (210 mg, 648 μmol, 1.00 eq) in dioxane (4.00 mL) was added H2O (0.20 mL), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (600 mg, 1.62 mmol, 2.50 eq), Ru-Phos-Pd-G3 (108 131 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mg, 129 μmol, 0.20 eq) and K3PO4 (413 mg, 1.95 mmol, 3.00 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.20) and purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 3 - 33% acetonitrile in water containing 0.5% FA over 15 min at a flow rate of 25.0 mL/min to give the title compound (118 mg, 242 μmol, 37.3% yield, 98.0% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.00 (s, 1H), 7.95 - 7.85 (m, 2H), 7.63 - 7.48 (m, 6H), 7.22 (s, 1H), 5.17 (dd, J = 5.2, 13.2 Hz, 1H), 4.62 - 4.41 (dd, J = 8.6, 17.6 Hz, 2H), 3.77 (s, 3H), 3.54 (s, 3H), 3.01 - 2.89 (m, 1H), 2.70 - 2.60 (m, 1H), 2.45 - 2.40 (m, 1H), 2.11 - 2.01 (m, 1H). (ESI+) m/z: 481.1 (M+H)+, (C27H24N6O3). EXAMPLE 50 [0478] Synthesis of 3-(5-(1-methyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0479] A. 1-Methyl-4,5-diphenyl-1H-imidazole: To a solution of 4,5-diphenyl-1H- imidazole (1.00 g, 4.54 mmol, 1.00 eq) in THF (10.0 mL) was added NaH (272 mg, 6.81 mmol, 60% purity, 1.50 eq) at 0 °C. The mixture was stirred at 20 °C for 0.5 h under N2. Then MeI (966 mg, 6.81 mmol, 423 μL, 1.50 eq) was added to the mixture at 0 °C under N2. The mixture was stirred at 20 °C for 1 h under N2. After the reaction was completed, the reaction mixture was poured into saturated NH4Cl aqueous solution (30.0 mL), then was extracted with ethyl acetate (3 x 30.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate= 100: 1 to 0: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate= 0: 1)) to give the title compound (1.00 g, 4.27 mmol, 94.0% yield, 100% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.50 -7.45 (m, 3H), 7.37 (d, J = 7.6 Hz, 132 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 4H), 7.18 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 3.44 (s, 3H). (ESI+) m/z: 235.1 (M+H)+, (C16H14N2). [0480] B. 2-Bromo-1-methyl-4,5-diphenyl-1H-imidazole: To a solution of 1-methyl- 4,5-diphenyl-imidazole (500 mg, 2.13 mmol, 1.00 eq) in ACN (5.00 mL) was added NBS (398 mg, 2.24 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O (10.0 mL). The mixture was extracted with ethyl acetate (3 x 10.0 mL) and the combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate= 100: 1 to 3: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate= 3: 1)) to give the title compound (300 mg, 934 μmol, 43.8% yield, 97.6% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.54 - 7.51 (m, 3H), 7.42 -7.39 (m, 2H), 7.33 -7.30 (m, 2H), 7.20 (t, J = 7.6 Hz, 2H), 7.16 -7.11 (m, 1H), 3.37 (s, 3H). (ESI+) m/z: 313.0 (M+H)+, (C16H13BrN2). [0481] C. 3-(5-(1-Methyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-4,5-diphenyl-imidazole (200 mg, 623 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added 3-[1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (576 mg, 1.56 mmol, 2.50 eq), Ru-Phos-Pd-G3 (104 mg, 124 μmol, 0.20 eq) and K3PO4 (396 mg, 1.87 mmol, 3.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate= 10: 1, Rf = 0.30) and by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 5 μm) and gradient of 16 - 46% acetonitrile in water containing 0.5% FA over 10 min at a flow rate of 25.0 mL/min to give the title compound (31.4mg, 65.8 μmol, 10.5% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.09 (s, 1H), 8.02 - 7.94 (m, 2H), 7.59 - 7.55 (m, 3H), 7.52 - 7.49 (m, 2H), 7.44 (d, J = 7.2 Hz, 2H), 7.33 - 7.24 (m, 3H), 5.18 (dd, J = 12.8, 4.4 Hz, 1H), 4.54 (dd, J = 51.2, 18.0 Hz, 2H), 3.57 (s, 3H), 2.99 - 2.89 (m, 1H), 2.67 - 2.66 (m, 1H), 2.35 - 2.31 (m, 1H), 2.08 - 2.04 (m, 1H). (ESI+) m/z: 477.1 (M+H)+, (C29H24N4O3). 133 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 51 [0482] Synthesis of 3-(5-(2-isobutyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0483] A. 5-Bromo-2-isobutyl-1-phenyl-1H-imidazole: To a solution of 2-isobutyl-1- phenyl-imidazole (680 mg, 2.60 mmol, 1.00 eq) in ACN (6.80 mL) was addded NBS (486 mg, 2.73 mmol, 1.05 eq) at 0 °C.The mixture was stirred at 25 °C for 2 h. [0484] The mixture was stirred at 25 °C for 2 h. The mixture was poured into NH4Cl (aq. 20.0 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 30.0 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 50/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to give the title compound (400 mg, 1.41 mmol, 54.1% yield, 98.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, CD3CN) δ 7.59 - 7.52 (m, 3H), 7.29 - 7.26 (m, 2H),6.98 (s, 1H), 2.36 (d, J = 7.2 Hz, 2H), 1.91 - 1.84 (m, 1H), 0.79 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 280.2 (M+H)+, (C13H15N2Br). [0485] B. 3-(5-(2-Isobutyl-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-2-isobutyl-1-phenyl-imidazole (200 mg, 705 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (653 mg, 1.76 mmol, 2.50 eq) in dioxane (4.00 mL) and H2O (0.200 mL) was added K3PO4 (299 mg, 1.41 mmol, 2.00 eq) and RuPhos - Pd - G3 (59.0 mg, 70.5 μmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 2 h. The mixture was filtered and the filtrate was to concentrated under vacuum at 45 °C to get residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 100/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to get residue 1.The residue 1 was purified by preparative- HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 10% - 40% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (120 mg, 271 μmol, 39.1% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.07 (s, 1H), 7.64(d, J = 8.0 Hz, 1H), 7.60 - 7.53 (m, 5H), 7.45 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.40 - 4.21 (m, 2H), 2.93 - 2.84 (m, 1H), 2.68 (d, J = 7.2 Hz, 2H), 2.60 - 2.56 (m, 1H), 2.42 - 12.32 134 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (m, 1H), 1.99 - 1.96 (m, 1H), 1.91 - 1.84 (m, 1H),0.82 (d, J = 6.4 Hz, 6H). (ESI+) m/z: 443.2 (M+H)+, (C26H26N4O3). EXAMPLE 52 [0486] Synthesis of 3-(5-(1,4-dimethyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0487] A. 1,4-Dimethyl-1H-imidazole: To a solution of 4-methyl-1H-imidazole (10.0 g, 121 mmol, 1.00 eq) in acetone (120 mL) was added K2CO3 (25.2 g, 182 mmol, 1.50 eq) at 25 °C, then a solution CH3I (20.7 g, 146mmol, 9.10 mL, 1.20 eq) in acetone (10.0 mL) was slowly dropwise to the mixture at 25 °C, then the mixture was stirred at 25 °C for 5 h. The mixture was poured into H2O (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 20/1, TLC: Dichloromethane/Methanol = 10/1, Rf = 0.36) to give a residue. The residue was purified by SFC (column: DAICEL CHIRALPAK IK (250mm x 30mm, 10um); mobile phase: [CO2-EtOH]; B%:15%, isocratic elution mode) to give the title compound (620 mg, 6.43 mmol, 5.29% yield, 99.7% purity LCMS at 220 nm) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.28 (s, 1H), 6.56 (s, 1H), 3.59 (s, 3H), 2.19 (s, 3H). (ESI+) m/z: 97.0 (M+H)+, (C5H8N2). [0488] B. 1,4-Dimethyl-5-phenyl-1H-imidazole: To a solution of 1,4-dimethyl-1H- imidazole (600 mg, 6.22 mmol, 1.00 eq) ) in DMF (12.0 mL) was added bromobenzene (2.93 g, 18.6 mmol, 1.97 mL, 3.00 eq), K2CO3 (1.72 g, 12.4 mmol, 2.00 eq), Pd(OAc)2 (139 mg, 622 μmol, 0.10 eq) and P(Oxole) (144 mg, 622 μmol, 0.10 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 16 h under N2. It was poured into water (50.0 mL) and extracted with Ethyl acetate (3 x 30.0 mL) to collect the organic layer. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC: Petroleum ether/ Ethyl acetate = 0/1, Rf = 0.40) to give the title compound (320 mg, 1.84 mmol, 29.5% yield, 98.8% purity LCMS at 135 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 220 nm) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.49 - 7.45 (m, 2H), 7.38 - 7.35 (m, 3H), 3.50 (s, 3H), 2.09 (s, 3H). (ESI+) m/z: 172.9 (M+H)+, (C11H12N2). [0489] C. 2-Bromo-1,4-dimethyl-5-phenyl-1H-imidazole: To a solution of 1,4- dimethyl-5-phenyl-1H-imidazole (320 mg, 1.84 mmol, 1.00 eq) in THF (3.20 mL) was added n-BuLi (2.5 M, 2.20 mL, 3.00 eq) dropwise at - 78 °C under N2. The mixture was stirred at - 78 °C for 0.5 h, then a solution of 1,2-dibromo-1,1,2,2-tetrafluoroethane (953 mg, 3.67 mmol, 2.00 eq) in THF (1.60 mL) was added dropwise at -78 °C. Then the mixture was stirred at 25 °C for 4 h under N2. The reaction mixture was quenched with saturated NH4Cl (20.0 mL) solution at 0 °C under N2. Then the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 50/1, Dichloromethane/Methanol = 15/1, Rf = 0.75) give the title compound (80.0 mg, 312 μmol, 17.0% yield, 98.2% purity LCMS at 220 nm) as a light yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.46 - 7.42 (m, 2H), 7.39 - 7.35 (m, 1H), 7.26 - 7.24 (m, 2H), 3.44 (s, 3H), 2.16 (s, 3H). (ESI+) m/z: 250.9 (M+H)+, (C11H11BrN2). [0490] D. 3-(5-(1,4-Dimethyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1,4-dimethyl-5-phenyl-1H-imidazole (80.0 mg, 312 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (289 mg, 782 μmol, 2.50 eq) in dioxane (1.60 mL) and H2O (0.08 mL) was added K3PO4 (132 mg, 625 μmol, 2.00 eq) and Ruphos-Pd-G3 (26.1 mg, 31.2 μmol, 0.10 eq) at 25 °C, then the mixture was stirred at 100 °C for 2 h under N2. It was concentrated under vacuum. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 8 - 38% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (51.1 mg, 121 μmol, 38.8% yield, 98.4% purity HPLC at 220 nm) as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.09 (s, 1H), 8.05 - 8.03(m, 1H), 7.96 - 7.94 (m, 1H), 7.65 - 7.57 (m, 5H), 5.18 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.64 - 4.47 (m, 2H), 3.67 (s, 3H), 2.98 - 2.89 (m, 1H), 2.65 - 2.61 (m, 1H), 2.45 - 2.44 (m, 1H), 2.32 (s, 3H), 2.08 - 2.03 (m, 1H). (ESI+) m/z: 415.2 (M+H)+, (C24H22N4O3). 136 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 53 [0491] Synthesis of 3-(1-oxo-5-(2-phenylthiazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione: [0492] A. 3-(5-(2-Bromoacetyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(1-ethoxyvinyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.27 mmol, 1.00 eq) in [Bmim]PF6 (10.0 mL) was added TsOH.H2O (48.4 mg, 254 μmol, 0.20 eq) and NBS (271 mg, 1.53 mmol, 1.20 eq). The mixture was stirred at 25°C for 12 h. After the reaction was completed, the mixture was used for next step directly without work-up and purification to give to give the title compound (460 mg, crude, 64.8% yield). (ESI+) m/z: 364.9 (M+H)+, (C15H13O4N2Br). [0493] B. 3-(1-Oxo-5-(2-Phenylthiazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of3-(5-(2-bromoacetyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (460 mg, 1.26 mmol, 1.00 eq) in [Bmim]PF6 (5.00 mL) was added benzothioamide (190 mg, 1.39 mmol, 1.10 eq) and K2CO3 (208 mg, 1.51 mmol, 1.20 eq). The mixture was stirred at 25°C for 5 h. After the reaction was completed, the reaction mixture was diluted with H2O (10.0 mL) and extracted with DCM (5 x 10.0 mL). Then, the extract was washed with sat. aq. Na2SO3 solution (10.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 10:1, Rf = 0.43) to give crude product. The crude product was purified by column chromatography followed by preparative-HPLC using a Phenomenex Luna C18 (250 x 70mm, 10 μm) and gradient of 30 - 60% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min to give the title compound (128 mg, 310 μmol, 24.6% yield, 98.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.08 - 8.05 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.60 - 7.54 (m, 3H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.58 - 4.41 (m, 2H), 2.98 - 2.92 (m, 1H), 2.64 (s, 1H), 2.43 - 2.40 (m, 1H), 2.06 - 2.03 (m, 1H). (ESI+) m/z: 404.0 (M+H)+, (C22H17O3N3S). 137 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 54 [0494] Synthesis of 3-(5-(2-(cyclopropylmethyl)-1-phenyl-1H-imidazol-5-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0495] A. 5-Bromo-2-(cyclopropylmethyl)-1-phenyl-1H-imidazole: To a solution of 2- (cyclopropylmethyl)-1-phenyl-imidazole (212 mg, 1.07 mmol, 1.00 eq) in ACN (2.00 mL) was added NBS (199 mg, 1.12 mmol, 1.05 eq) at 0 °C. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (2 x 10.0 mL) to get the organic layers, the organic layers was washed with brine (20.0 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The crude product was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 3/1, Rf = 0.55) to give the title compound (181 mg, 653.05 μmol, 61.07% yield, 100% purity in LCMS at 220 nm) as a colorless oil.1H NMR: (400 MHz, CD3CN) δ 7.55 - 7.53 (m, 3H), 7.26 - 7.24 (m, 2H),6.98 (s,1H), 2.41 (d, J = 6.8 Hz, 2H), 0.90 - 0.88 (m, 1H), 0.38 - 0.33 (m, 2H), 0.02 - 0.01 (m, 2H). (ESI+) m/z: 277.0 (M+H)+, (C13H13N2Br). [0496] B. 3-(5-(2-(Cyclopropylmethyl)-1-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-2-(cyclopropylmethyl)-1-phenyl- imidazole (150 mg, 541 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.08 mmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.100 mL) was added K3PO4 (229 mg, 1.08 mmol, 2.00 eq) and RuPhos Pd G3 (45.2 mg, 54.1 μmol, 0.10 eq) at 25 °C under N2. The mixture was stirred for 2 h at 100 °C under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.38) to get a residue. The residue was purified by Preparative-HPLC using a Welch Ultimate C18 (150 mm x 25 mm x 5 μm) and gradiente of 8 - 38% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (42.6 mg, 95.9 μmol, 17.7% yield, 99.1% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO)δ 10.9 (s, 1H), 8.07 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 - 7.54 (m, 5H), 7.45 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.13 - 5.08 (m, 1H), 4.46 - 4.28 (m, 2H), 2.93 - 2.91 (m, 1H), 2.74 - 2.72 (m, 2H), 2.63 - 2.59 (m, 1H), 2.45 - 2.43 (m, 1H), 2.05 - 2.00 (m, 138 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 0.99 - 0.93 (m, 1H), 0.44 - 0.40 (m, 2H), 0.11 - 0.08 (m, 2H). (ESI+) m/z: 441.0 (M+H)+ (C26H24N4O3). EXAMPLE 55 [0497] Synthesis of 3-(5-(4-ethyl-1-methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: [0498] A. 4-Ethyl-1-methyl-5-phenyl-1H-imidazole: To a solution of 1-methyl-5- phenyl-4-vinyl-imidazole (600 mg, 3.26 mmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (60 mg, 10% purity) at 25 °C under N2. Degassed under vacuum and purged with H2 there times. The mixture was stirred at 25 °C under H2 (15 psi) for 12 h. The mixture was diluted with MeOH (10.0 mL), filtered through celite and the filter cake was washed with MeOH (3 x 10.0 mL). The filtrate was concentrate under vacuo to give the title compound (600 mg, 3.18 mmol, 97.6% yield, 98.7% purity in LCMS) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.42 - 7.34 (m, 4H), 7.26 - 7.24 (m, 2H), 3.47 (s, 3H), 2.54 - 2.48 (m, 2H), 1.17 (t, J = 7.6 Hz, 3H). (ESI+) m/z: 187.2 (M+H)+ (C12H14N2). [0499] B. 2-Bromo-4-ethyl-1-methyl-5-phenyl-1H-imidazole:To a solution of 4-ethyl-1- methyl-5-phenyl-imidazole (300 mg, 1.59 mmol, 1.00 eq) in THF (5.00 mL) was added dropwise n-BuLi (2.5 M, 1.59 mL, 2.50 eq) at -78 °C under N2. The reaction mixture was stirred for additional 0.5 h, then 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (433.71 mg, 1.67 mmol, 1.05 eq) was added dropwise at -78 °C. Then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated NH4Cl solution (20.0 mL) at 0 °C under N2. Then the mixture was extracted with ethyl acetate (3 x 8.00 mL) to collect the organic layers. The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 2/1, Rf = 0.35) to give the title compound (140 mg, 523 μmol, 32.91% yield, 99.1% purity in LCMS) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.47 - 7.43 (m, 3H), 7.41 - 7.29 (m, 2H), 3.42 (s, 3H), 2.51 - 2.46 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). (ESI+) m/z: 266.8 (M+H)+ (C12H13BrN2). [0500] C.3-(5-(4-Ethyl-1-methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-4-ethyl-1-methyl-5-phenyl-imidazole 139 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (140 mg, 523 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (387 mg, 1.05 mmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.100 mL) was added RuPhos Pd G3 (43.76 mg, 52.33 μmol, 0.1 eq) and K3PO4 (222 mg, 1.05 mmol, 2.00 eq) at 25 °C under N2. The mixture was stirred for 3 h at 100 °C under N2. The mixture diluted with DCM (20.0 mL), filtered and the filtrate was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 20/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.35) to give the crude product. The crude product by prep-HPLC using a Phenomenex luna (150 mm x 25 mm x 10 μm) and gradiente of 5 - 35% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (69.83 mg, 161.50 μmol, 30.8% yield, 99.1% purity in HPLC) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.02 (s, 1H), 7.92 (s, 2H), 7.57 - 7.49 (m, 5H), 5.19 - 5.14 (m, 1H), 4.60 - 4.43 (m, 2H), 3.65 (s, 3H), 2.98 - 2.89 (m, 1H), 2.60 - 2.52 (m, 3H), 2.43 - 2.42 (m, 1H), 2.06 - 2.03 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H). (ESI+) m/z: 429.1 (M+H)+ (C25H24N4O3). EXAMPLE 56 [0501] Synthesis of 3-[5-[1-methyl-5-phenyl-4-(tetrahydropyran-4-ylmethyl)imidazol- 2-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione: [0502] A. 1-Methyl-5-phenyl-4-(tetrahydropyran-4-ylidenemethyl)imidazole: To a solution of 4-bromo-1-methyl-5-phenyl-imidazole (500 mg, 2.11 mmol, 1.00 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added 4,4,5,5-tetramethyl-2-(tetrahydropyran-4- ylidenemethyl)-1,3,2-dioxaborolane (945 mg, 4.22 mmol, 2.00 eq), K3PO4 (1.34 g, 6.33 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (137 mg, 211 μmol, 0.10 eq). The mixture was stirred at 65 °C for 16 h under N2. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.43 (Petroleum ether: Ethyl acetate = 3: 1)) to give the title compound (490 mg, 1.89 mmol, 91.2% yield, 98% purity in LCMS at 220 nm) as 140 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.50 - 7.38 (m, 4H), 7.32 (d, J = 6.8 Hz, 2H), 5.96 (s, 1H), 3.75 - 3.66 (m, 4H), 3.53 (s, 3H), 3.01 (t, J = 5.2 Hz, 2H), 2.27 (t, J = 5.2 Hz, 2H). (ESI+) m/z: 255.1 (M+H)+, (C16H18N2O). [0503] B. 1-Methyl-5-phenyl-4-(tetrahydropyran-4-ylmethyl)imidazole: To a solution of 1-methyl-5-phenyl-4-(tetrahydropyran-4-ylidenemethyl)imidazole (490 mg, 1.93 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (205 mg, 10.0% purity) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (20 Psi) at 25 °C for 8 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound (480 mg, 1.87 mmol, 97.1% yield) as yellow oil, which was used in the next step directly without further purification.1H NMR: (400 MHz, DMSO-d6) δ 7.58 (m, 1H), 7.50 - 7.44 (m, 2H), 7.41 - 7.36 (m, 1H), 7.35 - 7.31 (m, 2H), 3.73 (m, 2H), 3.46 (s, 3H), 3.19 - 3.15 (m, 2H), 2.33 (d, J = 7.2 Hz, 2H), 1.82 (m, 1H), 1.51 - 1.42 (m, 2H), 1.08 - 1.05 (m, 2H). (ESI+) m/z: 257.1 (M+H)+, (C16H20N2O). [0504] C. 2-Bromo-1-methyl-5-phenyl-4-(tetrahydropyran-4-ylmethyl)imidazole: To a solution of 1-methyl-5-phenyl-4-(tetrahydropyran-4-ylmethyl)imidazole (470 mg, 1.83 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (358 mg, 2.02 mmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.43 (Petroleum ether: Ethyl acetate = 1: 1)) to give the title compound (600 mg, 1.70 mmol, 92.7% yield, 95.0% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.54 - 7.47 (m, 2H), 7.44 (m, 1H), 7.35 (m, 2H), 3.78 - 3.68 (m, 2H), 3.39 (s, 3H), 3.19 (t, J = 11.2 Hz, 2H), 2.30 (d, J = 6.8 Hz, 2H), 1.86 - 1.73 (m, 1H), 1.46 (d, J = 12.4 Hz, 2H), 1.28 - 1.14 (m, 1H), 1.07 (m, 1H). (ESI+) m/z: 335.0 (M+H)+, (C16H19BrN2O). [0505] D. 3-[5-[1-Methyl-5-phenyl-4-(tetrahydropyran-4-ylmethyl)imidazol-2-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-5-phenyl-4- (tetrahydropyran-4-ylmethyl)imidazole (200 mg, 596 μmol, 1.00 eq) in dioxane (4.00 mL) was added H2O (0.20 mL), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (552 mg, 1.49 mmol, 2.50 eq), Ru-Phos-Pd-G3 (99.7 mg, 119 μmol, 0.20 eq) and K3PO4 (379 mg, 1.79 mmol, 3.00 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.24) and purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient 141 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT of 7 - 37% acetonitrile in water containing 0.5% FA over 13 min at a flow rate of 25.0 mL/min to give the title compound (39.9 mg, 79.2 μmol, 13.2% yield, 99.0% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.96 (m, 1H), 7.90 - 7.81 (m, 2H), 7.57 - 7.50 (m, 2H), 7.44 (m, 3H), 5.15 (m, 1H), 4.59 - 4.38 (dd, J = 17.2, 52 Hz, 2H), 3.75 (br d, J = 8.8 Hz, 2H), 3.56 (s, 3H), 3.22 (m, 2H), 2.99 - 2.87 (m, 1H), 2.64 (m, 1H), 2.43 (d, J = 6.8 Hz, 3H), 2.09 - 1.99 (m, 1H), 1.94 - 1.83 (m, 1H), 1.54 (d, J = 12.8 Hz, 2H), 1.15 - 1.02 (m, 2H) (ESI+) m/z: 499.2 (M+H)+, (C29H30N4O4). EXAMPLE 57 [0506] Synthesis of 3-(6-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-3-oxo-1,3- dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione: [0507] A. Methyl 6-chloro-4-methylnicotinate: To a solution of 6-chloro-4-methyl- pyridine-3-carboxylic acid (5.00 g, 29.1 mmol, 1.00 eq) in SOCl2 (40.9 g, 344 mmol, 25.0 mL, 11.8 eq) was addded DMF (213 mg, 2.91 mmol, 224 μL, 0.10 eq) at 25 °C under N2. The mixture was stirred at 25 °C for 4 h.The dropwised slowly MeOH (15.8 g, 494 mmol, 20.0 mL, 16.9 eq) to the mixture. The mixture was stirred at 10 min. The mixture was concentrated under reduced pressure to get a residue at 50 °C. Then the residuewas dissolved with MeOH (50.0 mL) and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1/0 to 20/1, TLC: Petroleum ether / Ethyl acetate = 5/1, Rf = 0.30) to give the title compound (3.70 g, 19.9 mmol, 68.4% yield, 100% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.56 (s, 1H), 3.85 (s, 3H), 2.51 (s, 3H). (ESI+) m/z: 186.0 (M+H)+, (C8H8O2Cl). [0508] B. Methyl 4-(bromomethyl)-6-chloronicotinate: To a solution of methyl 6- chloro-4-methyl-pyridine-3-carboxylate (3.70 g, 19.9 mmol, 1.00 eq) in CCl4 (37.0 mL) was addded NBS (3.90 g, 21.9 mmol, 1.10 eq) and AIBN (654 mg, 3.99 mmol, 0.20 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 16 h. The mixture was poured into H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a 142 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1/0 to 50/1, TLC: Petroleum ether/Ethyl acetate = 50/1, Rf = 0.30) to give the title compound (3.70 g, 6.70 mmol, 33.6% yield, 47.9% purity in HPLC at 220 nm) as a yellow solid.. (ESI+) m/z: 265.9 (M+H)+, (C8H7NO2ClBr). [0509] C. 3-(6-Chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine- 2,6-dione: To a solution of methyl 4-(bromomethyl)-6-chloro-pyridine-3-carboxylate (3.47 g, 6.29 mmol, 1.00 eq) and 3-aminopiperidine-2,6-dione (1.55 g, 9.43 mmol, 1.50 eq, HCl) in DMF (87.0 mL) was addded DIEA (1.62 g, 12.5 mmol, 2.19 mL, 2.00 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 16 h. The mixture was poured into H2O ( 500 mL ) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 5/1, TLC: Petroleum ether / Ethyl acetate = 5/1, Rf = 0.30) to give the title compound (370 mg, 1.24 mmol, 19.7% yield, 93.8% purity in HPLC at 220 nm) as a green solid.1H NMR: (400 MHz, DMSO-d6) δ11.0 (s, 1H), 8.79 (s, 1H), 7.86 (s, 1H), 5.13 = 13.2 Hz, J2 = 5.2 Hz, 1H), 4.58 - 4.41 (m, 2H), 2.95 - 2.86 (m, 1H), 2.62 - 2.57 (m, 1H), 2.42 - 2.32 (m, 1H), 2.02 - 1.99 (m, 1H). (ESI+) m/z: 280.0 (M+H)+, (C12H10N3O3Cl). [0510] D. 1-(Difluoromethyl)-5-phenyl-3-(tributylstannyl)-1H-pyrazole: To a solution of 3-bromo-1-(difluoromethyl)-5-phenyl-pyrazole (1.50 g, 5.49 mmol, 1.00 eq) in toluene (15.0 mL) was addded Pd(PPh3)4 (634 mg, 549 μmol, 0.10 eq) and tributyl(tributylstannyl)stannane (7.45 g, 12.8 mmol, 6.43 mL, 2.34 eq) at 25 °C under N2. The mixture was stirred at 110 °C for 16 h. The mixture was quenched by adding dropwise saturated KF solution (50.0 mL ) at - 40 °C, then the mixture was poured into NH4Cl solution (100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 100/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to get the compound (500 mg, 1.03 mmol, 18.8% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.50 - 7.44 (m, 5H), 7.39 - 7.12 (m, 1H), 6.44 (s, 1H), 1.62 - 1.36 (m, 6H), 1.35 - 1.33( m, 6H), 1.16 - 1.12 (m, 6H), 0.93 - 0.89 (m, 9H). (ESI+) m/z: 484.3 (M+H)+, (C22H34N2SnF2). [0511] E. 3-(6-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-3-oxo-1,3-dihydro-2H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione: To a solution of 1-(difluoromethyl)-5- 143 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT phenyl-3-(tributylstannyl)-1H-pyrazole (194 mg, 402 μmol, 1.20 eq) in dioxane (6.00 mL) was added cataCXiumA Pd G2 (44.8 mg, 67.0 μmol, 0.200 eq) at 25 °C under N2. Then 3-(6- chloro-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (100 mg, 335 μmol, 1.00 eq) was added to the mixture. The mixture was stirred at 110 °C for 4 h under N2. The mixture was concentrated under vacuum at 45 °C to get residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 50/1, TLC: DCM/MeOH = 20/1, Rf = 0.30) to get residue 1. The residue 1 was purified by preparative-HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 27% - 57% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (59.9 mg, 137 μmol, 40.8% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 7.97 - 7.66 (m, 1H), 7.65 - 7.58 (m, 5H), 7.27 (s, 1H), 5.20 - 5.15 (m, 1H), 4.66 - 4.49 (m, 2H), 2.97 - 2.88 (m, 1H), 2.66 - 2.59 (m, 1H), 2.44 - 2.32 (m, 1H), 2.05 - 2.02 (m, 1H). (ESI+) m/z: 438.1 (M+H)+, (C22H17N5O3F2). EXAMPLE 58 [0512] Synthesis of 3-(6-(1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-3- oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione: [0513] A. (1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)boronic acid: To a solution of 4-bromo-1-methyl-2-[4-(trifluoromethyl)phenyl]imidazole (600 mg, 1.92 mmol, 1.00 eq) in dioxane (6.00 mL) was added BPD (976 mg, 3.85 mmol, 2.00 eq), XPhos (183 mg, 384 μmol, 0.20 eq), KOAc (377 mg, 3.85 mmol, 2.00 eq) and Pd2(dba)3 (176 mg, 192 μmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 12 h under N2. The mixture was concentrated under reduced pressure to give the title compound (500 mg, Crude) as a black brown solid. (ESI+) m/z: 270.9 (M+H)+, (C11H10N2BF3O2). [0514] B. 3-(6-(1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-3-oxo-1,3- dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione: To a solution of (1-methyl- 2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)boronic acid (289 mg, 1.07 mmol, 2.00 eq) and 3-(6-chloro-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (153 mg, 536 μmol, 1.00 eq) in dioxane (3.00 mL) and H2O (0.750 mL) was added Cs2CO3 (349 mg, 1.07 mmol, 2.00 eq), Pd(OAc)2 (12.0 mg, 53.6 μmol, 0.10 eq) and bis(1-adamantyl)-butyl- 144 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT phosphane (38.4 mg, 107 μmol, 0.20 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 1 h. The mixture was concentrated under reduced pressure to get a residue. The crude product was purified by Preparative -TLC (Dichloromethane/Methanol = 15/1, Rf = 0.29) to get a residue. to get a residue. The residue was purified by Preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradiente of 18 - 48% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (41.99 mg, 87.3 μmol, 16.2% yield, 97.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO)δ 11.0 (s, 1H), 8.88 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 5.13 - 5.08 (m, 1H), 4.46 - 4.28 (m, 2H), 3.97(s, 3H), 2.93 - 2.91 (m, 1H), 2.63 - 2.59 (m, 1H), 2.45 - 2.43 (m, 1H), 2.05 - 2.00 (m, 1H). (ESI+) m/z: 470.1 (M+H)+ (C23H18N5O3F3). EXAMPLE 59 [0515] Synthesis of 3-(2-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-5-oxo-5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione: [0516] A. Methyl 2-(bromomethyl)-6-chloronicotinate: A mixture of methyl 6-chloro- 2-methylnicotinate (1.00 g, 5.39 mmol, 1.00 eq) and AIBN (176 mg, 1.08 mmol, 0.20 eq) in CCl4 (5.00 mL) was degassed and purged with N2 for 3 times, and then was added NBS (767 mg, 4.31 mmol, 0.80 eq) the mixture was stirred at 80°C for 12 h under N2 atmosphere. After the reaction was completed, the solids were filtered off and the filtrate was concentrated under vacuum to give crude product. The residue was purified by column chromatography (SiO2, Ethyl acetate: Petroleum ether = 500: 1 to 100: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate = 10: 1)) to give the title compound (800 mg, crude) was obtained as a yellow oil.1H NMR: (400 MHz,CDCl3) δ 8.26 - 8.24 (m, 1H), 7.38 - 7.36 (m, 1H), 4.98 (s, 2H), 3.98 (s, 3H). (ESI+) m/z: 265.8 (M+H)+, C8H7O2ClNBr. [0517] B. 3-(2-Chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione: A mixture of methyl 2-(bromomethyl)-6-chloronicotinate (100 mg, 378 μmol, 1.00 eq) in DMF (2 mL) and then was added 3-aminopiperidine-2,6-dione (58.1 mg, 353 μmol, 3.00 eq, HCl), DIEA (97.7 mg, 756 μmol, 131 μL, 2.00 eq) was degassed and purged 145 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT with N2 for 3 times, and then the mixture was stirred at 100°C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was quenched by H2O (30.0 mL) and extracted with dichloromethane 30.0 mL (3 x 30.0 mL). The combined organic layers were washed with saturated sodium chloride solution 50.0 mL (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1, Rf = 0.5) to give title compound (34.0 mg, 120 μmol).1H NMR: (400 MHz,CDCl3) δ 8.13 - 8.11 (m, 1H), 7.50 - 7.48 (m, 1H), 4.56 - 4.37 (m, 2H), 3.95 (s, 1H), 2.90 - 2.85 (m, 1H), 2.44 - 2.39 (m, 2H), 2.89 - 2.7 (m, 2H). (ESI+) m/z: 280.0 (M+H)+, C12H10O3N3Cl [0518] C. 3-(2-Chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine- 2,6-dione: A mixture of 1-(difluoromethyl)-5-phenyl-3-(tributylstannyl)-1H-pyrazole (190 mg, 393 μmol, 1.10 eq) and 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)piperidine-2,6-dione (100 mg, 357 μmol, 1.00 eq) in dioxane (5.00 mL) was added cataCXium A-Pd-G2 (47.8 mg, 71.5 μmol, 0.20 eq) and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 4 h under N2 atmosphere. The reaction mixture was concentrated. Water (10.0 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (3 x 10.0 mL). The combined organic phase was washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.. The crude product was purified by preparative-HPLC using a Welch Xtimate C18 150 x 25 mm x 5 μm) and gradiente of 24 - 54% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give title compound (40.5 mg, 91.8 μmol, 25.6% yield, 99.0% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.13 - 10.92 (m, 1H), 8.31 - 8.18 (m, 2H), 7.99 – 7.70 (m, 1H), 7.66 - 7.54 (m, 5H), 7.27 (s, 1H), 5.22 - 5.18 (m, 1H), 4.67 - 4.40 (m, 2H), 3.00 - 2.89 (m, 1H), 2.69 - 2.62 (m, 1H), 2.46 - 2.39 (m, 1H), 2.11 - 2.01 (m, 1H). (ESI+) m/z: 438.1 (M+H)+, (C22H17F2N5O3) 146 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 60 [0519] Synthesis of 3-(5-(1-methyl-5-phenyl-4-(pyrrolidine-1-carbonyl)-1H-imidazol- 2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0520] A. (1-Methyl-1H-imidazol-4-yl)(pyrrolidin-1-yl)methanone: To a solution of 1- methyl-1H-imidazole-4-carboxylic acid (3.00 g, 23.7 mmol, 1.00 eq), pyrrolidine (3.38 g, 47.5 mmol, 3.97 mL, 2.00 eq), EDCI (5.47 g, 28.5 mmol, 1.20 eq) and HOBt (3.86 g, 28.5 mmol, 1.20 eq) in ACN (30.0 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into H2O (100 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 15:1, TLC: Dichloromethane: Methanol=15: 1, Rf = 0.40) to give the title compound (3.70 g, 20.3 mmol, 85.4% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.61 (s, 2H), 3.96 – 3.87 (m, 2H), 3.67 (s, 3H), 3.43 - 3.40 (m, 2H), 1.88 - 1.75(m, 4H). (ESI+) m/z: 180.0 (M+H)+, (C9H13N3O). [0521] B. (1-Methyl-5-phenyl-1H-imidazol-4-yl)(pyrrolidin-1-yl)methanone: To a solution of (1-methyl-1H-imidazol-4-yl)(pyrrolidin-1-yl)methanone (1.00 g, 5.58 mmol, 1.00 eq), bromobenzene (2.63 g, 16.74 mmol, 1.76 mL, 3.00 eq) P(oxole)3 (259 mg, 1.12 mmol, 0.20 eq), K2CO3 (1.54 g, 11.2 mmol, 2.00 eq) in DMF (15.0 mL) was added Pd(OAc)2 (125 mg, 557 mmol, 0.10 eq) under N2.The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was poured into H2O (100 mL) and extracted with Dichloromethane (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25 mm x 5 μm) and gradiente of 1 - 31% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (300 mg, 1.17 mmol, 21.0% yield, 99.8% purity in HPLC at 220 nm) as light yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.56 - 7.40 (m, 5H), 3.62 (s, 3H), 3.40 – 3.16(m, 4H), 1.70 (s, 4H). (ESI+) m/z: 256.2 (M+H)+, (C15H17N3O). 147 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0522] C. (2-Bromo-1-methyl-5-phenyl-1H-imidazol-4-yl)(pyrrolidin-1-yl)methanone: To a solution of (1-methyl-5-phenyl-1H-imidazol-4-yl) (pyrrolidin-1-yl)methanone (400 mg, 1.57 mmol, 1.00 eq) in DMF (10.0 mL) was added NBS (334 mg, 1.88 mmol, 1.20 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (100 mL) and extracted with Dichloromethane (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Dichloromethane: Methanol=15: 1, Rf = 0.50) to give the title compound (280 mg, 814 μmol, 51.9% yield, 97.2% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) 7.47 - 7.41 (m, 5H), 3.52 – 3.49 (m, 2H), 3.43 (s, 3H), 3.38 – 3.36(m, 2H), 1.78 - 1.70 (m, 4H). (ESI+) m/z: 335.7 (M+H)+, (C15H16BrN3O). [0523] D. 3-(5-(1-Methyl-5-phenyl-4-(pyrrolidine-1-carbonyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of (2-bromo-1-methyl-5-phenyl-1H- imidazol-4-yl)(pyrrolidin-1-yl)methanone (200 mg, 598 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (553 mg, 1.5 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (381 mg, 1.80 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (50.0 mg, 59.8 μmol, 0.20 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 11% - 41% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (102 mg, 205 μmol, 34.2% yield, 99.4% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6): δ 11.02 – 10.99 (m, 1H), 8.02 - 7.88 (m, 3H), 7.56 - 7.46 (m, 5H), 5.18 - 5.14 (m, 1H), 4.59 - 4.42 (m, 2H), 3.60 – 3.56 (m, 3H), 3.54 – 3.52 (m, 2H), 3.41 – 3.37 (m, 2H), 2.96 – 2.92 (m, 1H), 2.64 – 2.60 (m, 1H), 2.46 - 2.42 (m, 1H), 2.05 – 2.02 (m, 1H), 1.77 – 1.72 (m, 4H),. (ESI+) m/z: 498.2 (M+H)+, (C28H27N5O4). EXAMPLE 61 [0524] Synthesis of 3-(1-oxo-5-(3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2- yl)isoindolin-2-yl)piperidine-2,6-dione: 148 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0525] A. 3-Iodo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole: To a solution of 5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (1.00 g, 6.57 mmol, 1.00 eq) in DMF (5.00 mL) was added NIS (1.77 g, 7.89 mmol, 1.20 eq) and NaHCO3 (662 mg, 7.89 mmol, 306 μL, 1.20 eq) at 25 °C. The mixture was stirred at 60 °C for 12 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (3 x 10.0 mL) to collect the organic layers. The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 30/1 to 4/1, TLC: Petroleum ether/Ethyl acetate = 2/1, Rf = 0.24) to give the title compound (950 mg, 4.02 mmol, 61.1% yield, 99.0% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz,CDCl3) δ 7.48 (s, 1H), 4.22 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.63 (m, 2H). (ESI+) m/z: 235.0 (M+H)+ (C6H7N2I). [0526] B. 3-Phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole: To a solution of 3-iodo-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole (950 mg, 4.02 mmol, 1.00 eq) and phenylboronic acid (734 mg, 6.03 mmol, 1.50 eq) in DMF (10.0 mL) and water (0.100 mL) was added K2CO3 (1.67 g, 12.0 mmol, 3.00 eq) and Pd(PPh3)4 (464 mg, 401 μmol, 0.10 eq) at 25 °C under N2. The mixture was stirred at 110 °C under N2 for 12 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2 x 50.0 mL) to collect the organic layers. The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 30/1 to 5/1, TLC: Petroleum ether/Ethyl acetate = 3/1, Rf = 0.22) to give the title compound (300 mg, 848 μmol, 21.1% yield, 52.1% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.49 - 7.43 (m, 4H), 7.25 – 7.20 (m, 1H), 4.19 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.73 - 2.66 (m, 2H). (ESI+) m/z: 185.3 (M+H)+, (C12H12N2). [0527] C. 2-Bromo-3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole: To a solution of 3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (300 mg, 848 μmol, 1.00 eq) in ACN (3.00 mL) was added NBS (196 mg, 1.10 mmol, 1.30 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (2 x 10.0 mL) to collect the organic layers. The combined organic layers was washed with brine (30.0 mL) and dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by Preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradiente of 40 - 70% 149 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) to give the title compound (75.0 mg, 285 μmol, 33.6% yield, 100% purity in LCMS at 220 nm) as a colorless oil.1H NMR: (400 MHz,CDCl3) δ7.54 – 7.52 (m, 2H), 7.42 – 7.40 (m, 2H), 7.35 – 7.30 (m, 1H), 4.20 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 6.8 Hz, 2H), 2.73 - 2.66 (m, 2H). (ESI+) m/z: 263.0 (M+H)+, (C12H11N2Br). [0528] D. 3-(1-Oxo-5-(3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 2-bromo-3-phenyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole (75.0 mg, 285 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (263 mg, 712 μmol, 2.50 eq) in dioxane (1.00 mL) and water (0.0500 mL) was added RuPhos Pd G3 (23.8 mg, 28.5 μmol, 0.10 eq) and K3PO4 (121 mg, 570 μmol, 2.00 eq) at 25 °C under N2. The mixture was stirred for 3 h at 100 °C under N2. The mixture was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.31) to get a residue. The residue was purified by Preparative-HPLC using a Welch Ultimate C18 (150 mm x 25 mm x 5 μm) and gradiente of 28 - 58% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (86.5 mg, 201 μmol, 70.7% yield, 99.4% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 9.2 Hz, 1H), 7.33 (t, J = 6.8 Hz, 2H), 7.23 (t, J = 7.6 Hz, 3H), 5.11 - 5.06 (m, 1H), 4.45 - 4.25 (m, 2H), 4.19 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.96 - 2.94 (m, 1H), 2.62 - 2.61 (m, 3H), 2.39 - 2.32 (m, 1H), 2.00 - 1.99 (m, 1H). (ESI+) m/z: 427.2 (M+H)+, (C25H22N3O4). EXAMPLE 62 [0529] Synthesis of 3-(5-(2-(4-(2-hydroxypropan-2-yl)phenyl)-1-methyl-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0530] A. 2-(4-(4-Bromo-1-methyl-1H-imidazol-2-yl)phenyl)propan-2-ol: To a solution of 2,4-dibromo-1-methyl-imidazole (500 mg, 2.08 mmol, 1.00 eq) in THF (10.0 mL) was added [4-(1-hydroxy-1-methyl-ethyl)phenyl]boronic acid (412 mg, 2.29 mmol, 1.10 eq), K3PO4 (1.33 g, 6.25 mmol, 3.00 eq), tris(4-fluorophenyl)phosphane (32.9 mg, 104 μmol, 0.05 150 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT eq) and Pd(OAc)2 (23.4 mg, 104 μmol, 0.05 eq) under N2. The mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative- TLC (Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.40) to give the title compound (350 mg, 1.12 mmol, 53.5% yield, 94.1% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.61 - 7.55 (m, 4H), 7.39 (s, 1H), 5.11 (s, 1H), 3.71 (s, 3H), 1.45 (s, 6H). (ESI+) m/z: 295.0 (M+H)+, (C13H15N2BrO). [0531] B. 3-(5-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-[4-(4-bromo-1-methyl- imidazol-2-yl)phenyl]propan-2-ol (300 mg, 956 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (885 mg, 2.39 mmol, 2.50 eq), Ru-Phos-Pd G3 (79.9 mg, 95.6 μmol, 0.10 eq) and K3PO4 (406. mg, 1.91 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 5 μm) and gradient of 0 - 30% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min to give the title compound (178 mg, 368 μmol, 38.5% yield, 94.9% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 5.14 (dd, J = 13.2, 5.2 Hz, 1H), 4.48 (dd, J = 53.6, 17.2 Hz, 2H), 3.87 (s, 3H), 2.97 - 2.88 (m, 1H), 2.64 - 2.59 (m, 1H), 2.46 - 2.42 (m, 1H), 2.05 - 2.01 (m, 1H), 1.49 (s, 6H). (ESI+) m/z: 459.2 (M+H)+, (C26H26N4O4). EXAMPLE 63 [0532] Synthesis of 3-(5-(2-(3-chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0533] A. 4-Bromo-1-methyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1H-imidazole: To a solution of 2,4-dibromo-1-methyl-1H-imidazole (600 mg, 2.50 mmol, 1 eq) in THF (10.0 mL) was added (2-methyl-4-(trifluoromethyl)phenyl)boronic acid (561 mg, 2.75 mmol, 151 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1.10 eq), K3PO4 (1.59 g, 7.50 mmol, 3.00 eq), tris(4-fluorophenyl)phosphane (39.5 mg, 125 μmol, 0.0500 eq) and Pd(OAc)2 (28.0 mg, 125 μmol, 0.0500 eq) at 25 °C, then the mixture was stirred at 80 °C for 16 h under N2. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 5/1, TLC: Petroleum ether/Ethyl acetate = 7/1, Rf = 0.33). The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 40 - 70% acetonitrile in water containing 0.05% FA over 20 min at a flow rate of 25 mL/min to give the title compound (150 mg, 470 μmol, 18.7% yield, 100% purity LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 3.47 (s, 3H), 2.27 (s, 3H). (ESI+) m/z: 320.7 (M+H)+, (C12H10BrF3N2). [0534] B. 3-(5-(1-Methyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-2-(2-methyl- 4-(trifluoromethyl)phenyl)-1H-imidazole (150 mg, 470 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (435 mg, 1.18 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (199 mg, 940 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (39.3 mg, 47.0 μmol, 0.100 eq) at 25 °C, then the mixture was stirred at 100 °C for 4 h under N2. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 33/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.32) to give a residue. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 14 - 44% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (31.6 mg, 64.9 μmol, 13.8% yield, 99.1% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.99 (d, J = 10 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.72 - 7.64 (m, 3H), 5.12 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.50 - 4.32 (m, 2H), 3.55 (s, 3H), 2.92 - 2.87 (m, 1H), 2.62 - 2.58 (m, 1H), 2.42 - 2.38 (m, 1H), 2.35(s, 3H), 2.02 - 1.99 (m, 1H). (ESI+) m/z: 483.2 (M+H)+, (C25H21F3N4O3). 152 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 64 [0535] Synthesis of 3-(5-(1-methyl-2-(3-methyl-4-(trifluoromethyl)phenyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0536] A. 4-Bromo-1-methyl-2-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazole: To a solution of 2,4-dibromo-1-methyl-1H-imidazole (500 mg, 2.08 mmol, 1.00 eq) and (3- methyl-4-(trifluoromethyl)phenyl)boronic acid (467 mg, 2.29 mmol, 1.10 eq) in THF (10.0 mL) and H2O (0.500 mL) was added K3PO4 (1.33 g, 6.25 mmol, 3.00 eq), tris(4- fluorophenyl)phosphine (32.9 mg, 104 μmol, 0.0500 eq) and Pd(OAc)2 (23.4 mg, 104 μmol, 0.05 eq) at 25 °C under N2. Then the mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, PE/EtOAc = 100/0 to 20/1, TLC: PE/EtOAc = 5/1, Rf = 0.50) to get a residue. The residue was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 44-74% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 30 mL/min to give the title compound (210 mg, 658 μmol, 31.5% yield, 100% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CD3CN) δ 7.74 - 7.72 (m, 1H), 7.66 (s, 1H), 7.61 - 7.59 (m, 1H), 7.14 (s, 1H), 3.73 (s, 3H), 2.53 (s, 3H). (ESI+) m/z: 316.6 (M+H)+, (C12H10N2F3Br). [0537] B. 3-(5-(1-Methyl-2-(3-methyl-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-2-(3-methyl- 4-(trifluoromethyl)phenyl)-1H-imidazole (210 mg, 658 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (487 mg, 1.32 mmol, 2.00 eq) in dioxane (8.00 mL) and H2O (0.400 mL) was added K3PO4 (279 mg, 1.32 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (55.0 mg, 65.8 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 96/4, TLC: DCM/MeOH = 10/1, Rf = 0.50) to get a residue. The residue was purified by preparative- HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 18-48% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give 153 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT the title compound (52.7 mg, 109 μmol, 16.5% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.96 - 7.94 (m, 1H), 7.88 (s, 1H), 7.80 (s, 2H), 7.73 (t, J = 8.0 Hz, 1H), 5.10 (dd, J = 5.2 Hz, J = 13.2 Hz, 1H), 4.52 - 4.34 (m, 2H), 3.86 (s, 3H), 2.93 - 2.92 (m, 1H), 2.63 - 2.58 (m, 1H), 2.54 (s, 3H), 2.43 - 2.40 (m, 1H), 2.03 - 2.01 (m, 1H). (ESI+) m/z: 483.1 (M+H)+, (C25H21N4O3F3). EXAMPLE 65 [0538] Synthesis of 3-(5-(5-methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0539] A. Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate: To a solution of tetrahydro-2H-pyran-4-ol (5.00 g, 48.9 mmol, 4.89 mL, 1.00 eq) in DCM (30.0 mL) was added TEA (7.43 g, 73.4 mmol, 10.2 mL, 1.50 eq) at 25°C. The mixture was stirred at 0 °C. Then TosCl (10.2 g, 53.8 mmol, 1.10 eq) in DCM (20.0 mL) was added to the mixture. The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (100 mL) and extracted with DCM (3 x 50.0 mL) to collect the organic layers. The combined organic layers was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, PE/EtOAc = 50/1 to 10/1, TLC: PE/EtOAc= 3/1, Rf = 0.48) to give the title compound (7.70 g, 30.0 mmol, 61.3% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.82 - 7.80 (m, 2H), 7.36 - 7.34 (m, 2H), 4.73 - 4.67 (m, 1H), 3.90 - 3.85 (m, 2H), 3.50 - 3.44 (m, 2H), 2.45 (s, 3H), 1.87 - 1.84 (m, 2H), 1.77 - 1.74 (m, 2H). (ESI+) m/z: 273.9 (M+18)+, (C12H16O4S). [0540] B. 5-Methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole: To a solution of tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (3.89 g, 15.1 mmol, 1.20 eq) in DMF (15.0 mL) was added 5-methyl-4-phenyl-1H-pyrazole (2.00 g, 12.6 mmol, 1.00 eq) and Cs2CO3 (5.56 g, 17.0 mmol, 1.35 eq) at 25 °C. The mixture was stirred at 80 °C for 12 h. The mixture was poured into water (50.0 mL) and extracted with ethyl acetate (3 x 20.0 mL) to collect the organic layers. The combined organic layers was washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, 154 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT PE/EtOAc = 30/1 to 5/1, TLC: PE/EtOAc= 2/1, Rf = 0.35) to give the title compound (530 mg, 2.13 mmol, 16.8% yield, 97.6% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.42 - 7.38 (m, 4H), 7.37 - 7.35 (m, 1H), 4.30 - 4.27 (m, 1H), 4.18 - 4.14 (m, 2H), 3.60 - 3.54 (m, 2H), 2.42 (s, 3H), 2.39 - 2.36 (m, 2H), 1.92 - 1.88 (m, 2H). (ESI+) m/z: 243.1 (M+H)+, (C15H18N2O). [0541] C. 3-Bromo-5-methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole: To a solution of 5-methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (330 mg, 1.33 mmol, 1.00 eq) in ACN (3.50 mL) was added NBS (189 mg, 1.06 mmol, 0.800 eq) at 25 °C. Then the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (2 x 50.0 mL) to get the organic layers, the organic layers was washed with brine (20.0 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by preparative-TLC (TLC: PE/EtOAc= 2/1, Rf= 0.55) to get a residue. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 42-72% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 30 mL/min) to get the solution. The solution was adjusted to pH = 7 with saturated solution of NaHCO3 solution and extracted with DCM (2 x 50.0 mL) to get the organic layers, the organic layers was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give the title compound (80.0 mg, 248 μmol, 18.6% yield, 99.7% purity in LCMS at 220 nm) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.45 - 7.41 (m, 2H), 7.35 - 7.32 (m, 3H), 4.17 - 4.16 (m, 1H), 4.14 - 4.13 (m, 2H), 3.57 - 3.51 (m, 2H), 2.44 - 2.35 (m, 2H), 2.32 (s, 3H), 1.92 - 1.86 (m, 2H). (ESI+) m/z: 322.7 (M+H)+, (C15H17N2OBr). [0542] D. 3-(5-(5-Methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To s solution of 3-bromo-5-methyl-4-phenyl-1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazole (80.0 mg, 248 μmol, 1 eq) and 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (229 mg, 620 μmol, 2.50 eq) in dioxane (3.00 mL) and H2O (0.15 mL) was added K3PO4 (105 mg, 496 μmol, 2.00 eq) and Ruphos-Pd-G3 (20.7 mg, 24.8 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 97.5/2.5, TLC: DCM/MeOH = 10/1, Rf = 0.50) to get a residue. The residue was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 30-60% acetonitrile in 155 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (75.1 mg, 155 μmol, 62.4% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.58 - 7.56 (m, 2H), 7.39 - 7.31 (m, 4H), 7.19 - 7.17 (m, 2H), 5.10 (dd, J = 4.8 Hz, J = 13.2 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.40 - 4.22 (m, 2H), 4.02 - 3.99 (m, 2H),3.56 - 3.50 (m, 2H), 2.95 - 2.85 (m, 1H), 2.60 - 2.56 (m, 1H), 2.35 - 2.29 (m, 1H), 2.27 (s, 3H), 2.18 - 2.14 (m, 3H), 1.93 - 1.90 (m, 2H). (ESI+) m/z: 485.2 (M+H)+, (C28H28N4O4). EXAMPLE 66 [0543] Synthesis of 3-(5-(1-methyl-4-(oxetan-3-ylmethyl)-5-phenyl-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0544] A. 4,4,5,5-Tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane: tetramethyl-piperidine (3.23 g, 22.9 mmol, 0.33 eq) was dissolved in THF (100 mL) and cooled to –30 °C under N2 atmosphere. Then n-BuLi (2.50 M, 9.16 mL, 0.33 eq) was added dropwise, and the reaction mixture was stirred at -30 °C for 30 min. Next, the reaction was cooled to –78 °C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (5.02 g, 18.7 mmol, 0.27 eq) in THF (37.0 mL) was added dropwise. After stirring for 30 min, a solution of oxetan-3-one (5.00 g, 69.3 mmol, 1.00 eq) in THF (37.0 mL) was added dropwise at –78 °C. The reaction mixture was allowed to slowly warm up to 25 °C, and stirred for 10 h. The mixture was cooled to 0 °C, and aq. NH4Cl (150 mL) was added dropwise. After stirring for 10 min, the mixture was filtered and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was washed with brine (150 mL), dried with the anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1: 1, Rf = 0.43 (Petroleum ether: Ethyl acetate = 1: 1)) to give the title compound (2.80 g, 14.2 mmol, 20.5% yield) as yellow oil. (ESI+) m/z: 197.1 (M+H)+, (C10H17BO3). [0545] B. 1-Methyl-4-(oxetan-3-ylidenemethyl)-5-phenyl-1H-imidazole: To a solution of 4-bromo-1-methyl-5-phenyl-imidazole (500 mg, 2.11 mmol, 1.00 eq) in dioxane (10.0 mL) 156 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was added H2O (2.50 mL), 4,4,5,5-tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2- dioxaborolane (826 mg, 4.22 mmol, 2.00 eq), K3PO4 (1.34 g, 6.33 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (137 mg, 210 μmol, 0.10 eq). The mixture was stirred at 65 °C for 10 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1: 1, Rf = 0.15 (Petroleum ether: Ethyl acetate = 1: 1)) to give the title compound (104 mg, 432 μmol, 20.4% yield) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.50 - 7.45 (m, 3H), 7.44 - 7.39 (m, 1H), 7.34 - 7.29 (m, 2H), 5.93 (m, 1H), 5.64 (m, 2H), 5.34 - 5.29 (m, 2H), 3.54 (s, 3H). (ESI+) m/z: 227.1 (M+H)+, (C14H14N2O). [0546] C. 1-Methyl-4-(oxetan-3-ylmethyl)-5-phenyl-1H-imidazole: To a solution of 1- methyl-4-(oxetan-3-ylidenemethyl)-5-phenyl-imidazole (344 mg, 1.52 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (161 mg, 152 μmol, 10.0% purity, 0.10 eq) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (20 Psi) at 25 °C for 10 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (282 mg, 1.19 mmol, 78.0% yield) as yellow oil, which was used in the next step directly without further purification.1H NMR: (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.52 - 7.45 (m, 2H), 7.43 - 7.33 (m, 3H), 4.56 (t, J = 6.8 Hz, 2H), 4.25 (t, J = 6.0 Hz, 2H), 3.47 (s, 3H), 3.24 - 3.14 (m, 1H), 2.77 (d, J = 8.0 [0547] D. 2-Bromo-1-methyl-4-(oxetan-3-ylmethyl)-5-phenyl-imidazole: To a solution of 1-methyl-4-(oxetan-3-ylmethyl)-5-phenyl-imidazole (282 mg, 1.19 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (232 mg, 1.30 mmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.43) to give the title compound (210 mg, 649 μmol, 54.7% yield) as yellow oil. (ESI+) m/z: 307.0 (M+H)+, (C14H15BrN2O). [0548] E. 3-(5-(1-methyl-4-(oxetan-3-ylmethyl)-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-4-(oxetan-3- ylmethyl)-5-phenyl-imidazole (210 mg, 683 μmol, 1.00 eq) in dioxane (4.00 mL) was added H2O (0.50 mL), K3PO4 (435 mg, 2.05 mmol, 3.00 eq), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (632 mg, 1.71 mmol, 2.50 eq), Ru- Phos-Pd-G3 (114 mg, 136 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: 157 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Methanol= 10: 1, Rf = 0.31) and purified by preparative-HPLC using a CD07-Daisogel SP- 100-8-ODS-PK (150 mm x 25 mm x 10 μm) and gradient of 20 - 50% acetonitrile in water containing 0.5% NH4HCO3 over 15 min at a flow rate of 25.0 mL/min to give the title compound (44.0 mg, 91.6 μmol, 13.4% yield, 98% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.94 (s, 1H), 7.89 - 7.80 (m, 2H), 7.58 - 7.51 (m, 2H), 7.49 - 7.43 (m, 3H), 5.15 (dd, J = 13.2, 5.2 Hz, 1H), 4.62 - 4.38 (m, 4H), 4.28 (t, J = 6.0 Hz, 2H), 3.56 (s, 3H), 3.26 (m, 1H), 2.98 - 2.91 (m, 1H), 2.87 (m, 2H), 2.62 (m, 1H), 2.41 (m, 1H), 2.08 - 1.99 (m, 1H). (ESI+) m/z: 471.2 (M+H)+, (C27H26N4O4). EXAMPLE 67 [0549] Synthesis of 3-[6-fluoro-5-[1-methyl-2-[4-(trifluoromethyl)phenyl]imidazol-4- yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione: [0550] A. 3-[6-Fluoro-5-[1-methyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-2-[4- (trifluoromethyl)phenyl]imidazole (100 mg, 327 μmol, 1.00 eq) in dioxane (4.00 mL) was added H2O (0.20 mL), 3-[6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (254 mg, 655 μmol, 2.00 eq), K3PO4 (208 mg, 983 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (54.8 mg, 65.5 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 3, Rf = 0.22) and purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 28 - 58% acetonitrile in water containing 0.5% FA over 13 min at a flow rate of 25.0 mL/min to give the title compound (15.0 mg, 29.6 μmol, 9.03% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.92 - 7.86 (m, 3H), 7.60 (d, J = 10 Hz, 1H), 5.12 (m, 1H), 4.54 - 4.33 (m, 2H), 3.90 (s, 3H), 2.97 - 2.85 (m, 1H), 2.62 (s, 1H), 2.43 - 2.36 (m, 1H), 2.07 - 1.98 (m, 1H). (ESI+) m/z: 487.1 (M+H)+, (C24H18F4N4O3). 158 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 68 [0551] Synthesis of 3-(5-(5-isobutyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0552] A. 5-Isobutyl-4-phenyl-4H-1,2,4-triazole-3-thiol: To a solution of isothiocyanatobenzene (2 g, 14.79 mmol, 1.77 mL, 1 eq) in EtOH (40 mL) was added 3- methylbutanehydrazide (1.72 g, 14.79 mmol, 1 eq) at 0 °C. The mixture was stirred at 80 °C for 2 h. After cooling, filtration, solid drying, the dried solid was added to 1N NaOH (40 mL) and refluxed for 2 h. After the reaction, it was neutralized with a 1 N hydrochloric acid solution. Filtered, washed with water to give the title compound (2.02 g, 8.64 mmol, 58.43% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H), 7.61 - 7.54 (m, 3H), 7.32 (d, J = 6.4 Hz, 2H), 2.37 (d, J = 7.2 Hz, 2H), 1.71 (s, 1H), 0.88 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 234.2 (M+H)+, (C12H15N3S). [0553] B. 3-Isobutyl-4-phenyl-4H-1,2,4-triazole: 5-isobutyl-4-phenyl-1,2,4-triazole-3- thiol (2 g, 8.57 mmol, 1 eq) was suspended in DCM (120 mL) , cooled to 0 °C and treated with H2O2 (2.97 g, 26.19 mmol, 2.52 mL, 30% purity, 3.06 eq) and AcOH (14.69 g, 244.55 mmol, 14 mL, 28.53 eq) dropwise, and then the mixture was stirred at 25 °C for1 h. The reaction mixture was poured into saturated Na2SO3 solution (5 mL). The reaction mixture was adjusted to pH=8 with 1N aq. NaOH. The aqueous layer was extracted with DCM (3 x 100 mL). The organic layer was washed with saturated Na2SO3 solution (100 mL). The aqueous layer was checked with starch potassium iodide paper. The organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 100: 80; TLC, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.29) to give the title compound (1.27 g, 4.51 mmol, 52.56% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.59 - 7.49 (m, 3H), 7.31 - 7.23 (m, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.062 - 1.995(m, 1H), 0.93 - 0.84 (m, 6H). (ESI+) m/z: 202.2 (M+H)+, (C12H15N3). [0554] B. 3-Bromo-5-isobutyl-4-phenyl-4H-1,2,4-triazole: A mixture of 3-isobutyl-4- phenyl-1,2,4-triazole (500 mg, 2.48 mmol, 1 eq), NBS (574.81 mg, 3.23 mmol, 1.3 eq) in ACN (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred 159 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT at 25 °C for 12 h under N2 atmosphere. The reaction mixture was poured into ice-H2O (10 mL). The aqueous layer was extracted DCM (3 x 20 mL). The combined organic layer was washed with brine (80 mL), dried over MgSO4, filtered and concentrated to give the title compound (872 mg, crude) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.64 - 7.55 (m, 3H), 7.28 - 7.22 (m, 2H), 2.55 (d, J = 7.2 Hz, 2H), 2.03 - 1.94 (m, 1H), 0.89 (d, J = 6.4 Hz, 6H). (ESI+) m/z: 281.7 (M+H)+, (C12H14BrN3). [0555] C. 3-(5-(5-Isobutyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-bromo-5-isobutyl-4-phenyl-1,2,4-triazole (300 mg, 1.07 mmol, 1 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (1.39 g, 3.75 mmol, 3.5 eq), K3PO4 (454.59 mg, 2.14 mmol, 2 eq) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (179.12 mg, 214.16 μmol, 0.2 eq) in dioxane (6 mL) and H2O (0.3 mL) was degassed and purged with N2 for 3 times at 25 °C, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to 25 °C and filtered. The filtrate was concentrated. The crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25mm x 5um) and gradient of 17%- 47% acetonitrile in water containing 0.05% TFA over 19 min at a flow rate of 25 mL/min to give the title compound (39.89 mg, 89.94 μmol, 8.40% yield, 98.9% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.67 - 7.61 (m, 2H), 7.58 - 7.53 (m, 3H), 7.448 - 7.425(m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.106 - 5.062 (m, 1H), 4.46 - 4.21 (m, 2H), 2.98 - 2.83 (m, 1H), 2.62 - 2.54 (m, 2H), 2.41 - 2.30 (m, 2H), 2.05 - 1.95 (m, 1H), 1.917 - 1.850 (m, 1H), 0.85 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 444.2 (M+H)+, (C25H25N5O3). EXAMPLE 69 [0556] Synthesis of 3-(5-(5-isobutyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0557] A. 5-Isobutyl-4-phenyl-4H-1,2,4-triazole-3-thiol: To a solution of isothiocyanatobenzene (2 g, 14.79 mmol, 1.77 mL, 1 eq) in EtOH (40 mL) was added 3- 160 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT methylbutanehydrazide (1.72 g, 14.79 mmol, 1 eq) at 0 °C. The mixture was stirred at 80 °C for 2 h. After cooling, filtration, solid drying, the dried solid was added to 1N NaOH (40 mL) and refluxed for 2 h. After the reaction, it was neutralized with a 1 N hydrochloric acid solution. Filtered, washed with water to give the title compound (2.02 g, 8.64 mmol, 58.43% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H), 7.61 - 7.54 (m, 3H), 7.32 (d, J = 6.4 Hz, 2H), 2.37 (d, J = 7.2 Hz, 2H), 1.71 (s, 1H), 0.88 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 234.2 (M+H)+, (C12H15N3S). [0558] B. 3-Isobutyl-4-phenyl-4H-1,2,4-triazole: 5-isobutyl-4-phenyl-1,2,4-triazole-3- thiol (2 g, 8.57 mmol, 1 eq) was suspended in DCM (120 mL) , cooled to 0 °C and treated with H2O2 (2.97 g, 26.19 mmol, 2.52 mL, 30% purity, 3.06 eq) and AcOH (14.69 g, 244.55 mmol, 14 mL, 28.53 eq) dropwise, and then the mixture was stirred at 25 °C for1 h. The reaction mixture was poured into saturated Na2SO3 solution (5 mL). The reaction mixture was adjusted to pH=8 with 1N aq. NaOH. The aqueous layer was extracted with DCM (3 x 100 mL). The organic layer was washed with saturated Na2SO3 solution (100 mL). The aqueous layer was checked with starch potassium iodide paper. The organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 100: 80; TLC, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.29) to give the title compound (1.27 g, 4.51 mmol, 52.56% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.59 - 7.49 (m, 3H), 7.31 - 7.23 (m, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.062 - 1.995(m, 1H), 0.93 - 0.84 (m, 6H). (ESI+) m/z: 202.2 (M+H)+, (C12H15N3). [0559] C. 3-Bromo-5-isobutyl-4-phenyl-4H-1,2,4-triazole: A mixture of 3-isobutyl-4- phenyl-1,2,4-triazole (500 mg, 2.48 mmol, 1 eq), NBS (574.81 mg, 3.23 mmol, 1.3 eq) in ACN (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was poured into ice-H2O (10 mL). The aqueous layer was extracted DCM (3 x 20 mL). The combined organic layer was washed with brine (80 mL), dried over MgSO4, filtered and concentrated to give the title compound (872 mg, crude) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.64 - 7.55 (m, 3H), 7.28 - 7.22 (m, 2H), 2.55 (d, J = 7.2 Hz, 2H), 2.03 - 1.94 (m, 1H), 0.89 (d, J = 6.4 Hz, 6H). (ESI+) m/z: 281.7 (M+H)+, (C12H14BrN3). [0560] D. 3-(5-(5-Isobutyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-bromo-5-isobutyl-4-phenyl-1,2,4-triazole (300 mg, 1.07 mmol, 1 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (1.39 g, 3.75 mmol, 3.5 eq), K3PO4 (454.59 mg, 2.14 mmol, 2 eq) and 161 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (179.12 mg, 214.16 μmol, 0.2 eq) in dioxane (6 mL) and H2O (0.3 mL) was degassed and purged with N2 for 3 times at 25 °C, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to 25 °C and filtered. The filtrate was concentrated. The crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25mm x 5um) and gradient of 17%- 47% acetonitrile in water containing 0.05% TFA over 19 min at a flow rate of 25 mL/min to give the title compound (39.89 mg, 89.94 μmol, 8.40% yield, 98.9% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.67 - 7.61 (m, 2H), 7.58 - 7.53 (m, 3H), 7.448 - 7.425(m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.106 - 5.062 (m, 1H), 4.46 - 4.21 (m, 2H), 2.98 - 2.83 (m, 1H), 2.62 - 2.54 (m, 2H), 2.41 - 2.30 (m, 2H), 2.05 - 1.95 (m, 1H), 1.917 - 1.850 (m, 1H), 0.85 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 444.2 (M+H)+, (C25H25N5O3). EXAMPLE 70 [0561] Synthesis of 3-(5-(2-(2-chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0562] A. 4-Bromo-2-(2-chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazole: To a solution of 2,4-dibromo-1-methyl-1H-imidazole (500 mg, 2.08 mmol, 1.00 eq) , (2- chloro-4-(trifluoromethyl)phenyl)boronic acid (514 mg, 2.29 mmol, 1.10 eq) ,K3PO4 (1.33 g, 6.25 mmol, 3.00 eq) and tris(4-fluorophenyl)phosphine (65.9 mg, 208 μmol, 0.10 eq) in H2O (5.00 mL) and dioxane (15.0 mL) was added Pd(PPh3)2Cl2 (146 mg, 208 μmol, 0.10 eq) under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC (Petroleum ether: Ethyl acetate=10: 1, Rf = 0.40) to give the title compound (510 mg, 1.37 mmol, 65.8% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.87 – 7.85 (m, 1H), 7.78 – 7.76 (m, 1H), 7.53 – 7.51 (m, 1H), 3.49 (s, 3H). (ESI+) m/z: 340.8 (M+H)+, (C11H7BrClF3N2). [0563] B. 3-(5-(2-(2-Chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(2-chloro-4- 162 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (trifluoromethyl)phenyl)-1-methyl-1H-imidazole (200 mg, 589 μmol, 1.00 eq) and 3-(1-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (654 mg, 1.77 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (381 mg, 1.80 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (49.2 mg, 58.9 μmol, 0.10 eq) under N2. The mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 18% - 48% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (26.0 mg, 51.6 μmol, 8.76% yield, 99.8% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6): δ 11.00 – 10.99 (m, 1H), 8.11 – 8.01 (m, 3H), 7.93 - 7.85 (m, 4H), 5.14 - 5.09 (m, 1H), 4.50 - 4.33 (m, 2H), 3.58 (s, 3H), 2.95 - 2.88 (m, 1H), 2.62 - 2.58 (m, 1H), 2.39 - 2.37 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI+) m/z: 503.1 (M+H)+, (C24H18ClF3N4O3). EXAMPLE 71 [0564] Synthesis of 3-(5-(2-(3-chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0565] A. 4-Bromo-2-(3-chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazole: To a solution of 2,4-dibromo-1-methyl-1H-imidazole (800 mg, 3.33 mmol, 1.00 eq) in THF (12.0 mL) was added (3-chloro-4-(trifluoromethyl)phenyl)boronic acid (823 mg, 3.67 mmol, 1.10 eq), K3PO4 (2.12 g, 10.0 mmol, 3.00 eq) ,tris(4-fluorophenyl)phosphane (52.7 mg, 166 μmol, 0.0500 eq) and Pd(OAc)2 (37.4 mg, 166 μmol, 0.05 eq) at 25°C, then the mixture was stirred at 80 °C for 16 h under N2. It was concentrated under vacuum. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 42 - 72% acetonitrile in water containing 0.05% FA over 16 min at a flow rate of 25 mL/min to give the title compound (260 mg, 765 μmol, 22.9% yield, 100% purity LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 3.81 (s, 3H). (ESI+) m/z: 340.5 (M+H)+, (C11H7BrClF3N2). 163 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0566] B. 3-(5-(2-(3-Chloro-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(3-chloro-4- (trifluoromethyl)phenyl)-1-methyl-1H-imidazole (260 mg, 765 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (708 mg, 1.91 mmol, 2.50 eq), K3PO4 (325 mg, 1.53 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (64.0 mg, 76.5 μmol, 0.10 eq) at 25 °C , then the mixture was stirred at 100 °C for 4 h under N2. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 33/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.34) to give a residue. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 26 - 56% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (104 mg, 251 μmol, 32.1% yield, 99.5% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.13 (s, 1H), 8.05 - 8.04 (m, 2H), 7.98 - 7.96 (m, 3H), 7.74 - 7.72 (m, 1H), 5.13 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.52 - 4.34 (m, 2H), 3.90 (s, 3H), 2.96 - 2.87 (m, 1H), 2.63 - 2.58 (m, 1H), 2.43 - 2.39 (m, 1H), 2.04 - 2.00 (m, 1H). (ESI+) m/z: 503.1 (M+H)+, (C24H18ClF3N4O3). EXAMPLE 72 [0567] Synthesis of 3-(5-(1-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0568] A. 5-(4-Bromo-1-methyl-1H-imidazol-2-yl)-2-(trifluoromethyl)pyridine: To a solution of 2,4-dibromo-1-methyl-imidazole (500 mg, 2.08 mmol, 1.00 eq) and [6- (trifluoromethyl)-3-pyridyl]boronic acid (437.7 mg, 2.29 mmol, 1.10 eq) in THF (10.0 mL) and H2O (2.00 mL) was added tris(4-fluorophenyl)phosphine (32.9 mg, 104.2 μmol, 0.05 eq), Pd(OAc)2 (23.4 mg, 104.2 μmol, 0.05 eq), K3PO4 (1.33 g, 6.25 mmol, 3.00 eq) under N2. Then the reaction mixture was stirred at 80 °C for 16 h under N2. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1; TLC, Petroleum ether: Ethyl acetate = 20: 1 , Rf = 0.40) and preparative-HPLC (using a 164 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Welch Xtimate C18 (150 mm x 25 mm x 5 μm) and gradient of 27-47% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25.0 mL/min) to give the title compound (90.0 mg, 294 μmol, 14.1% yield) as white oil.1H NMR: (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.23 - 8.21 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 3.82 (m, 3H). (ESI+) m/z: 305.1 (M+H)+, (C10H7BrF3N3). [0569] B. 3-(5-(1-Methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 5-(4-bromo-1-methyl-imidazol-2- yl)-2-(trifluoromethyl)pyridine (80.0 mg, 261 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl]piperidine-2,6-dione (241 mg, 653 μmol, 2.50 eq), Ru-Phos-Pd-G3 (21.7 mg, 26.1 μmol, 0.10 eq) and K3PO4 (111 mg, 523 μmol, 2.00 eq) under N2, then the reaction mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered through a pad of celite the pad or filter cake was washed with DCM (3 x 20.0 mL), the filtrate was concentrated to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1; TLC, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.20) and preparative-HPLC using a Welch Xtimate C18 (150 mm x 25 mm x 10 μm) and gradient of 18-48% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 30.0 mL/min to give the title compound (31.4 mg, 63.9 μmol, 24.5% yield, 95.7% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.20 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.08 - 8.04 (m, 3H) 7.97 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 5.14 - 5.10 (m, 1H), 4.53 - 4.35 (m, 2H), 3.91 (s, 3H), 2.97 - 2.90 (m, 1H), 2.63 - 2.59 (m, 1H), 2.45 - 2.40 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI+) m/z: 470.1 (M+H)+, (C23H18F3N5O3). EXAMPLE 73 [0570] Synthesis of 3-(5-(5-methyl-1-(2-morpholinoethyl)-4-phenyl-1H-pyrazol-3-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0571] A. 4-(2-(3-Bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)ethyl)morpholine: To a solution of 3-bromo-5-methyl-4-phenyl-1H-pyrazole (1.00 g, 4.22 mmol, 1.00 eq) in DMF (10.0 mL) was added 4-(2-chloroethyl)morpholine (631 mg, 4.22 mmol, 1.00 eq) and K2CO3 165 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (582 mg, 4.22 mmol, 1.00 eq) at 25 °C, then the mixture was stirred at 65 °C for 16 h. The mixture was poured into H2O (50.0 mL) and extracted with ethyl acetate (2 x 30.0 mL).The combined organic layer was washed with brine (3 x 50.0 mL) and dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by SFC (column: REGIS(S,S)WHELK-O1(250mm x 25mm, 10um);mobile phase: [CO2- MeOH];B%:40%, isocratic elution mode) to give the title compound (400 mg, 1.13 mmol, 26.8% yield, 99.1% purity LCMS at 220 nm) as a white oil.1H NMR: (400 MHz, DMSO-d6) δ 7.46 - 7.42 (m 2H), 7.35 - 7.31 (m 3H), 4.17 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 4.0 Hz, 4H), 2.67 (t, J = 6.4 Hz, 2H), 2.43 (s, 4H), 2.28 (s, 3H). (ESI+) m/z: 351.7 (M+H)+, (C16H20BrN3O). [0572] B. 5-(1-Methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazol-4-yl)-2-(2- oxopiperidin-3-yl)isoindolin-1-one: To a solution of 4-[2-(3-bromo-5-methyl-4-phenyl- pyrazol-1-yl)ethyl]morpholine (200 mg, 565 μmol, 1.00 eq) in dioxane (8.00 mL) and H2O (0.400 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (523 mg, 1.41 mmol, 2.50 eq), K3PO4 (240 mg, 1.13 mmol, 2.00 eq) and Ruphos-Pd-G3 (47.3 mg, 56.5 μmol, 0.10 eq) at 25 °C, then the mixture was stirred at 100 °C for 3 h under N2. It was filtered and the filter was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 24/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.32) The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 10 - 40% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (176 mg, 280 μmol, 49.4% yield, 99.5% purity HPLC at 220 nm, TFA) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 10.0 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.41 (d, J = 7.2 Hz, 3H), 7.36 - 7.34 (m, 1H), 7.18 (d, J = 7.2 Hz, 2H), 5.09 (dd, J = 13.6 Hz, J = 4.8 Hz, 1H), 4.58 (t, J = 5.6 Hz, 2H), 4.40 - 4.21 (m, 2H), 4.05 - 3.88 (m, 2H), 3.69(s, 4H), 3.35 - 3.24 (m, 4H), 2.95 - 2.85 (m, 1H), 2.61 - 2.57 (m, 1H), 2.38 - 2.34 (m, 1H), 2.29 (s, 3H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 514.3 (M+H)+, (C29H31N5O4). 166 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 74 [0573] Synthesis of 3-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0574] A. 3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-bromo-1-(difluoromethyl)-5- phenyl-1H-pyrazole (150 mg, 549 μmol, 1.00 eq) and 3-(6-fluoro-1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (1.07 g, 2.75 mmol, 5.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (233 mg, 1.10 mmol, 2.00 eq) and Pd(dtbpf)Cl2 (35.8 mg, 54.9 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative-HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 35% - 65% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (94.8 mg, 204 μmol, 37.3% yield, 98.2% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6): δ 11.01 – 10.99 (m, 1H), 8.27 – 8.23 (m, 1H), 7.96 - 7.68 (m, 2H), 7.59 – 7.53 (m, 5H), 7.09 – 7.06 (m, 1H), 5.17 – 5.10 (m, 1H), 4.56 – 4.39 (m, 2H), 2.92 – 2.89 (m, 1H), 2.63 - 2.59 (m, 1H), 2.44 – 2.39 (m, 1H), 2.07 – 2.04 (m, 1H),. (ESI+) m/z: 455.1 (M+H)+, (C23H17F3N4O3). EXAMPLE 75 [0575] Synthesis of 3-(6-fluoro-1-oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol- 4-yl)isoindolin-2-yl)piperidine-2,6-dione: [0576] A. 3-(6-Fluoro-1-oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-5-phenyl-1-(2,2,2- 167 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT trifluoroethyl)-1H-pyrazole (500 mg, 1.64 mmol, 1.00 eq), 3-(6-fluoro-1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (3.18 g, 8.19 mmol, 5.00 eq) in dioxane (10.0 mL) and H2O (0.50 mL) was added K3PO4 (695 mg, 3.28 mmol, 2.00 eq), Ru-Phos-Pd-G3 (106 mg, 163 μmol, 0.10 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 30: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.20) and preparative-HPLC using a Welch Xtimate C18 (150 mm x 25 mm x 10 μm) and gradiente of 30 - 60% acetonitrile in water (TFA) over 10 min at a flow rate of 25 mL/min to give the title compound (59.7 mg, 122 μmol, 7.46% yield, 99.4% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.96 (s, 1H), 7.50 - 7.45 (m, 4H), 7.37 - 7.33 (m, 3H), 5.09 - 5.00 (m, 1H), 4.98 - 4.95 (m, 2H), 4.34 - 4.16 (m, 2H), 2.91 - 2.84 (m, 1H), 2.59 - 2.52 (m, 1H), 2.37 - 2.33 (m, 1H), 1.99 - 1.96 (m, 1H). (ESI+) m/z: 488.1 (M+H)+, (C24H18F4N4O3). EXAMPLE 76 [0577] Synthesis of 3-(4-fluoro-5-(1-methyl-2-(4-(trifluoromethyl)phenyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0578] A. (1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)boronic acid: To a solution of 4-bromo-1-methyl-2-[4-(trifluoromethyl)phenyl]imidazole (600 mg, 1.97 mmol, 1.00 eq) in dioxane (6.00 mL) was added BPD (998 mg, 3.93 mmol, 2.00 eq), Xphos (468 mg, 983 μmol, 0.50 eq), KOAc (386 mg, 3.93 mmol, 2.00 eq) and Pd2(dba)3 (180 mg, 196 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 12 h under N2. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (530 mg, crude) as yellow oil. (ESI+) m/z: 271.0 (M+H)+, (C11H10BF3N2O2). [0579] B. 3-(4-Fluoro-5-(1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of [1-methyl-2-[4- (trifluoromethyl)phenyl]imidazol-4-yl]boronic acid (316. mg, 1.17 mmol, 2.00 eq) and 3-(5- bromo-4-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (200 mg, 586 μmol, 1.00 eq) in 168 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT dioxane (8.00 mL) and H2O (2.00 mL) was added Pd(OAc)2 (13.1 mg, 58.6 μmol, 0.10 eq), cataCXium A (42.0 mg, 117 μmol, 0.20 eq) and Cs2CO3 (382 mg, 1.17 mmol, 2.00 eq) under N2. The mixture was stirred at 80 °C for 1 h under N2. After the reaction was completed, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 20 - 50% acetonitrile in water containing 0.5% HCl over 10 min at a flow rate of 25.0 mL/min to give the title compound (34.7 mg, 70.7 μmol, 12.0% yield, 99.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.30 (t, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.92 - 7.88 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 5.13 (dd, J = 13.2, 5.2 Hz, 1H), 4.55 (dd, J = 70.0, 17.6 Hz, 2H), 3.91 (s, 3H), 2.96 - 2.89 (m, 1H), 2.64 - 2.59 (m, 1H), 2.44 - 2.40 (m, 1H), 2.08 - 2.01 (m, 1H). (ESI+) m/z: 487.4 (M+H)+, (C24H18F4N4O3). EXAMPLE 77 [0580] Synthesis of 3-(4-fluoro-1-oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol- 4-yl)isoindolin-2-yl)piperidine-2,6-dione: [0581] A.3-(4-Fluoro-1-oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 5-phenyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (284 mg, 732 μmol, 2.50 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-(5-bromo-4-fluoro-1-oxo-isoindolin-2- yl)piperidine-2,6-dione (100 mg, 293 μmol, 1.00 eq), Ru-Phos-Pd-G3(19.1 mg, 29.3 μmol, 0.10 eq) and K3PO4 (124 mg, 586 μmol, 2.00 eq) under N2, then the mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered through a pad of celite the pad or filter cake was washed with DCM (3 x 20.0 mL), the filtrate was concentrated to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 17: 3; TLC, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.30) and preparative-HPLC using a Welch Xtimate C18 (150 mm x 25 mm x 10 μm) and gradient of 29 - 59% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25.0 mL/min to give 169 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT the title compound (57.6 mg, 118 μmol, 40.2% yield, 99.5% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.98 (s, 1H), 7.50 - 7.49 (m, 3H), 7.42 (d, J = 7.6 Hz, 1H), 7.35 - 7.34 (m, 2H), 7.19 - 7.17 (m, 1H), 5.10 - 5.06 (m, 1H), 5.01 - 4.95 (m, 2H), 4.53 - 4.31 (m, 2H), 2.90 - 2.88 (m, 1H), 2.60 - 2.54 (m, 1H), 2.43 - 2.38 (m, 1H), 1.99 - 1.98 (m, 1H). (ESI+) m/z: 487.1 (M+H)+, (C24H18F4N4O3). EXAMPLE 78 [0582] Synthesis of 3-(1-oxo-5-(5-phenyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [0583] A. 3-(1-Oxo-5-(2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-(5-(2-bromoacetyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (1.00 g, 2.74 mmol, 1.00 eq), tetrahydro-2H-pyran-4-carbothioamide (517 mg, 3.56 mmol, 1.30 eq) and K2CO3 (454 mg, 3.29 mmol, 1.20 eq) in [Bmim]PF6 (10.0 mL) was stirred at 25 °C for 12 h. The residue was diluted with H2O (30.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with Na2S2O3 (2 x 30.0 mL), dried over dry Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (5.00 mL), stirred at 0 °C for 30 min and filtered. The filter cake was washed with ethyl acetate (2.00 mL) and concentrated to give the title compound (300 mg, 729 μmol, 26.6% yield) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.22 - 8.17 (m, 2H), 8.14 - 8.09 (m, 1H), 7.83 - 7.73 (m, 1H), 5.17 - 5.09 (m, 1H), 4.59 - 4.33 (m, 2H), 4.02 - 3.88 (m, 2H), 3.55 - 3.43 (m, 2H), 3.02 - 2.82 (m, 1H), 2.65 - 2.58 (m, 1H), 2.45 - 2.39 (m, 1H), 2.15 - 1.92 (m, 4H), 1.87 - 1.69 (m, 2H). (ESI+) m/z: 412.2 (M+H)+, (C21H21N3O4S). [0584] B. 3-(5-(5-Bromo-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(2-(tetrahydro-2H-pyran-4-yl)thiazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione (300 mg, 729 μmol, 1.00 eq) in DMF (3.00 mL) was added NBS (136 mg, 766 μmol, 1.05 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The residue was dissolved in ethyl acetate (5.00 mL), stirred at 25 °C for 30 min and filtered. The filter cake was washed with ethyl acetate (2.00 mL) and concentrated to give the 170 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT title compound (275 mg, 561 μmol, 76.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.10 (s, 1H), 8.05 - 8.01 (m, 1H), 7.88 - 7.81 (m, 1H), 5.19 - 5.09 (m, 1H), 4.63 - 4.27 (m, 2H), 3.98 - 3.88 (m, 2H), 3.52 - 3.42 (m, 3H), 2.98 - 2.91 (m, 1H), 2.66 - 2.59 (m, 1H), 2.44 - 2.38 (m, 1H), 2.08 - 1.98 (m, 3H), 1.84 - 1.68 (m, 2H). (ESI+) m/z: 492.0 (M+H)+, (C21H20BrN3O4S). [0585] C. 3-(1-Oxo-5-(5-phenyl-2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-2-(tetrahydro-2H-pyran-4- yl)thiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (275 mg, 561 μmol, 1.00 eq), phenylboronic acid (171 mg, 1.40 mmol, 2.50 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added Pd(dppf)Cl2 (82.0 mg, 112 μmol, 0.20 eq), K3PO4 (357 mg, 1.68 mmol, 3.00 eq) under N2. The reaction mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 1: 19; TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.50 ) and preparative-HPLC using a Welch Ultimate C18 (150 x 25mm x 5 μm) and gradient of 32 - 62% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (40.5 mg, 82.8 μmol, 14.7% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s, 1H), 7.66 - 7.61 (m, 1H), 7.52 - 7.47 (m, 1H), 7.44 - 7.33 (m, 5H), 5.14 - 5.06 (m, 1H), 4.46 - 4.25 (m, 2H), 4.00 - 3.92 (m, 2H), 3.54 - 3.46 (m, 2H), 2.96 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.44 - 2.35 (m, 1H), 2.10 - 1.97 (m, 4H), 1.87 - 1.74 (m, 2H). (ESI+) m/z: 488.2 (M+H)+, (C27H25N3O4S). EXAMPLE 79 [0586] Synthesis of 3-(5-(2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0587] A. 2-(6-(Trimethylstannyl)pyridin-3-yl)propan-2-ol: To a solution of 2-(6- bromopyridin-3-yl)propan-2-ol (500 mg, 2.31 mmol, 1.00 eq) and Me6Sn2 (1.32 g, 4.03 mmol, 835 μL, 1.74 eq) in dioxane (10.0 mL) was added Pd(PPh3)4 (267 mg, 231 μmol, 0.10 eq) under N2. The reaction mixture was stirred at 100 °C for 16 h under N2to give the title 171 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT compound (500 mg, 1.67 mmol, 72.0% yield) as a black-brown oil. (ESI+) m/z: 302.05 (M+H)+, (C11H19NOSn). [0588] B. 2-(6-(4-Bromo-1-methyl-1H-imidazol-2-yl)pyridin-3-yl)propan-2-ol: To a solution of 2-(6-(trimethylstannyl)pyridin-3-yl)propan-2-ol (500 mg, 1.67 mmol, 1.00 eq) and 2,4-dibromo-1-methyl-1H-imidazole (399 mg, 1.67 mmol, 1.00 eq) in dioxane (10.0 mL) was added Pd(PPh3)2Cl2 (117 mg, 167 μmol, 0.10 eq) under N2. The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 7: 3; TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.40) to give the title compound (130 mg, 439 μmol, 26.3% yield) as a light yellow solid. (ESI+) m/z: 297.9 (M+H)+, (C12H14BrN3O). [0589] C. 3-(5-(2-(5-(2-Hydroxypropan-2-yl)pyridin-2-yl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-(6-(4-bromo-1-methyl- 1H-imidazol-2-yl)pyridin-3-yl)propan-2-ol (120 mg, 405.18 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (450 mg, 1.22 mmol, 3.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (33.9 mg, 40.5 μmol, 0.10 eq), K3PO4 (172 mg, 810 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.40) and preparative-HPLC using a Welch Ultimate (C18150 x 25mm x 5μm) and gradient of 4 - 34% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound as a off-white solid (23.2 mg, 50.6 μmol, 12.5% yield, 99.2% purity in HPLC at 220 nm).1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.80 - 8.76 (m, 1H), 8.17 -8.11 (m, 1H), 8.08 - 8.01 (m, 3H), 7.99 - 7.96 (m, 1H), 7.79 - 7.74 (m, 1H), 5.17 - 5.09 (m, 1H), 4.56 - 4.35 (m, 2H), 4.12 (s, 3H), 2.99 - 2.86 (m, 1H), 2.65 - 2.57 (m, 1H), 2.45 - 2.38 (m, 1H), 2.07 - 1.99 (m, 1H), 1.51 (s, 6H). (ESI+) m/z: 460.1 (M+H)+, (C25H25N5O4). 172 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 80 [0590] Synthesis of 3-(5-(1-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0591] A. 2-(4-Bromo-1-methyl-1H-imidazol-2-yl)-5-(trifluoromethyl)pyridine: To a solution of 2,4-dibromo-1-methyl-1H-imidazole (500 mg, 2.08 mmol, 1.00 eq) and 2- (tributylstannyl)-5-(trifluoromethyl)pyridine (1.09 g, 2.50 mmol, 1.20 eq) in dioxane (10.0 mL) was added LiCl (265 mg, 6.25 mmol, 128 μL, 3.00 eq), CuI (39.7 mg, 208 μmol, 0.10 eq), Pd(PPh3)4 (481 mg, 417 μmol, 0.20 eq) under N2. The reaction mixture was stirred at 100 °C for 4 h under N2. The residue was diluted with H2O (20.0 mL) and extracted with ethyl acetate (3 x 30.0 mL), dried over drying Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 10: 1; TLC: Petroleum ether: Ethyl acetate = 10: 1 ;Rf = 0.40) to give the title compound (170 mg, 555 μmol, 26.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.32 - 8.26 (m, 1H), 8.25 - 8.18 (m, 1H), 7.60 (s, 1H), 4.07 (s, 3H). (ESI+) m/z: 307.8 (M+H)+, (C10H7BrF3N3). [0592] B. 3-(5-(1-Methyl-2-(5-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-(4-bromo-1-methyl-1H- imidazol-2-yl)-5-(trifluoromethyl)pyridine (170 mg, 555 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (617 mg, 1.67 mmol, 3.00 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added Ru-Phos-Pd-G3 (46.4 mg, 55.5 μmol, 0.10 eq), K3PO4 (235 mg, 1.11 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 80: 1; TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.40 ) and preparative-HPLC using a Phenomenex luna C18 (150 x 25mm x 10 μm) and gradient of 30 - 60% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min to give the title compound (30.2 mg, 63.9 μmol, 11.5% yield, 99.3% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.04 (s, 1H), 8.45 - 8.38 (m, 1H), 8.37 - 8.30 (m, 1H), 8.12 - 8.07 (m, 2H), 8.04 - 7.97 (m, 1H), 7.79 - 7.73 (m, 1H), 5.16 - 173 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 5.09 (m, 1H), 4.55 - 4.36 (m, 2H), 4.16 (s, 3H), 2.98 - 2.87 (m, 1H), 2.64 - 2.59 (m, 1H), 2.44 - 2.40 (m, 1H), 2.08 - 1.98 (m, 1H). (ESI+) m/z: 470.1 (M+H)+, (C23H18F3N5O3). EXAMPLE 81 [0593] Synthesis of 3-(5-(5-methyl-1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0594] A. 3-Bromo-5-methyl-1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole: To a solution of 3-bromo-5-methyl-4-phenyl-1H-pyrazole (1.40 g, 5.79 mmol, 1.00 eq) and 1- methylpyrrolidin-3-ol (702 mg, 6.94 mmol, 1.20 eq) in THF (14.0 mL) was addded 2- (tributyl-phosphanylidene)acetonitrile (2.09 g, 8.68 mmol, 1.50 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum at 45 °C to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 10/1, TLC: DCM/MeOH = 10/1, Rf = 0.30) to get residue. The residue was purified by SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm,10um), mobile phase: [CO2-i- PrOH(0.1%NH3H2O)], B%:25%, isocratic elution mode) to give the title compound (300 mg, 932 μmol, 16.1% yield, 99.5% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.44 - 7.40 (m, 2H), 7.35 - 7.27 (m, 3H), 4.97 - 4.90 (m, 1H), 3.42 - 3.38 (m, 1H), 3.13 - 3.07 (m, 1H), 2.99 - 2.88 (m, 2H), 2.55 (s, 3H), 2.50 - 2.34 (m, 2H), 2.29 (s, 3H). (ESI+) m/z: 321.2 (M+H)+, (C15H18N3Br). [0595] B. 3-(5-(5-Methyl-1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-bromo-5-methyl-1-(1- methylpyrrolidin-3-yl)-4-phenyl-pyrazole (150 mg, 466 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (345 mg, 932 μmol, 2.00 eq) in dioxane (6.00 mL) and H2O (0.300 mL) was added K3PO4 (197 mg, 932 μmol, 2.00 eq) and RuPhos - Pd - G3 (38.9 mg, 46.6 μmol, 0.10 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum at 45 °C to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 50/1, TLC: DCM/MeOH = 20/1, Rf = 0.30) to get residue. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 174 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (150 x 25 mm x 10 μm) and gradient of 12% - 42% acetonitrile in water containing 0.05% TFA over 13 min at a flow rate of 25 mL/min) to give the title compound (165 mg, 267 μmol, 57.4% yield, 96.8% purity in HPLC at 220 nm, CF3COOH) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.910.3 - 9.84 (m, 1H), 7.62(d, J = 7.4 Hz, 1H), 7.57(s, 1H), 7.54 - 7.32 (m, 4H), 7.18 (d, J = 7.4 Hz, 2H), 5.39 - 5.28 (m, 1H), 5.11 - 5.07 (m, 1H), 4.42 - 4.34 (m, 1H), 4.25 - 4.20 (m, 1H), 4.13 - 4.04 (m, 1H), 3.92 - 3.88 (m, 1H), 3.49 - 3.42 (m, 1H), 3.35 - 3.24 (m, 1H), 3.07 - 2.96 (m, 3H), 2.91 - 2.86 (m, 1H), 2.77 - 2.67 (m, 1H), 2.61 - 2.56 (m, 1H), 2.46 - 2.42(m, 1H), 2.38 - 2.30 (m, 1H), 2.28(s, 3H), 2.00 - 1.97(m, 1H). (ESI+) m/z: 484.3 (M2+H)+, (C28H29N5O3). EXAMPLE 82 [0596] Synthesis of 3-(5-(1-(2,2-difluoropropyl)-5-methyl-4-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0597] A. 3-Bromo-1-(2,2-difluoropropyl)-5-methyl-4-phenyl-1H-pyrazole: To a solution of 3-bromo-5-methyl-4-phenyl-1H-pyrazole (1.50 g, 6.33 mmol, 1.00 eq) and 2,2- difluoropropan-1-ol (729 mg, 7.59 mmol, 1.20 eq) in toluene (15.0 mL) was added 2- (tributyl-phosphanylidene)acetonitrile (2.29 g, 9.49 mmol, 1.50 eq) at 25 °C under N2. Then the mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (50.0 mL) and extracted with DCM (2 x 50.0 mL) to get the organic layers, the organic layers was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by preparative-TLC (TLC: PE/EtOAc = 15/1, Rf = 0.50) to give the title compound (600 mg, 1.86 mmol, 29.4% yield, 97.8% purity in LCMS at 220 nm) as a light yellow oil.1H NMR: (400 MHz, CD3CN) δ 7.46 - 7.42 (m, 2H), 7.37 - 7.34 (m, 3H), 4.42 (t, J = 12.0 Hz, 2H), 2.32 (s, 3H), 1.72 (t, J = 18.8 Hz, 3H). (ESI+) m/z: 316.6 (M+H)+, (C13H13N2F2Br). [0598] B. 3-(5-(1-(2,2-Difluoropropyl)-5-methyl-4-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-bromo-1-(2,2-difluoropropyl)- 5-methyl-4-phenyl-1H-pyrazole (150 mg, 465 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5- 175 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (430 mg, 1.16 mmol, 2.50 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added K3PO4 (197 mg, 930 μmol, 2.00 eq) and Ruphos-Pd-G3 (38.9 mg, 46.5 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 60/1, TLC: DCM/MeOH = 10/1, Rf = 0.50) to get a residue. The residue was purified by preparative-HPLC (using a CD04- Welch Utimate C18 (150 mm x 25 mm x 7 μm) and gradient of 33-63% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (149 mg, 311 μmol, 66.9% yield, 99.8% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.60 - 7.56 (m, 2H), 7.41 - 7.33 (m, 4H), 7.20 - 7.18 (m, 2H), 5.09 (dd, J = 4.8 Hz, J = 13.2 Hz, 1H), 4.73 (t, J = 13.2 Hz, 2H), 4.41 - 4.22 (m, 2H), 2.94 - 2.86 (m, 1H), 2.60 - 2.56 (m, 1H), 2.38 - 2.35 (m, 1H), 2.25 (s, 3H), 2.00 - 1.97 (m, 1H), 1.75 (t, J = 19.2 Hz, 3H). (ESI+) m/z: 479.2 (M+H)+, (C26H24N4O3F2). EXAMPLE 83 [0599] Synthesis of 3-(5-(5-methyl-1-(2-morpholino-2-oxoethyl)-4-phenyl-1H-pyrazol- 3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0600] A. 3-Bromo-4-iodo-5-methyl-1H-pyrazole: To a solution of 3-bromo-5-methyl- 1H-pyrazole (20.0 g, 124.22 mmol, 1.00 eq) in DCM (300 mL) was added (2,2,2- trifluoroacetyl)oxysilver (28.8 g, 130 mmol, 1.05 eq) and I2 (34.0 g, 134 mmol, 27.0 mL, 1.08 eq) at -15 °C. The mixture was stirred at 25 °C for 2 h. The mixture was poured into saturated Na2S2O3 (500 mL) and extracted with DCM (2 x 200 mL) to collect the organic layers. The combined organic layers was washed with brine (500 mL). Dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (29.0 g, 98.5 mmol, 79.3%yield, 97.5% purity in LCMS) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 10.9 (s, 1H), 2.39 (s, 3H). (ESI+) m/z: 288.7 (M+H)+ (C4H4BrIN2). 176 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0601] B. 3-Bromo-5-methyl-4-phenyl-1H-pyrazole: To a solution of phenylboronic acid (9.70 g, 79.5 mmol, 0.90 eq) in dioxane (300 mL) and H2O (120 mL) was added 3-bromo-4- iodo-5-methyl-1H-pyrazole (26.0 g, 88.3 mmol, 1.00 eq), RuPhos Pd G3 (3.70 g, 4.42 mmol, 0.05 eq), K3PO4(37.5 g, 176 mmol, 2.00 eq) and RuPhos (4.12 g, 8.84 mmol, 0.1 eq) at 25 °C under N2. The mixture was stirred at 80 ℃ under N2 for 4 h. The mixture was poured into water (1.00 L) and extracted with ethyl acetate (2 x 500 mL) to collect the organic layers. The combined organic layers was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 30/1 to 3/1, TLC: Petroleum ether/Ethyl acetate = 3/1 Rf = 0.29) to get a residue. The residue was triturated with Petroleum ether (100 mL) at 25 °C for 1 h to give the title compound (11.0 g, 45.4 mmol, 51.4% yield, 98.0% purity in LCMS) as a white solid.1H NMR: (400 MHz, CDCl3) δ 11.9 (s, 1H), 7.47 - 7.35 (m, 5H), 2.39 (s, 3H). (ESI+) m/z: 237.0 (M+H)+ (C10H9BrN2). [0602] C. 2-(3-Bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)-1-morpholinoethan-1-one: To a solution of 2-chloro-1-morpholino-ethanone (345 mg, 2.11 mmol, 1.00 eq) and 3- bromo-5-methyl-4-phenyl-1Hpyrazole (500 mg, 2.11 mmol, 1.00 eq) in DMF (10.0 mL) was added K2CO3 (582 mg, 4.22 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 80 °C for 12 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2 x 50.0 mL) to collect the organic layers. The organic layers was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 5/4, Rf = 0.30) to give the title compound (300 mg, 732 μmol, 34.72% yield, 88.9% purity in LCMS) was obtained as white. 1H NMR: (400 MHz, CDCl3) δ 7.45 - 7.35 (m, 5H), 4.94 (s, 2H), 3.67(d, J= 30.4 Hz, 8H), 2.31 (s, , 3H) (ESI+) m/z: 366.0 (M+H)+ (C16H18BrN3O2). [0603] D. 3-(5-(5-Methyl-1-(2-morpholino-2-oxoethyl)-4-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-(3-bromo-5-methyl-4-phenyl- pyrazol-1-yl)-1-morpholino-ethanone (100 mg, 244 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (180 mg, 488 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.100 mL) was added RuPhos Pd G3 (20.4 mg, 24.4 μmol, 0.100 eq) and K3PO4 (103 mg, 488 μmol, 2.00 eq) at 25 °C under N2. The mixture was stirred for 3 h at 100 °C under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography(SiO2, Dichloromethane/Methanol = 100/1 to 20/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.33) to get a residue. The residue was purified using 177 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT a CD04-Welch Utimate C18 (150 mm x 25 mm x 7 μm) and gradiente of 20 - 50% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (68.22 mg, 128.28 μmol, 52.56% yield, 99.2% purity in HPLC) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.59 - 7.52 (m, 2H), 7.40 - 7.32 (m, 4H), 7.19 - 7.17(m, 2H), 5.26 (s, 2H), 5.09 - 5.02 (m, 1H), 4.40 -4.26 (m, 2H), 3.66 (s, 2H), 3.65 - 3.57 (m, 4H), 3.49 - 3.47 (m, 2H), 2.90 - 2.89 (m, 1H), 2.60 - 2.59 (m, 1H), 2.37 - 2.30 (m, 1H), 2.15 (s, 3H), 2.02 - 1.96 (m, 1H). (ESI+) m/z: 528.3 (M+H)+ (C29H29N5O5). EXAMPLE 84 [0604] Synthesis of 3-(5-(1-methyl-5-phenyl-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0605] A. 4-(1-Chloro-2,2,2-trifluoroethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2,2,2-trifluoro-1-(1-methyl-5-phenyl-1H-imidazol-4-yl)ethan-1-ol (300 mg, 1.17 mmol, 1.00 eq) in DCM (6.00 mL) was added SOCl2 (1.60 M, 3.66 mL, 5.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give the title compound (290 mg, crude) as a yellow solid. (ESI+) m/z: 275.0 (M+H)+, (C12H10ClF3N2). [0606] B. 1-Methyl-5-phenyl-4-(2,2,2-trifluoroethyl)-1H-imidazole: To a solution of 4- (1-chloro-2,2,2-trifluoroethyl)-1-methyl-5-phenyl-1H-imidazole (290 mg, 1.06 mmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (50.0 mg, 10.0% purity) under N2. The reaction mixture was degassed and purged with N2 for 3 times, then degassed and purged with H2 for 3 times. The reaction mixture was warmed to 25 °C and stirred at 15 psi under H2 for 16 h. The reaction mixture was filtered through diatomite. The filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1; TLC: Petroleum ether: Ethyl acetate = 0: 1; Rf = 0.40) to give the title compound (170 mg, 629 μmol) as a white solid. (ESI+) m/z: 241.0 (M+H)+, (C12H11F3N2). [0607] C. 2-Bromo-1-methyl-5-phenyl-4-(2,2,2-trifluoroethyl)-1H-imidazole: To a solution of 1-methyl-5-phenyl-4-(2,2,2-trifluoroethyl)-1H-imidazole (150 mg, 624 μmol, 1.00 178 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT eq) in ACN (3.00 mL) was added NBS (122 mg, 687 μmol, 1.10 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by preparative - TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (140 mg, 438 μmol, 70.2% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.53 - 7.45 (m, 3H), 7.32 - 7.28 (m, 2H), 3.45 (s, 3H), 3.31 - 3.21 (m, 2H). (ESI+) m/z: 318.9 (M+H)+, (C12H10BrF3N2). [0608] D. 3-(5-(1-Methyl-5-phenyl-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-5-phenyl-4- (2,2,2-trifluoroethyl)-1H-imidazole (130 mg, 407 μmol, 1.00 eq), 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (377 mg, 1.02 mmol, 2.50 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (34.1 mg, 40.7 μmol, 0.10 eq), K3PO4 (173 mg, 815 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 20: 1 to 0: 1; TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.30 ) and preparative-HPLC using a Phenomenex luna C18 (150 x 25mm x 10 μm) and gradient of 15 - 45% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 25 mL/min to give the title compound (121 mg, 243 μmol, 59.7% yield, 96.8% purity purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.99 (s, 1H), 7.93 - 7.84 (m, 2H), 7.60 - 7.54 (m, 2H), 7.53 - 7.46 (m, 3H), 5.20 - 5.13 (m, 1H), 4.61 - 4.39 (m, 2H), 3.59 (s, 3H), 3.54 - 3.43 (m, 2H), 3.01 - 2.87 (m, 1H), 2.65 - 2.58 (m, 1H), 2.47 - 2.40 (m, 1H), 2.08 - 2.00 (m, 1H). (ESI+) m/z: 483.2 (M+H)+, (C25H21F3N4O3). EXAMPLE 85 [0609] Synthesis of 3-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0610] A. 3-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 1-(difluoromethyl)-5-phenyl-3- 179 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (tributylstannyl)-1H-pyrazole (202 mg, 419 μmol, 1.10 eq) and 3-(5-bromo-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione (130 mg, 381 μmol, 1.00 eq) in dioxane (5.00 mL) was added cataCXiumA Pd G2 (50.9 mg, 76.2 μmol, 0.20 eq) under N2. The mixture was stirred at 110 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 35% - 65% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (27.8 mg, 61.1 μmol, 16.0% yield, 99.6% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.21 – 8.17 (m, 1H), 7.93 - 7.69 (m, 2H), 7.60 – 7.56 (m, 5H), 7.11 – 7.10 (m, 1H), 5.17 – 5.12 (m, 1H), 4.68 – 4.67 (m, 2H), 2.96 – 2.88 (m, 1H), 2.63 - 2.59 (m, 1H), 2.46 – 2.44 (m, 1H), 2.07 – 2.02 (m, 1H). (ESI+) m/z: 455.1 (M+H)+, (C23H17F3N4O3). EXAMPLE 86 [0611] Synthesis of 3-(5-(2-methyl-5-phenylthiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0612] A. 3-(5-(1-Ethoxyvinyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20.0 g, 62.0 mmol, 1.00 eq) and tributyl(1-ethoxyvinyl)stannane (55.8 g, 154 mmol, 2.50 eq) in dioxane (200 mL) was added Pd(PPh3)4 (5.72 g, 4.96 mmol, 0.08 eq) under N2. The reaction mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was added to aq. NH4Cl (200 mL). The reaction mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with aq.KF (2 x 100 mL), dried over Na2SO4, filter and concentrated to give resiude. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1; TLC, Dichloromethane: Methanol = 20:1, Rf = 0.40).to give the title compound (12.0 g, 38.1 mmol, 62.5% yield) as a yellow solid. m/z: 315.0 (M+H)+, (C17H18N2O4). [0613] B. 3-(5-(2-Bromoacetyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(1-ethoxyvinyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12.0 g, 38.0 180 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mmol, 1.00 eq) in [Bmim]PF6 (100 mL) was added NBS (7.21 g, 45.6 mmol, 1.20 eq) and TsOH (1.44 g, 4.32 mmol, 0.20 eq). The reaction mixture was stirred at 25 °C for 16 h to give the title compound (12.0 g, crude) as a yellow solid. m/z: 364.9 (M+H)+, (C15H13BrN2O4). [0614] C. 3-(5-(2-Methylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(2-bromoacetyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (1.00 g, 2.74 mmol, 1.00 eq) in [Bmim]PF6 (2.00 mL) was added thioacetamide (226 mg, 3.01 mmol, 1.10 eq) and K2CO3 (454 mg, 3.29 mmol, 1.20 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into saturated Na2SO3 aqueous solution (100 mL) and extracted with ethyl acetate (3 x 60.0 mL). The combined organic layer was washed with brine (2 x 30.0 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative-HPLC (using a Welch Ultimate C18 (250 x 50mm x 10 μm) and gradient of 10 - 40% acetonitrile in water containing 0.05% TFA over 5 min at a flow rate of 100 mL/min) to give the title compound (240 mg, 688 μmol, 22.0% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 8.00 - 7.97 (m, 2H), 7.93 - 7.91 (m, 1H), 7.46 (s, 1H), 5.27 - 5.22 (m, 1H), 4.57 - 4.36 (m, 2H), 2.89 - 2.85 (m, 1H), 2.80 (s, 3H), 2.42 - 2.37 (m, 1H), 2.27 - 2.22 (m, 1H), 1.26 (s, 1H) m/z: 341.9 (M+H)+, (C17H15N3O3S). [0615] D. 3-(5-(5-Bromo-2-methylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione: To a solution of 3-[5-(2-methylthiazol-4-yl)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (220 mg, 644 μmol, 1.00 eq) in DMF (4.00 mL) was added solution of NBS (120 mg, 676 μmol, 1.05 eq) in DMF (2.00 mL) at 0 °C. Then the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum to give residue. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1: 3; TLC, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.30) to give the title compound (240 mg, 522 μmol, 81.3% yield) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.09 (s, 1H), 8.03 - 8.01 (m, 1H), 7.84 - 7.82 (m, 1H), 5.17 - 5.12 (m, 1H), 4.56 - 4.38 (m, 2H), 2.95 - 2.91 (m, 1H), 2.70 (s, 3H), 2.59 - 2.50 (m, 1H), 2.43 - 2.40 (m, 1H), 2.04 - 2.02 (m, 1H). m/z: 422.0 (M+H)+, (C17H14BrN3O3S). [0616] E. 3-(5-(2-Methyl-5-phenylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione: To a solution of 3-[5-(5-bromo-2-methyl-thiazol-4-yl)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (200 mg, 475 μmol, 1.00 eq) in DMF (5.00 mL) was added phenylboronic acid (174 mg, 1.43 mmol, 3.00 eq), Pd(dppf)Cl2 (34.8 mg, 47.5 μmol, 0.10 eq) and K3PO4 (303 mg, 1.43 mmol, 3.00 eq) under N2, then the mixture was stirred at 90 °C for 12 h under N2. The mixture was filtered through a pad of celite and filter cake was washed with dichloromethane (3 x 20.0 mL ), the filtrate was concentrated to give residue. The 181 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1; TLC, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.30) and preparative-HPLC using a Welch Ultimate C18 (150 x 25mm x 10 μm) and gradient of 30 - 60% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 30 mL/min to give the title compound (12.2 mg, 28.8 μmol, 6.05% yield, 98.2% purity in HPLC at 220 nm) as a off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s, 1H), 7.63 - 7.60 (m, 1H), 7.48 - 7.46 (m, 1H), 7.40 - 7.32 (m, 5H), 5.12 - 5.07 (m, 1H), 4.43 - 4.25 (m, 2H), 2.95 - 2.91 (m, 1H), 2.70 (s, 3H), 2.59 - 2.50 (m, 1H), 2.43 - 2.40 (m, 1H), 2.01 - 1.98 (m, 1H). m/z: 418.1 (M+H)+, (C23H19N3O3S). EXAMPLE 87 [0617] Synthesis of 3-(5-(2-isopropyl-5-phenylthiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0618] A. 3-(5-(2-Isopropylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(2-bromoacetyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (750 mg, 2.05 mmol, 1.00 eq) in [Bmim]PF6 (17.0 mL) was added 2-methylpropanethioamide (233 mg, 2.26 mmol, 1.10 eq) and K2CO3 (340 mg, 2.46 mmol, 1.20 eq) at 25 °C, then the mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into H2O (20.0 mL), extracted with Ethyl acetate (3 x 10.0 mL); the organic layer was washed with Na2SO3 (4 x 25.0 mL), dried over Na2SO4 and the filtrate was concentrated in vacuum to give residue. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 40 mm x 10 μm) and gradient of 24 - 54% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min give the title compound (310 mg, 828 μmol, 46.1% yield, 98.7% purity LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.18 - 8.10 (m, 3H), 7.78 (d, J = 8.0 Hz, 1H), 5.13 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.54 - 4.37 (m, 2H), 3.39 - 3.38 (m, 1H), 2.96 - 2.87 (m, 1H), 2.63 - 2.59 (m, 1H), 2.44 - 2.39 (m, 1H), 2.04 - 2.01 (m, 1H), 1.39 (d, J = 6.8Hz, 6H). (ESI+) m/z: 370.0 (M+H)+, (C19H19N3O3S). 182 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0619] B. 3-(5-(5-Bromo-2-isopropylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione: To a solution of 3-(5-(2-isopropylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (300 mg, 800 μmol, 1.00 eq) in DMF (6.00 mL) was added NBS (150 mg, 840 μmol, 1.05 eq) at 0 °C, then the mixture was stirred at 25 °C for 18 h. It was filtered and the filter cake was concentrated under vacuum.to give the title compound (150 mg, 325 μmol, 52.0% yield, 97.7% purity) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 5.14 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.54 - 4.37 (m, 2H), 3.30 - 3.27 (m, 1H), 2.95 - 2.87 (m, 1H), 2.63 - 2.59 (m, 1H), 2.44 - 2.39 (m, 1H), 2.05 - 2.02 (m, 1H), 1.35 (d, J = 7.2 Hz, 6H). (ESI+) m/z: 449.6 (M+H)+, (C19H18BrN3O3S). [0620] C. 3-(5-(2-Isopropyl-5-phenylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione: To a solution of 3-(5-(5-bromo-2-isopropylthiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (110 mg, 239 μmol, 1.00 eq) in dioxane (2.20 mL) and H2O (0.110 mL) was added phenylboronic acid (87.6 mg, 719 μmol, 3.00 eq) ,K3PO4 (152 mg, 719 μmol, 3.00 eq) and Pd(dppf)Cl2 (17.5 mg, 23.9 μmol, 0.100 eq) at 25 °C, then the mixture was stirred at 90 °C for 2 h under N2. It was filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (SiO2, Dichloromethane/Methanol = 100/0 to 30/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.35) to give a residue. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 7 μm) and gradient of 36 - 66% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (18.8 mg, 42.4 μmol, 17.6% yield, 100% purity HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.9 - 7.47 (m, 1H), 7.40 - 7.38 (m, 3H), 7.35 - 7.33 (m, 2H), 5.10 (dd, J = 13.6 Hz, J = 5.2Hz, 1H), 4.44 - 4.26 (m, 2H), 3.37 - 3.35 (m, 1H), 2.95 - 2.86 (m, 1H), 2.61 - 2.56 (m, 1H), 2.40 - 2.35 (m, 1H), 2.02 - 1.97 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H),. (ESI+) m/z: 446.1 (M+H)+, (C25H23N3O3S). 183 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 88 [0621] Synthesis of 3-(5-(2-(tert-Butyl)-5-phenylthiazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione: [0622] A. 3-(5-(2-(tert-Butyl) thiazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione: To a solution of 3-[5-(2-bromoacetyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (600 mg, 1.64 mmol, 1.00 eq) in [Bmim]PF6 (10.0 mL) was added 2,2-dimethylpropanethioamide (211 mg, 1.81 mmol, 1.10 eq) and K2CO3 (272 mg, 1.97 mmol, 1.20 eq). The mixture was stirred at 25 °C for 5 h. After the reaction was completed, the reaction mixture was diluted with H2O (20.0 mL) and extracted with dichloromethane 50.00 mL (5 x 50.0 mL). Then, the extract was washed with sat. aq. Na2SO3 solution (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate: Petroleum ether= 500: 1 to 80: 1, Rf = 0.43 (Dichloromethane: Methanol= 20:1)) to give the title compound (500 mg, 1.12 mmol, 40.0% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.09 (s, 1H), 8.18 - 8.11 (m, 3H), 4.17 - 4.14 (m, 1H), 3.84 (s, 2H), 2.96 - 2.88 (m, 2H), 2.66 - 2.59 (m, 2H), 1.45 (s, 9H). (ESI+) m/z: 384.0 (M+H)+, (C20H21O3N3S). [0623] B. 3-(5-(5-Bromo-2-(tert-butyl) thiazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione: To a solution of 3-(5-(2-(tert-butyl)thiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (500 mg, 1.30 mmol, 1.00 eq) in DMF (10.0 mL) was added NBS (243 mg, 1.37 mmol, 1.05 eq) in DMF (2.00 mL). The mixture was stirred at 0°C for 2 h. After the reaction was completed, the reaction mixture was quenched by H2O (20.0 mL) and extracted with ethyl acetate 50.0 mL (3 x 50.0 mL). The combined organic layers were washed with saturated sodium chloride solution 50.0 mL (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500:1 to 20:1, Rf = 0.54 (Dichloromethane: Methanol = 15:1)) to give the title compound (5.00 g, 18.1 mmol, 62.3% yield) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.11 (s, 1H), 184 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 8.05 - 8.03 (m, 1H), 7.87 - 7.85 (s, 1H), 5.17 - 5.13 (m, 1H), 4.58 - 4.40 (m, 2H), 2.98 - 2.90 (m, 1H), 2.67 - 2.51 (m, 3H), 1.43 (s, 9H). (ESI+) m/z: 464.0 (M+H)+, (C20H20O3N3BrS). [0624] C. 3-(5-(2-(tert-Butyl)-5-phenylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: A mixture of 3-(5-(5-bromo-2-(tert-butyl)thiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (180 mg, 389 μmol, 1.00 eq) in DMF (1.00 mL), then was added phenylboronic acid (142 mg, 1.17 mmol, 3.00 eq), K3PO4 (247 mg, 1.17 mmol, 3.00 eq) and Pd(dppf)Cl2 (28.4 mg, 38.9 μmol, 0.10 eq) under N2, then the mixture was stirred at 90 °C for 12 h under N2 atmosphere. After the reaction was completed, the reaction mixture was quenched by H2O (20.0 mL) and extracted with dichloromethane 50.0 mL (3 x 50.0 mL). The combined organic layers were washed with saturated sodium chloride solution 50.0 mL (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500:1 to 20:1, Rf = 0.40 (Dichloromethane: Methanol = 15: 1)) to give the title product. The residue was purified by preparative-HPLC using a column: Welch Xtimate C18 150 x 25mm x 5um and gradient of 52 - 82% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min to give the title compound (13.4 mg, 50.5 μmol, 7.30% yield, 96.7% purity in HPLC at 220nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.70 (s, 1H), 7.64 - 7.62 (m, 1H), 7.40 - 7.39 (m, 1H), 7.36 (s, 3H), 7.35 - 7.34 (m, 2H), 5.12 - 5.08 (m, 1H), 4.45 – 4.26 (m, 2H), 2.94 - 2.87 (m, 1H), 2.61 – 2.57 (m, 1H), 2.40 - 2.33 (m, 1H), 2.02 – 2.00 (m, 1H), 1.47 (s, 9H). (ESI+) m/z: 460.1 (M+H)+, (C26H25O3N3S). EXAMPLE 89 [0625] Synthesis of 3-(5-(2-cyclopropyl-5-phenylthiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0626] A. 3-(5-(2-Cyclopropylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(2-bromoacetyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (800 mg, 2.19 mmol, 1.00 eq) in [Bmim]PF6 (2.00 mL) was added cyclopropanecarbothioamide (243 185 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mg, 2.41 mmol, 1.10 eq) and K2CO3 (363 mg, 2.63 mmol, 1.20 eq) at 25 °C, then was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated Na2SO3 aqueous solution (100 mL) and extracted with ethyl acetate (3 x 60.0 mL). The combined organic layer was washed with brine (2 x 30.0 mL), dried over Na2SO4, filtered and concentrated. The crude product was triturated with ACN (3.00 mL) at 0 °C for 30 min. The filter cake was washed with ACN (2.00 mL) and concentrated to give the title compound (200 mg, 532 μmol, 24.4% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.14 - 8.03 (m, 3H), 7.77 - 7.75 (m, 1H), 5.14 - 5.10 (m, 1H), 4.53 - 4.36 (m, 2H), 2.93 - 2.88 (m, 1H), 2.63 - 2.60 (m, 1H), 2.47 - 2.39 (m, 2H), 2.03 - 2.01 (m, 1H), 1.19 - 1.15 (m, 2H), 1.05 - 1.03 (m, 2H). (ESI+) m/z: 368.0 (M+H)+, (C19H17N3O3S). [0627] B. 3-(5-(5-Bromo-2-cyclopropylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 3-[5-(2-cyclopropylthiazol-4-yl)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (160 mg, 435 μmol, 1.00 eq) in DMF (1.00 mL) was added solution of NBS (81.3 mg, 457μmol, 1.05 eq) in DMF (1.00 mL) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The mixture was filtered through a pad of celite and was washed with ACN (3 x 20.0 mL), the filtrate was concentrated to give the title compound (140 mg, 313 μmol, 70.0% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.06 (s, 1H), 8.00 - 7.98 (m, 1H), 7.83 - 7.81 (m, 1H), 5.16 - 5.11 (m, 1H), 4.55 - 4.38 (m, 2H), 2.95 - 2.89 (m, 1H), 2.63 - 2.59 (m, 1H), 2.47 - 2.42 (m, 2H), 2.04 - 2.02 (m, 1H), 1.18 - 1.15 (m, 2H), 1.06 - 1.04 (m, 2H). (ESI+) m/z: 448.0 (M+H)+, (C19H16BrN3O3S). [0628] C. 3-(5-(2-Cyclopropyl-5-phenylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 3-[5-(5-bromo-2-cyclopropyl-thiazol-4-yl)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (140 mg, 313 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added phenylboronic acid (114 mg, 941 μmol, 3.00 eq), Pd(dppf)Cl2 (22.9 mg, 31.3 μmol, 0.10 eq) and K3PO4 (199 mg, 941 μmol, 3.00 eq) under N2, then the mixture was stirred at 90 °C for 2 h under N2. The mixture was filtered through a pad of celite and filter cake was washed with ethyl acetate (3 x 20.0 mL), the filtrate was concentrated to give residue. The crude compound was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.60) and preparative- HPLC (using a Welch Ultimate C18 (150 x 25mm x 7 μm) and gradient of 37 - 67% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (8.94 mg, 20.1 μmol, 6.41% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.68 (s, 1H), 7.64 - 7.60 (m, 1H), 7.44 - 7.39 (m, 1H), 7.38 - 7.31 (m, 5H), 5.12 - 5.07 (m, 1H), 4.43 - 4.25 (m, 2H), 2.91 - 2.89 186 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (m, 1H), 2.61 - 2.56 (m, 1H), 2.46 - 2.45 (m, 1H), 2.44 - 2.36 (m, 1H), 2.01 - 1.99 (m, 1H), 1.19 - 1.15 (m, 2H), 1.07 - 1.05 (m, 2H). (ESI+) m/z: 444.1 (M+H)+, (C25H21N3O3S). EXAMPLE 90 [0629] Synthesis of 3-(5-(1-(difluoromethyl)-5-phenyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0630] A. 1-(Difluoromethyl)-5-phenyl-1H-1,2,3-triazole: To a solution of 5-phenyl- 1H-1,2,3-triazole (2.00 g, 13.7 mmol, 1.00 eq), diethyl (bromodifluoromethyl) phosphonate (5.89 g, 22.0 mmol, 1.60 eq) in ACN (40.0 mL) was added KOH (5.41 g, 96.4 mmol, 7.00 eq) under N2.The mixture was stirred at 25 °C for 3 h under N2. The reaction mixture was poured into H2O (50.0 mL) and extracted with Ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (3 x 50.0 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate =100: 1 to 7:1, TLC: Petroleum ether: Ethyl acetate = 7:1, Rf = 0.40) and preparative - SFC using a DAICEL CHIRALPAK AD (250 x 30 mm x 10 um) and gradient of 10% Methanol for CO2 containing 0.05% DEA over 10 min at a flow rate of 3 mL/min to give the title compound (600 mg, 3.07 mmol, 22.3% yield) was obtained as white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.39 - 8.11(m, 2H), 7.58 - 7.50 (m, 5H). (ESI+) m/z: 196.1 (M+H)+, (C9H7F2N3). [0631] B. 4-Bromo-1-(difluoromethyl)-5-phenyl-1H-1,2,3-triazole: To a solution of 1- (difluoromethyl)-5-phenyl-1H-1,2,3-triazole (230 mg, 1.18 mmol, 1.00 eq) in ACN (5.00 mL) and H2O (5.00 mL) was added KBr (350 mg, 2.95 mmol, 127 μL, 2.50 eq) and Oxone (1.81 g, 2.95 mmol, 2.50 eq) at 20 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into H2O (100 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with Na2SO3 (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.50) to give the title compound (130 mg, 469 μmol, 38.9% yield, 98.9% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) 8.29 - 8.01 (m, 1H), 7.62 - 7.54 (m, 5H). (ESI+) m/z: 274.0 (M+H)+, (C9H6BrF2N3). 187 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0632] C. 3-(5-(1-(Difluoromethyl)-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-(difluoromethyl)-5-phenyl-1H-1,2,3- triazole (100 mg, 364 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione (337 mg, 912 μmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (232 mg, 1.09 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (30.5 mg, 36.4 μmol, 0.10 eq) under N2. The mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 7 um) and gradient of 24% - 54% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (37.1 mg, 83.4 μmol, 22.8% yield, 98.2% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6): δ 10.96 - 10.93 (m, 1H), 8.23 - 8.05 (m, 1H), 7.75 - 7.49 (m, 8H), 5.11 - 5.07 (m, 1H), 4.45 - 4.26 (m, 2H), 2.91 - 2.88 (m, 1H), 2.60 - 2.56 (m, 1H), 2.39 - 2.35 (m, 1H), 2.00 - 1.97 (m, 1H),. (ESI+) m/z: 438.1 (M+H)+, (C22H17F2N5O3). EXAMPLE 91 [0633] Synthesis of 3-(5-(1-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0634] A. 1-Benzyl-4-phenyl-1H-1,2,3-triazole: To a solution of 3-phenylpropiolic acid (1.10 g, 7.51 mmol, 1.00 eq) in ACN (10.0 mL) was added (azidomethyl)benzene (1.00 g, 7.51 mmol, 1.00 eq) and Cu2O (53.7 mg, 375 μmol, 38.3 μL, 0.05 eq) at 25 °C, then the mixture was stirred at 80 °C for 16 h under N2. It was poured into water (100 mL) and adjusted pH = 9 with Na2CO3 solution (10.0 mL) and extracted with dichloromethane (3 x 100 mL) to collect the organic layers, the combined layers were dried over NaSO4 and filtered and the filter was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 0/1, TLC: Petroleum ether/Ethyl acetate = 4/1, Rf = 4/1) to give the title compound (1.46 g, 6.16 mmol, 82.0% yield, 99.3% purity LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3) δ 188 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.81 (d, J = 1.6 Hz, 2H), 7.66 (s, 1H), 7.42 - 7.38 (m, 5H), 7.33- 7.32 (m, 3H), 5.58 (s, 2H). (ESI+) m/z: 236.1 (M+H)+, (C15H13N3). [0635] B. 1-Benzyl-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium iodide: To a solution of 1-benzyl-4-phenyl-1H-1,2,3-triazole (1.46 g, 6.16 mmol, 1.00 eq) in ACN (15.0 mL) was added CH3I (4.37 g, 30.8 mmol, 1.92 mL, 5.00 eq) at 25 °C, then the mixture was stirred at 80 °C for 16 h. It was concentrated under vacuum. The crude product was triturated with ethyl acetate (45.0 mL) to give the title compound (1.65 g, 4.34 mmol, 70.4% yield, 99.3% purity LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3) δ 9.43 (s, 1H), 7.70 - 7.68 (m, 4H), 7.57 - 7.53 (m, 3H), 7.43- 7.41 (m, 3H), 6.04 (s, 2H), 4.29 (s, 3H). (ESI+) m/z: 249.9 (M+H)+, (C16H16IN3). [0636] C. 1-Methyl-5-phenyl-1H-1,2,3-triazole: To a solution of 1-benzyl-3-methyl-4- phenyl-1H-1,2,3-triazol-3-ium iodide (1.65 g, 6.55 mmol, 1.00 eq) in THF (100 mL) was added t-BuOK (1.95 g, 17.4 mmol, 2.66 eq) at 0 °C, then the mixture was stirred at 25 °C for 16 h. It was poured into water (100 mL) and extracted with ethyl acetate (3 x 100 mL) to collect the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 15/1, TLC: Petroleum ether/Ethyl acetate = 3/1, Rf = 0.31) to give the title compound (450 mg, 2.54 mmol, 38.8% yield, 90.0% purity LCMS at 220 nm) as an orange oil.1H NMR: (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.62 - 7.60 (m, 2H), 7.54 - 7.48 (m, 3H), 4.07 (s, 3H). (ESI+) m/z: 159.9 (M+H)+, (C9H9N3). [0637] D. 4-Bromo-1-methyl-5-phenyl-1H-1,2,3-triazole: To a solution of 1-methyl-5- phenyl-1H-1,2,3-triazole (180 mg, 1.02 mmol, 1.00 eq) in DMF (3.00 mL) was added NBS (190 mg, 1.07 mmol, 1.05 eq) and at 0 °C, then the mixture was stirred at 25°C for 20 h. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (2 x 10.0 mL) to get the organic layers, the organic layers was washed with saturated solution of Na2SO3 (15.0 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 2/1, Rf = 0.43) to give the title compound (150 mg, 589 μmol, 57.8% yield, 93.5% purity at 220 nm) as a white solid.1H NMR: (400 MHz, CD3CN) δ 7.58 - 7.56 (m, 3H), 7.50 - 7.48 (m, 2H), 3.95 (s, 3H). (ESI+) m/z: 237.7 (M+H)+, (C9H8BrN3). [0638] E. 3-(5-(1-Methyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-5-phenyl-1H-1,2,3-triazole 189 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (120 mg, 471 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added 3-(1-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (436 mg, 1.18 mmol, 2.50 eq), K3PO4 (200 mg, 942 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (39.4 mg, 47.1 μmol, 0.100 eq) at 25 °C, then the mixture was stirred at 100°C for 3 h under N2. It was filtered and the filter was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 30/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.40) to give a residue. The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 16 - 46% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (70.7 mg, 176 μmol, 37.3% yield, 100% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 - 7.57 (m, 3H), 7.50 - 7.48 (m, 3H), 5.09 (dd, J = 13.2 Hz, J = 4.8 Hz, 1H), 4.44 - 4.25 (m, 2H), 3.91 (s, 3H), 2.94 - 2.85 (m, 1H), 2.60 - 2.56 (m, 1H), 2.42 - 2.31 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 402.2 (M+H)+, (C22H19N5O3). EXAMPLE 92 [0639] Synthesis of 3-(5-(1-isobutyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0640] A. 1-Isobutyl-5-phenyl-triazole: To a solution of 4-phenyl-1H-triazole (2.00 g, 13.7 mmol, 1.00 eq) in DMF (20.0 mL) was added 1-bromo-2-methyl-propane (2.83 g, 20.6 mmol, 2.25 mL, 1.50 eq) and K2CO3 (3.81 g, 27.5 mmol, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.43 (Dichloromethane: Methanol = 10: 1)) and purified by Chiral-SFC (column: REGIS (R,R)WHELK-O1(250mm*25mm, 10 um);mobile phase: [CO2-MeOH];B%: 20%, isocratic elution mode, Rt = 1.001, 1.315) to give the title compound (150 mg, 745 μmol, 5.41% yield) as a white solid.1H NMR: (400 MHz, 190 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT CDCl3) δ 7.69 (s, 1H), 7.53 - 7.46 (m, 3H), 7.40 - 7.35 (m, 2H), 4.17 (d, J = 7.2 Hz, 2H), 2.17 (m, 1H), 0.83 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 202.1 (M+H)+, (C12H15N3). [0641] B. 4-Bromo-1-isobutyl-5-phenyl-1H-1,2,3-triazole: To a solution of 1-isobutyl- 5-phenyl-triazole (40.0 mg, 198 μmol, 1.00 eq) in ACN (0.50 mL) was added H2O (0.50 mL), Oxone (100 mg, 596 μmol, 3.00 eq) and KBr (70.9 mg, 596 μmol, 25.8 μL, 3.00 eq). The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (5.00 mL) and extracted with Ethyl acetate (3 x 5.00 mL). The combined organic layer was washed with saturated NaCl aqeous (3 x 5.00 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Ethyl acetate = 50: 1, Rf = 0.43) to give the title compound (40.0 mg, 142 μmol, 71.8% yield) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.72 (d, J = 5.6 Hz, 3H), 7.56 (d, J = 8.4 Hz, 2H), 4.22 (d, J = 7.1 Hz, 2H), 2.33 - 2.21 (m, 1H), 1.00 (d, J = 6.4 Hz, 6H). (ESI+) m/z: 280.0 (M+H)+, (C12H14BrN3). [0642] C. 3-(5-(1-Isobutyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-isobutyl-5-phenyl-triazole (40.0 mg, 142 μmol, 1.00 eq) in dioxane (1.00 mL) was added H2O (0.12 mL), 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (132 mg, 356 μmol, 2.50 eq), Ru-Phos-Pd-G3 (11.9 mg, 14.2 μmol, 0.10 eq) and K3PO4 (90.9 mg, 428 μmol, 3.00 eq). The mixture was stirred at 80 °C for 2 h under N2 atmosphere. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.43) and purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 32 - 62% acetonitrile in water containing 0.5% FA over 13 min at a flow rate of 25.0 mL/min) to give the title compound (26.0 mg, 58.4 μmol, 40.9% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.10 - 10.85 (m, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.52 - 7.43 (m, 3H), 5.13 - 5.04 (m, 1H), 4.46 - 4.22 (m, 2H), 4.07 (d, J = 7.2 Hz, 2H), 2.97 - 2.82 (m, 1H), 2.58 (d, J = 12.4 Hz, 1H), 2.43 - 2.36 (m, 1H), 2.04 - 1.90 (m, 2H), 0.76 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 444.2 (M+H)+, (C25H25N5O3). 191 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 93 [0643] Synthesis of 3-(5-(2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0644] A. (6-(2-Hydroxypropan-2-yl)pyridin-3-yl)boronic acid: A mixture of 2-(5- bromopyridin-2-yl)propan-2-ol (1.00 g, 4.63 mmol, 1.00 eq) in dioxane (10.0 mL) was added BPD (1.41 g, 5.55 mmol, 1.20 eq), KOAc (908 mg, 9.26 mmol, 2.00 eq) and Pd(dppf)Cl2.CH2Cl2 (377 mg, 462 μmol, 0.10 eq) and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 16 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate. Water (20.0 mL) was added to the residue. The resulting mixture was extracted with dichloromethane (3 x 20.0 mL). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (2.20 g, crude) as a black brown oil.1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 0.8 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.67 (d, J = 7.2 Hz, 1H), 4.49 (d, J = 1.2 Hz, 1H), 4.22 (d, J = 2.0 Hz, 1H), 1.80 (s, 6H) [0645] B. 2-(5-(4-Bromo-1-methyl-1H-imidazol-2-yl)pyridin-2-yl)propan-2-ol: A mixture of (6-(2-hydroxypropan-2-yl)pyridin-3-yl)boronic acid (754 mg, 4.17 mmol, 1.00 eq) in dioxane (12.0 mL) and H2O (4.00 mL) was added 2,4-dibromo-1-methyl-1H-imidazole (1.00 g, 4.17 mmol, 1.00 eq) tris(4-fluorophenyl)phosphane (131 mg, 416 μmol, 0.10 eq), K3PO4 (2.65 g, 12.5 mmol, 3.00 eq) and Pd(PPh3)2Cl2 (292 mg, 416 μmol, 0.10 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated. Water (30.0 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (3 x 30.0 mL). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=1: 0 to 7: 10, TLC: Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.52) to give the title compound (860 mg, 1.46 mmol, 35.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 1.6 Hz, 1H), 8.07 - 8.05 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 5.31 (s, 1H), 3.75 (s, 3H), 1.47 (s, 6H). (ESI+) m/z: 297.8 (M+H)+, (C12H14BrN3O). 192 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0646] C. tert-Butyl 5-amino-4-(5-(2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1- methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: A mixture of 2-(5-(4- bromo-1-methyl-1H-imidazol-2-yl)pyridin-2-yl)propan-2-ol (400 mg, 1.35 mmol, 1.00 eq) in dioxane (10.0 mL) and H2O (0.50 mL) was added tert-butyl 5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.20 g, 2.70 mmol, 2 eq), K3PO4 (860 mg, 4.05 mmol, 3.00 eq), RuPhos Pd G3 (112 mg, 135 μmol, 0.10 eq) and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere.The reaction liquid is filtered to collect the filtrate and concentrate under reduced pressure to get residue.The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate= 0: 1, Rf = 0.12) to give the title compound (357 mg, 619 μmol, 45.8% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 1.6 Hz, 1H), 8.17 - 8.14 (m, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.17 (s, 1H), 5.32 (s, 1H), 4.76 - 4.70 (m, 1H), 4.65 - 4.45 (m, 2H), 3.84 (s, 3H), 2.23 - 2.09 (m, 4H), 1.49 (s, 6H), 1.33 (s, 9H). (ESI+) m/z: 534.4 (M+H)+, (C29H35N5O5). [0647] D. 3-(5-(2-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of tert-butyl 5-amino-4-(5-(2-(6- (2-hydroxypropan-2-yl)pyridin-3-yl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (300 mg, 562 μmol, 1.00 eq) in ACN (6.00 mL) was added TsOH (387 mg, 2.25 mmol, 4.00 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated directly in vacuum to give residue. The crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 0 - 30% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (117 mg, 254 μmol, 45.3% yield, 100% purity in HPLC at 220 nm) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.93 (d, J = 1.6 Hz, 1H), 8.20 - 8.27 (m, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 5.16 - 5.11 (m, 1H), 4.54 - 4.45 (m, 2H), 3.89 (s, 3H), 3.00 - 2.87 (m, 1H), 2.68 - 2.57 (m, 1H), 2.47 - 2.38 (m, 1H), 2.07 - 1.98 (m, 1H), 1.51 (s, 6H). (ESI+) m/z: 460.2 (M+H)+, (C25H25N5O4). 193 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 94 [0648] Synthesis of 3-[5-(1-methyl-2-{[(1-methyl-1H-pyrazol-4-yl)amino]methyl}-1H- imidazol-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: [0649] A. tert-Butyl 5-amino-4-(5-(1-methyl-2-(((1-methyl-1H-pyrazol-4- yl)amino)methyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 μmol, 1.00 eq) and 1-methyl-1H- pyrazol-4-amine (14.6 mg, 150 μmol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 μL, 300 μmol, 3.00 eq) under protection of N2. The mixture was stirred at 30 °C for 16 hrs. After the reaction was completed, checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 508.3 (M+H)+, (C26H33N7O4). [0650] B. 3-[5-(1-Methyl-2-{[(1-methyl-1H-pyrazol-4-yl)amino]methyl}-1H-imidazol- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(1-methyl-2-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)- 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq) in CH3CN (1.00 mL) was added H2SO4 (200 μL). The mixture was stirred at 65 °C for 1 hr. After the reaction was completed, checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Welch Ultimate C18 (150*25 mm*5 μm) and gradient of 0% - 10% acetonitrile in water containing 0.225% FA over 11 mins at a flow rate of 25 mL/min to give final product (13.1 mg, 30.3 μmol, 30.3% yield, 99.1% purity in HPLC at 220 nm) as a grey solid. (ESI+) m/z: 434.3 (M+H)+, (C22H23N7O3). 194 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 95 [0651] Synthesis of 3-{5-[1-methyl-2-({[(3S)-1-methylpyrrolidin-3-yl]amino}methyl)- 1H-imidazol-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [0652] A. tert-butyl 5-amino-4-(5-(1-methyl-2-((((S)-1-methylpyrrolidin-3-yl) amino)methyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 μmol, 1.00 eq) and (3S)-1- methylpyrrolidin-3-amine (15.0 mg, 150 μmol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 μL, 300 μmol, 3.00 eq) under protection of N2. The mixture was stirred at 30 °C for 16 hrs. After the reaction was completed, checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 511.3 (M+H)+, (C27H38N6O4). [0653] B. 3-{5-[1-Methyl-2-({[(3S)-1-methylpyrrolidin-3-yl]amino}methyl)-1H- imidazol-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(1-methyl-2-((((S)-1-methylpyrrolidin-3- yl)amino)methyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq) in ACN (1.00 mL) was added TsOH·H2O (152 mg, 800 μmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. After the reaction was completed, checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Welch Ultimate C18 (150*25 mm*5 μm) and gradient of 0% - 10% acetonitrile in water containing 0.225% FA over 11 min at a flow rate of 25 mL/min to give final product (17.0 mg, 39.0 μmol, 39.0 % yield, 93.1% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 437.3 (M+H)+, (C23H28N6O3). 195 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 96 [0654] Synthesis of 3-(5-{2-[({imidazo[1,2-a]pyridin-3-yl}amino)methyl]-1-methyl-1H- imidazol-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: [0655] A. tert-Butyl 5-amino-4-(5-(2-((imidazo[1,2-a]pyridin-3-ylamino)methyl)-1- methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 μmol, 1.00 eq) and imidazo[1,2- a]pyridin-3-amine (19.9 mg, 150 μmol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 μL, 300 μmol, 3.00 eq) under protection of N2. The mixture was stirred at 30 °C for 16 hrs. After the reaction was completed, checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 544.3 (M+H)+, (C29H33N7O4). [0656] B. 3-(5-{2-[({Imidazo[1,2-a]pyridin-3-yl}amino)methyl]-1-methyl-1H-imidazol- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-((imidazo[1,2-a]pyridin-3-ylamino)methyl)-1-methyl- 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq) in ACN (1.00 mL) was added TsOH·H2O (152 mg, 800 μmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. After the reaction was completed, checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Welch Ultimate C18 (150*25 mm*5 μm) and gradient of 0% - 12% acetonitrile in water containing 0.225% FA over 11 min at a flow rate of 25 mL/min to give final product (4.95 mg, 10.6 μmol, 10.6% yield, 100% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 470.3 (M+H)+, (C25H23N7O3). 196 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 97 [0657] Synthesis of 3-[5-(2-{[(isoquinolin-6-yl)amino]methyl}-1-methyl-1H-imidazol-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: [0658] A. tert-Butyl 5-amino-4-(5-(2-((isoquinolin-6-ylamino)methyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate (44.7 mg, 100 μmol, 1.00 eq) and isoquinolin-6-amine (21.6 mg, 150 μmol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 μL, 300 μmol, 3.00 eq) under protection of N2. The mixture was stirred at 30 °C for 16 hrs. After the reaction was completed, checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 555.3 (M+H)+, (C31H34N6O4). [0659] B. 3-[5-(2-{[(Isoquinolin-6-yl)amino]methyl}-1-methyl-1H-imidazol-4-yl)-1- oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-((isoquinolin-6-ylamino)methyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq) in ACN (1.00 mL) was added TsOH·H2O (152 mg, 800 μmol, 8.00 eq). The mixture was stirred at 8 °C for 2 hrs. After the reaction was completed, checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Waters Xbridge C18 (150 *25 mm*10 μm) and gradient of 0% - 30% acetonitrile in water containing 0.1% ammonium bicarbonate over 10 min at a flow rate of 25 mL/min to give final product (6.31 mg, 13.1 μmol, 13.1% yield, 95.4% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 481.3 (M+H)+, (C27H24N6O3). 197 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 98 [0660] Synthesis of 3-[5-(2-{[(isoquinolin-5-yl)amino]methyl}-1-methyl-1H-imidazol-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: [0661] A. tert-Butyl 5-amino-4-(5-(2-((isoquinolin-5-ylamino)methyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate (44.7 mg, 100 μmol, 1.00 eq) and isoquinolin-5-amine (21.6 mg, 150 μmol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 μL, 300 μmol, 3.00 eq) under protection of N2. The mixture was stirred at 30 °C for 16 hrs. After the reaction was completed, checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 555.3 (M+H)+, (C31H34N6O4). [0662] B. 3-[5-(2-{[(Isoquinolin-5-yl)amino]methyl}-1-methyl-1H-imidazol-4-yl)-1- oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-((isoquinolin-5-ylamino)methyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq) in ACN (1.00 mL) was added TsOH·H2O (152 mg, 800 μmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. After the reaction was completed, checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Welch Ultimate C18 (150 *25 mm*5 μm) and gradient of 0% - 12% acetonitrile in water containing 0.225% FA over 11 min at a flow rate of 25 mL/min to give final product (6.08 mg, 12.7 μmol, 12.7% yield, 100% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 481.3 (M+H)+, (C27H24N6O3). 198 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 99 [0663] Synthesis of 3-{5-[2-({1H,2H,3H-[1,3]diazolo[1,2-a]imidazol-1-yl}methyl)-1- methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [0664] A. tert-Butyl 5-amino-4-(5-(2-((2,3-dihydro-1H-imidazo[1,2-a]imidazol-1- yl)methyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(chloromethyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.7 mg, 100 μmol, 1.00 eq) and 1H,2H,3H- imidazo[1,2-a][1,3]diazole (16.4 mg, 150 μmol, 1.50 eq) in DMF (1.00 mL) was added DIEA (52.0 μL, 300 μmol, 3.00 eq) under protection of N2. The mixture was stirred at 30 °C for 16 hrs. After the reaction was completed, checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 520.3 (M+H)+, (C27H33N7O4). [0665] B. 3-{5-[2-({1H,2H,3H-[1,3]Diazolo[1,2-a]imidazol-1-yl}methyl)-1-methyl-1H- imidazol-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-((2,3-dihydro-1H-imidazo[1,2-a]imidazol- 1-yl)methyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq) in ACN (1.00 mL) was added H2SO4 (200 μL). The mixture was stirred at 65 °C for 1 hr. After the reaction was completed, checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Welch Ultimate C18 (150 *25 mm*5 μm) and gradient of 0% - 10% acetonitrile in water containing 0.225% FA over 11 min at a flow rate of 25 mL/min to give final product (8.39 mg, 18.8 μmol, 18.8% yield, 100% purity in HPLC at 220 nm) as a white gum. (ESI+) m/z: 446.3 (M+H)+, (C23H23N7O3). 199 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 100-111 [0666] The compounds of Examples 100-111 were prepared according to the following synthetic scheme: [0667] Experimental Procedure [0668] Step 1: To a vial containing a solution of 0018_Bi (400 µmol, 1.00 eq) in EtOH (4.00 mL) was added pyridine (94.8 mg, 1200 µmol, 3.00 eq), NH2OH·HCl (82.8 mg, 1.20 mmol, 3.00 eq). The mixture was shaken at 30 °C for 16 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediates used for the next step. [0669] Step 2: To a vial containing a solution of 0018_Bi_1 (~300 µmol, 1.00 eq) in DMF (3.00 mL) was added NCS (19.5 mg, 150 µmol, 0.50 eq), the mixture was stirred at 30 °C, after 15 minutes, then NCS (99.7 mg, 750 µmol, 2.50 eq) was added. The resulting mixture was stirred at 30 °C for 2.75 hrs. Spot checked by LCMS. The reaction mixture was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediates used for next step. [0670] Step 3: To a vial containing a solution of 0018_Bi_2 (~200 µmol, 1.00 eq) in DMSO (4.00 mL) was added 0018_A001 (53.6 mg, 200 µmol, 1.00 eq). The mixture was 200 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT stirred at 50 °C for 16 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. [0671] Step 4 (for Boc compounds): To a vial containing a solution of 0018_Bi_Boc (~100 µmol, 1.00 eq) in HCl·Dioxane (2 M) (2.00 mL). The mixture was stirred at 30 °C for 3 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 201 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 202 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 112 [0672] Synthesis of 3-{5-[3-(1-benzylpiperidin-4-yl)-1,2-oxazol-5-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [0673] A. 1-Benzylpiperidine-4-carbaldehyde oxime: To a solution of 1- benzylpiperidine-4-carbaldehyde (40.6 mg, 400 μmol, 1.00 eq) in EtOH (4.00 mL) was added pyridine (94.8 mg, 1200 μmol, 3.00 eq), H2NOH·HCl (82.8 mg, 1200 μmol, 3.00 eq). The mixture was shaking at 30 °C for 16 hrs. After the reaction was completed, the reaction mixture was filtered. The reaction mixture was concentrated under nitrogen gas to give crude intermediate to use for next step. (ESI+) m/z: 219.1 (M+H)+, (C13H18N2O). [0674] B. 1-Benzyl-N-hydroxypiperidine-4-carbimidoyl chloride: To a solution of 1- benzylpiperidine-4-carbaldehyde oxime (crude, ~300 μmol, 1.00 eq) in DMF (3.00 mL) was added NCS (19.9 mg, 150 μmol, 0.50 eq), the mixture was stirred at 30 °C for 15 minutes, then NCS (99.7 mg, 750 μmol, 2.50 eq) was added. The mixture was stirred at 30 °C for 2.75 hrs. The reaction mixture was diluted with H2O (3.00 mL) and extracted with ethyl acetate (6.00 mL * 3). The combined organic layers were dried over Na2SO4. The organic layer was concentrated under nitrogen gas to give crude intermediate (crude) to use for next step. (ESI+) m/z: 254.1 (M+H)+, (C13H17ClN2O). [0675] C. 3-{5-[3-(1-Benzylpiperidin-4-yl)-1,2-oxazol-5-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: A mixture of 1-benzyl-N-hydroxypiperidine-4- carbimidoyl chloride (crude, ~200 μmol, 1.00 eq) and 3-(5-ethynyl-1-oxoisoindolin-2- yl)piperidine-2,6-dione (53.6 mg, 200 μmol, 1.00 eq) in DMSO (4.00 mL) was stirred at 50 °C for 16 hrs. After the reaction was completed, it was checked by LCMS. The mixture was concentrated under nitrogen gas and purified by prep-HPLC (using a column: Welch Ultimate C18 (150*25 mm*7 μm) and gradient of 25% - 55% acetonitrile in water containing 0.225% FA over 10 min at a flow rate of 25 mL/min to give final product (9.68 mg, 20.0 μmol, 10.0% yield, 90.1% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 485.2 (M+H)+, (C28H28N4O4). 203 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 113-130 [0676] The compounds of Examples 113-130 were prepared according to the following synthetic scheme: [0677] Experimental Procedure [0678] Step 1: To a vial containing a solution of 0020_A001 (40.8 mg, 0.15 mmol, 1.00 eq) in EtOH (1.50 mL) was added pyridine (35.0 µL, 0.45 mmol, 3.00 eq) and H2NOH·HCl (31.1 mg, 0.45 mmol, 3.00 eq). The mixture was stirred at 30 °C for 16 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediates used for next step. [0679] Step 2: To a vial containing a solution of 0020_A001_1 (~0.15 mmol, 1.00 eq) in DMF (1.50 mL) was added NCS (9.98 mg, 0.075 mmol, 0.50 eq). The mixture was stirred at 30 °C for 15 mins. Then NCS (49.9 mg, 0.375 mmol, 2.50 eq). The mixture was stirred at 30 °C for 2.75 hrs. Spot checked by LCMS. The reaction mixture was diluted with H2O (1.00 mL) and extracted with ethyl acetate (2.00 mL x 3), dried over Na2SO4, filtered, and concentrated to give crude intermediates used for next step. [0680] Step 3: To a vial containing a solution of 0020_A001_2 (~0.15 mmol, 1.00 eq) and 0020_Bi (0.30 mmol, 2.00 eq) in DMF (1.50 mL) was added NaHCO3 (126 mg, 1.50 mmol, 10.00 eq). The mixture was stirred at 30 °C for 16 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 204 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0681] Step 4: (For BBs with Boc): To a vial containing a solution of 0020_A001Bi_Boc (~0.15 mmol, 1.00 eq) in DCM (1.00 mL) was added TFA (200 µL). The mixture was stirred at 30 °C for 2 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 205 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 206 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 207 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 131-137 [0682] The compounds of Examples 131-137 were prepared according to the following synthetic scheme: [0683] Experimental Procedure [0684] A. For X = H (0018_A001): To a vial containing a solution of 0021_Bi (100 μmol, 1.00 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (2.13 mg, 15.0 μmol, 0.15 eq), sodium ascorbate (1.98 mg, 10.0 μmol, 0.10 eq) and NaN3 (20.0 mg) in DMSO (1.00 mL) and H2O (0.20 mL) was degassed and purged with N2 for 3 times, then CuI (1.90 mg, 10.0 μmol, 0.10 eq) and 0018_A001 (26.8 mg, 100 μmol, 1.00 eq) was added, and then the mixture was stirred at 30 °C for 2 hrs under N2 atmosphere. Spot checked by LCMS. The reaction mixture was quenched by addition N-Acetyl-L-cysteine (NAC, 12% in H2O) 1.00 mL at 30 °C, and then extracted with ethyl acetate 6.00 mL (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under N2 to give a residue. The residue was purified by prep-HPLC to give the desired product. [0685] B. For X = Me (0019_A001): 208 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0686] Step 1: To a solution of 0021_Bi (500 μmol, 1.00 eq) in ACN (1.00 mL) was cooled at 0 °C and added t-BuONO (77.3 mg, 750 μmol, 1.50 eq). Then the mixture was added TMSN3 (69.0 mg, 600 μmol, 1.20 eq) dropwise. The mixture was stirred at 30 °C for 1 hr. Spot checked by LCMS. The reaction mixture was quenched by addition N-Acetyl-L- cysteine (NAC, 12% in H2O) 2.00 mL at 30 °C, and then extracted with ethyl acetate 12.0 mL (4.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under N2 to give a residue. The residue was concentrated under nitrogen gas used for next step without purification. [0687] Step 2: To a solution of 0021_Bi_1 (~400 μmol, 1.00 eq) in toluene (4.00 mL) was added Compound_1 (197 mg, 600 μmol, 1.50 eq). Then the mixture was stirred at 120 °C for 2 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas. The residue was diluted with H2O (1.00 mL) mL and extracted with ethyl acetate 6.00 mL (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the liquid was concentrated under nitrogen gas to give a residue. The residue was purified by prep- HPLC to give 0021_Bi_2. [0688] Step 3: Under N2 atmosphere, to a solution of 0021_Bi_2 (~200 μmol, 1.00 eq) in toluene (2.00 mL) was added Compound_2 (96.9 mg, 300 μmol, 1.50 eq) and Pd(PPh3)4 (23.1 mg, 20.0 μmol, 0.10 eq). Then the mixture was stirred at 100 °C for 16 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas. The residue was diluted with H2O (1.00 mL) mL and extracted with ethyl acetate 6.00 mL (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the liquid was concentrated under nitrogen gas to give a residue. The residue was purified by prep-HPLC to give desired product. 209 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 210 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 138 [0689] Synthesis of 3-(5-(4-(cyclopropylmethyl)-1-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0690] A. 1-Phenyl-1H-imidazole-4-carbaldehyde: To a solution of 1H-imidazole-4- carbaldehyde (20.0 g, 208 mmol, 1.00 eq) in DMF (300 mL) was addded CuI (5.95 g, 31.2 mmol, 0.15 eq), 1,10-phenanthroline (5.63 g, 31.2 mmol, 0.15 eq) and K3PO4 (88.3 g, 416 mmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h, then bromobenzene (23.5 g, 149 mmol, 15.7 mL, 0.720 eq) was addded to the mixture .The mixture was stirred at 120 °C for 24 h under N2. The mixture was poured into NH4Cl ( 200 mL) and extracted with ethyl acetate (3 x 100 mL) to collect the organic layers, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Dichlorometh- ane/Methanol = 1/0 to 20/1, TLC: Dichloromethane / Methanol = 15/1, Rf = 0.30) to give the title compound (10.3 g, 56.7 mmol, 27.2% yield, 94.9% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.94 (d, J = 17.2 Hz, 2H), 7.57 - 7.42 (m, 5H). (ESI+) m/z: 173.1 (M+H)+, (C10H8ON2). [0691] B. Cyclopropyl(1-phenyl-1H-imidazol-4-yl)methanol: To a solution of 1- phenylimidazole-4-carbaldehyde (5.00 g, 27.5 mmol, 1.00 eq) in THF (60.0 mL) was added bromo(cyclopropyl)magnesium (0.50 M, 110 mL, 2.00 eq) at -78 °C under N2.The mixture was stirred at -78 °C for 4 h. The mixture was poured into NH4Cl ( 200 mL) and extracted with ethyl acetate (100 mL x 3) to collect the organic layers, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/1 to 50/1, TLC: DCM / MeOH = 20/1, Rf = 0.30) to give the title compound (2.20 g, 10.2 mmol, 37.2% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.82 (d, J = 1.2 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.41 - 7.36 (m, 3H), 7.28 (s, 1H), 4.10 (d, J = 8.0 Hz, 1H),1.39 - 1.31 (m, 1H), 0.71 - 0.60 (m, 2H), 0.59 - 0.52 (m, 1H), 0.46 - 0.41 (m, 1H) (ESI+) m/z: 215.2 (M+H)+, (C13H14N2O). 211 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0692] C. 4-(Cyclopropylmethyl)-1-phenyl-1H-imidazole: To a solution of cyclopropyl- (1-phenylimidazol-4-yl)methanol (1.30 g, 6.07 mmol, 1.00 eq) in DCM (5.00 mL) was addded TFA (4.15 g, 36.4 mmol, 2.70 mL, 6.00 eq) and Et3SiH (4.23 g, 36.4 mmol, 5.81 mL, 6.00 eq) at 25 °C.The mixture was stirred at 25 °C for 20 hr. The mixture was poured into H2O ( 100 mL ) extracted with ethyl acetate (300 mL *3) to collect the organic layers, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 100/1, TLC: DCM/MeOH = 20/1, Rf = 0.30) to give the title compound (370 mg, 1.79 mmol, 29.5% yield, 96.0% purity in HPLC at 220 nm) as a green solid.1H NMR: (400 MHz, CDCl3) δ 7.79 (d, J = 1.2 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.40 - 7.32 (m, 3H), 7.11 (s, 1H), 2.58 (d, J = 7.2 Hz, 2H), 1.14 - 1.04 (m, 1H), 0.61 - 0.49 (m, 2H), 0.29 - 0.22 (m, 2H). (ESI+) m/z: 199.2 (M+H)+, (C13H14N2). [0693] D. 2-Bromo-4-(cyclopropylmethyl)-1-phenyl-1H-imidazole: To a solution of 4- (cyclopropylmethyl)-1-phenyl-imidazole (200 mg, 706 μmol, 1.00 eq) in THF (4.00 mL) was added n-BuLi (2.50 M, 423 μL, 1.50 eq) at -70 °C under N2. The reaction mixture was stirred for additional 0.5 h, then 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (192 mg, 741 μmol, 1.05 eq) in THF (4.00 mL) was added dropwise at -78 °C under N2. Then the reaction mixture was stirred at 25 °C for 5 h. The mixture was poured into NH4Cl solution (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 50/1, TLC: DCM/MeOH = 15/1, Rf = 0.30) to get the title compound (75.0 mg, 267 μmol, 37.8% yield, 98.8% purity in HPLC at 220 nm) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.52 - 7.42 (m, 3H), 7.39 - 7.37 (m, 2H), 6.99 (s, 1H), 2.54 (d, J = 6.8 Hz, 2H), 1.14 - 0.98( m, 1H), 0.58 - 0.52 (m, 2H), 0.23 - 0.19 (m, 2H). (ESI+) m/z: 278.1 (M+H)+, (C13H13N2Br). [0694] E. 3-(5-(4-(Cyclopropylmethyl)-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-4-(cyclopropylmethyl)-1-phenyl- imidazole (75.0 mg, 267 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (197 mg, 534 μmol, 2.00 eq) in dioxane (1.50 mL) and H2O (0.0700 mL) was added RuPhos - Pd - G3 (22.3 mg, 26.7 μmol, 0.10 eq) and K3PO4 (113 mg, 534 μmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 2 h. The mixture was concentrated under vacuum at 45 °C to get residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 30/1, TLC: DCM/MeOH = 212 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 20/1, Rf = 0.30) to get residue 1. The residue 1 was purified by preparative-HPLC (using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 12% - 42% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (39.1 mg, 88.9 μmol, 33.2% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H),7.75 - 7.69 (m, 3H), 7.53 - 7.44 (m, 6H), 5.12 (dd, J1 = 13.2 Hz, J2 = 5.0 Hz, 1H), 4.46 - 4.28 (m, 2H), 2.95 - 2.85 (m, 1H), 2.63 (d, J = 6.8 Hz, 2H), 2.59 - 2.55 (m, 1H), 2.43 - 2.32 (m, 1H), 2.03 - 1.99 (m, 1H), 1.11 - 1.08 (m, 1H), 0.58 - 0.53 (m, 2H), 0.32 - 0.28 (m, 2H). (ESI+) m/z: 441.3 (M+H)+, (C22H24N4O3). EXAMPLE 139 [0695] Synthesis of 3-(5-(5-methyl-1-((1-methylpiperidin-4-yl)methyl)-4-phenyl-1H- pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0696] A. 4-((3-Bromo-5-methyl-4-phenyl-1H-pyrazol-1-yl)methyl)-1- methylpiperidine: To a solution of (1-methylpiperidin-4-yl)methanol (2.18 g, 16.9 mmol, 2.00 eq) and 3-bromo-5-methyl-4-phenyl-1H-pyrazole (2.00 g, 8.44 mmol, 1.00 eq) in THF (50.0 mL) was added a solution of CMBP (4.07 g, 16.9 mmol, 2.00 eq) in THF (10.0 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h under N2. The mixture was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/5, TLC: Dichloromethane/Methanol = 10/1, Rf = 0.19) to give a residue. The residue was purified by preparative-SFC using a DAICEL CHIRALCEL OJ (250 mm x 30 mm x 10 μm) and gradient of 9-39% acetonitrile in CO2-EtOH containing 0.01% NH3H2O over 10 min at a flow rate of 30 mL/min to give the title compound (220 mg, 629 μmol, 7.45% yield, 99.5% purity in HPLC at 220 nm) as a light yellow gum.1H NMR: (400 MHz, CD3CN) δ 7.44 - 7.35 (m, 2H), 7.34 - 7.33 (m, 3H), 3.94 (d, J = 7.2 Hz, 2H), 2.79 (d, J = 11.6 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 1.86 - 1.83 (m, 3H), 1.57 - 1.54 (m, 2H), 1.33 - 1.29 (m, 2H). (ESI+) m/z: 348.1 (M+H)+, (C17H22BrN3) 213 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0697] B. 3-(5-(5-Methyl-1-((1-methylpiperidin-4-yl)methyl)-4-phenyl-1H-pyrazol-3- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-((3-bromo-5-methyl-4- phenyl-1H-pyrazol-1-yl)methyl)-1-methylpiperidine (190 mg, 543 μmol, 1.00 eq) and 3-(1- oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (502 mg, 1.36 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.250 mL) was added K3PO4 (230 mg, 1.09 mmol, 2.00 eq) and RuPhos-Pd-G3 (45.4 mg, 54.3 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 100 °C for 2.5 h under N2. The mixture was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/0 to 100/7, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.32). The residue was purified by preparative-HPLC using a Welch Ultimate C18 (150 mm x 25 mm x 5 μm) and gradient of 4-34% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give a residue. The residue was purified by preparative- TLC (SiO2, Dichloromethane/Methanol = 20/1, Rf = 0.32) to give a residue. The residue was purified by preparative-HPLC using a CD04-Welch Utimate C18 (150 mm x 25 mm x 7 μm) and gradient of 17-37% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give a residue. The residue was purified by preparative-HPLC using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 5-35% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (36.0 mg, 70.4 μmol, 13.0% yield, 100% purity in HPLC at 220 nm, HCOOH) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.21 (s, 1H), 7.59 - 7.55 (m, 2H), 7.39 - 7.37 (m, 3H), 7.34 - 7.32 (m, 1H), 7.20 - 7.17 (m, 2H), 5.11 (dd, J = 4.8 Hz, J = 13.6 Hz, 1H), 4.40 - 4.21 (m, 2H), 4.05 (d, J = 7.2 Hz, 2H), 2.90 - 2.85 (m, 1H), 2.82 - 2.61 (m, 2H), 2.60 - 2.58 (m, 1H), 2.46 - 2.43 (m, 1H), 2.23 (s, 3H), 2.21 (s, 3H), 2.00 - 1.99 (m, 3H), 1.97 - 1.96 (m, 1H), 1.62 - 1.59 (m, 1H), 1.37 - 1.34 (m, 2H),. (ESI+) m/z: 512.3 (M+H)+, (C30H33N5O3). 214 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 140 [0698] Synthesis of 3-(5-(4-(2, 2-difluoropropyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0699] A. (E)-4-(2-Ethoxyvinyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 4- bromo-1-methyl-5-phenyl-1H-imidazole (3.00 g, 12.6 mmol, 1.00 eq), (E)-2-(2-ethoxyvinyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.76 g, 18.9 mmol, 1.50 eq), K3PO4 (8.06 g, 37.9 mmol, 3.00 eq), RuPhos Pd G3 (2.12 g, 2.53 mmol, 0.20 eq) in dioxane (24.0 mL) and H2O (6.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 1 h under N2 atmosphere. Water (60.0 mL) was added to the resulting mixture. The resulting mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate = 1: 0 to 7: 10, TLC: Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.43).to give the title compound (1.70 g, 7.13 mmol, 56.3% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.52 - 7.44 (m, 2H), 7.43 - 7.33 (m, 3H), 7.14 (d, J = 12.8 Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 3.77 – 3.25 (m, 2H), 3.50 (s, 3H), 1.20 – 1.60 [0700] B. 2-(1-Methyl-5-phenyl-1H-imidazol-4-yl) acetaldehyde: To a solution (E)-4- (2-ethoxyvinyl)-1-methyl-5-phenyl-1H-imidazole (1.50 g, 6.57 mmol, 1.00 eq) in HCl/dioxane (10.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 2 h under N2 atmosphere. The reaction mixture was concentrated directly. under reduced pressure to give the title compound (1.10 g, 2.94 mmol, 44.6% yield ) as a yellow oil. (ESI+) m/z: 201.1 (M+H)+, (C12H12N2O). [0701] C. 1-(1-Methyl-5-phenyl-1H-imidazol-4-yl)propan-2-ol: To a solution of 2-(1- methyl-5-phenyl-1H-imidazol-4-yl)acetaldehyde (1.00 g, 4.99 mmol, 1.00 eq) in THF (10.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was added dropwise MeMgBr (3 M, 4.99 mL, 3.00 eq) at -24 °C. The resulting mixture was stirred at 25°C for 2 h under N2 atmosphere.The reaction was dropwise added into H2O (50.0 mL) at 0 °C under N2. 215 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT The resulting mixture was extracted with dichloromethane (3 x 30.0 mL). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol=1/0 to 1/50, TLC: Dichloromethane : Methanol = 15:1, Rf = 0.22) to give the title compound (400 mg, 1.77 mmol, 35.4% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.51 - 7.36 (m, 5H), 4.71 (d, J = 4.0 Hz, 1H), 3.95 - 3.83 (m, 1H), 3.49 (s, 3H), 2.58 - 2.52 (m, 1H), 2.44 - 2.36 (m, 1H), 0.99 (d, J = 6.4 Hz, 3H). (ESI+) m/z: 217.2 (M+H)+, (C13H16N2O). [0702] D. 1-(1-Methyl-5-phenyl-1H-imidazol-4-yl)propan-2-one: To a solution of (COCl)2 (399 mg, 3.14 mmol, 275 μL, 2.00 eq) in DCM (2.00 mL) was added DMSO (368 mg, 4.72 mmol, 368 μL, 3.00 eq) in DCM (1.00 mL) at -78 °C for 0.5 h and purged with N2 for 3 times, and then the mixture was added 1-(1-methyl-5-phenyl-1H-imidazol-4-yl)propan- 2-ol (340 mg, 1.57 mmol, 1.00 eq) in DCM (3.00 mL) at -78 °C for 0.5 h. Then the mixture was added TEA (954 mg, 9.43 mmol, 1.31 mL, 6.00 eq) in DCM (2.00 mL) at -78 °C. The mixture was stirred at -78 °C for 4 h under N2 atmosphere. The reaction mixture was concentrated. aq.NH4Cl (20.0 mL) was added to the residue. The resulting mixture was extracted with dichloromethane (3 x 20.0 mL). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Dichloromethane : Methanol=1/0 to 1/50, Rf = 0.45) to give the title compound (180 mg, 704 μmol, 44.8% yield,) as a yellow oil. (ESI+) m/z: 215.0 (M+H)+, (C13H14N2O). [0703] E. 4-(2,2-Difluoropropyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 1- (1-methyl-5-phenyl-1H-imidazol-4-yl)propan-2-one (180 mg, 840 μmol, 1.00 eq) in TFEDMA (2.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 4 h under N2 atmosphere.The reaction mixture was concentrated. aq.NaHCO3 (10.0 mL) was added to the residue. The resulting mixture was extracted with dichloromethane (3 x 10.0 mL). The combined organic phase was washed with brine (20.0 mL),dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get residue. The residue was purified by prep-TLC (SiO2, Dichloromethane : Methanol = 20:1, Rf = 0.32) to give the title compound (55.0 mg, crude) as a yellow oil. (ESI+) m/z: 237.0 (M+H)+, (C13H14F2N2). [0704] F. 2-Bromo-4-(2,2-difluoropropyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 4-(2,2-difluoropropyl)-1-methyl-5-phenyl-1H-imidazole (50.0 mg, 211 μmol, 1.00 eq) in ACN (2.00 mL) at 0 °C was added NBS (37.6 mg, 211 μmol, 1.00 eq) in ACN (0.50 216 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mL) and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated. Water (20.0 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (3 x 15.0 mL). The combined organic phase was washed with brine (3 x 20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (42.0 mg, 116 μmol, 55.1% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.37 (m, 5H), 3.41 (s, 3H), 2.98 (t, J = 14.8 Hz, 2H), 1.59 (t, J = 19.0 Hz, 3H).(ESI+) m/z: 315.1 (M+H)+, (C13H13BrF2N2). [0705] G. 3-(5-(4-(2,2-Difluoropropyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-4-(2,2-difluoropropyl)- 1-methyl-5-phenyl-1H-imidazole (30.0 mg, 95.1 μmol, 1.00 eq) in dioxane (1.00mL) and H2O (0.05 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (70.4 mg, 190 μmol, 2.00 eq), K3PO4 (40.41 mg, 190 μmol, 2.00 eq) and RuPhos Pd G3 (7.96 mg, 9.52 μmol, 0.10 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate under reduced pressure to get residue. The crude product was purified by preparative-HPLC using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 17 - 47% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (11.9 mg, 24.7 μmol, 26.0% yield, 99.1% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.03 (s, 1H), 7.99 - 7.89 (m, 2H), 7.64 - 7.47 (m, 5H), 5.21 - 5.13 (m, 1H), 4.64 - 4.43 (m, 2H), 3.59 (s, 3H), 3.23 - 3.16 (m, 2H), 2.99 - 2.89 (m, 1H), 2.69 - 2.63 (m, 1H), 2.45 - 2.36 (m, 1H), 2.09 - 2.00 (m, 1H), 1.67 (t, J = 19.0 Hz, 3H). (ESI+) m/z: 479.1 (M+H)+, (C26H24F2N4O3). 217 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 141 [0706] Synthesis of 3-(5-(2-(methoxymethyl)-5-phenylthiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0707] A. 3-(5-(2-(Methoxymethyl)thiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione: A mixture of 3-(5-(2-bromoacetyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.37 mmol, 1.00 eq) in [Bmim]PF6 (3.00 mL) was added 2-methoxyethanethioamide (173 mg, 1.64 mmol, 1.20 eq) and K2CO3 (378 mg, 2.74 mmol, 2.00 eq) and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 6 h under N2 atmosphere. The reaction mixture was concentrated. Water (20.0 mL) was added to the residue. The resulting mixture was extracted with dichloromethane (3 x 20.0 mL). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol =1: 0 to 1: 50, TLC: Dichloromethane: Methanol = 15:1, Rf = 0.40) to give the title compound (210 mg, 565 μmol, 41.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 5.15 - 5.10 (m, 1H), 4.79 (s, 2H), 4.58 - 4.34 (m, 2H), 3.45 (s, 3H), 2.97 - 2.87 (m, 1H), 2.63 - 2.58 (m, 1H), 2.44 - 2.39 (m, 1H), 2.09 - 1.97 (m, 1H). (ESI+) m/z: 372.0 (M+H)+, (C18H17N3O4S). [0708] B. 3-(5-(5-Bromo-2-(methoxymethyl)thiazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-(5-(2-(methoxymethyl)thiazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 538 μmol, 1.00 eq) in DMF (4.00 mL) at 0 °C was added NBS (100 mg, 565 μmol, 1.05 eq) in DMF (1.00 mL) and purged with N2 for 3 times, and then the mixture was stirred at 40 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated. Water (30.0 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (3 x 30.0 mL). The combined organic phase was washed with brine (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 15:1, Rf = 0.48) to give the title compound (212 mg, 438 μmol, 81.3% yield) as a white solid. 218 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 5.16 – 5.12 (m, 1H), 4.76 (s, 2H), 4.59 - 4.37 (m, 2H), 3.45 (s, 3H), 2.63 – 2.59 (m, 1H), 2.54 (s, 1H), 2.45 - 2.39 (m, 1H), 2.08 - 2.00 (m, 1H). (ESI+) m/z: 449.9 (M+H)+, (C18H16BrN3O4S). [0709] C. 3-(2-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione: A mixture of 3-(5-(5-bromo-2- (methoxymethyl)thiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 444 μmol, 1.00 eq) in DMF (5.00 mL) was added phenylboronic acid (162 mg, 1.33 mmol, 3.00 eq), K3PO4 (282 mg, 1.33 mmol, 3.00 eq) and Pd(dppf)Cl2 (32.5 mg, 44.4 μmol, 0.10 eq) and purged with N2 for 3 times, and then the mixture was stired at 90 °C for 16 h under N2 atmosphere.The reaction mixture was concentrated. Water (15.0 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (3 x 15.0 mL). The combined organic phase was washed with brine (3 x 30.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The crude product was purified by preparative- HPLC using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 30 - 60% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (13.5 mg, 29.8 μmol, 6.71% yield, 98.4% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 8 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.43 - 7.35 (m, 5H), 5.12 – 5.08 (m, 1H), 4.79 (s, 2H), 4.47 - 4.25 (m, 2H), 3.47 (s, 3H), 2.96 - 2.84 (m, 1H), 2.62 (s, 1H), 2.40 – 2.35 (m, 1H), 2.05 - 1.96 (m, 1H). (ESI+) m/z: 448.0 (M+H)+, (C24H21N3O4S). EXAMPLE 142 [0710] Synthesis of 3-(5-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0711] A. 3-Methyl-4-phenyl-4H-1,2,4-triazole: Acetohydrazide (2.63 g, 35.4 mmol, 1.10 eq) was dissolved in ACN (20.0 mL) and DMF-DMA (4.22 g, 35.4 mmol, 4.71 mL, 1.10 eq). The mixture was warmed to 50 °C for 0.5 h. Then a solution of aniline (3.00 g, 32.2 mmol, 2.94 mL, 1.00 eq) in ACN (1.00 mL) and AcOH (5.00 mL) was added into the 219 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture. The mixture was stirred at 120 °C for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove ACN and AcOH to give crude product. The crude was purified by column chromatography (SiO2, Ethyl acetate: Methanol = 100:0 to 100: 3, Rf = 0.43 (Ethyl acetate: Methanol = 10:1)) to give the title compound (1.50 g, 8.95 mmol, 31.2% yield) as yellow solid.1H NMR: (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.56 - 7.51 (m, 3H), 7.35 - 7.28 (m, 2H), 2.43 (s, 3H). (ESI+) m/z: 160.1 (M+H)+, (C9H9N3). [0712] B. 3-Bromo-5-methyl-4-phenyl-4H-1,2,4-triazole: To a solution of 3-methyl-4- phenyl-4H-1,2,4-triazole (500 mg, 3.14 mmol, 1.00 eq) in ACN (10.0 mL). A solution of NBS (614 mg, 3.46 mmol, 1.10 eq) in ACN (2.00 mL) was added into the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with H2O 20.0 mL and extracted with ethyl acetate 30.0 mL (3 x 30.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified prep-TLC (SiO2, Ethyl acetate: Petroleum ether = 1:1, Rf = 0.28) to give the title compound (470 mg, 1.93 mmol, 98% purity) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.59 - 7.56 (m, 3H), 7.27 - 7.24 (m, 2H), 2.35 (s, 3H). (ESI+) m/z: 239.9 (M+H)+, (C9H8N3Br). [0713] C. 3-(5-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-bromo-5-methyl-4-phenyl-1,2,4-triazole (200 mg, 840 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (777 mg, 2.10 mmol, 2.50 eq) and K3PO4 (534 mg, 2.52 mmol, 3.00 eq), and then was added Ru-Phos-Pd- G3 (70.2 mg, 84.0 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give crude product. The crude product was pre-purified by column chromatography followed by preparative- HPLC (using a CD04-Welch Utimate C18 (150 x 25 x 7um) and gradient of 7 - 37% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min) to give the title compound (8.91 mg, 21.8 μmol, 9.60% yield, 98.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.66 - 7.64 (m, 2H), 7.57 - 7.55 (m, 3H), 7.54 - 7.46 (m, 2H), 7.45 - 7.38 (m, 1H), 5.11 - 5.07 (m, 1H), 4.44 - 4.25 (m, 2H), 220 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2.93 - 2.84 (m, 1H), 2.61 - 2.60 (m, 1H), 2.39 - 2.36 (m, 1H), 2.27 (s, 3H), 2.00 - 1.99 (m, 1H). (ESI+) m/z: 402.1 (M+H)+, (C22H19O3N5). EXAMPLE 143 [0714] Synthesis of 3-(5-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0715] A. N-Phenylacetohydrazonoyl chloride: To a solution of N'- phenylacetohydrazide (5.00 g, 33.3 mmol, 1.00 eq) and PPh3 (10.5 g, 40.0 mmol, 1.20 eq) in ACN (60.0 mL) was added CCl4 (6.91 g, 44.9 mmol, 4.33 mL, 1.35 eq). The reaction mixture was stirred at 25 °C for 8 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 100: 1; TLC: Petroleum ether: Ethyl acetate = 20: 1, Rf = 0.90) to give the title compound (2.90 g, 17.2 mmol, 51.6% yield) as a violet solid.1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.31 - 7.23 (m, 2H), 7.0- 6.99 (m, 2H), 6.94 - 6.85 (m, 1H), 2.50 - 2.31 (m, 3H) (ESI+) m/z: 169.0 (M+H)+, (C8H9ClN2). [0716] B. 3-Methyl-1-phenyl-1H-1,2,4-triazole: To a solution of N- phenylacetohydrazonoyl chloride (2.40 g, 14.2 mmol, 1.00 eq) in ACN (30.0 mL) was added NMI (2.92 g, 35.6 mmol, 2.84 mL, 2.50 eq). The mixture was stirred at 70 °C for 4 h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 5: 1; TLC: Petroleum ether: Ethyl acetate = 20: 1, Rf = 0.30) to give the title compound (750 mg, 4.71 mmol, 33.1% yield) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.71 - 7.59 (m, 2H), 7.56 - 7.44 (m, 2H), 7.42 - 7.33 (m, 1H), 2.51 (s, 3H). (ESI+) m/z: 160.0 (M+H)+, (C9H9N3). [0717] C. 5-Bromo-3-methyl-1-phenyl-1H-1,2,4-triazole: To a solution of 3-methyl-1- phenyl-1H-1,2,4-triazole (400 mg, 2.51 mmol, 1.00 eq) in ACN (6.00 mL) was added AIBN (206 mg, 1.26 mmol, 0.50 eq), NBS (670 mg, 3.77 mmol, 1.50 eq). The reaction was stirred at 70 °C for 4 h. The mixture was poured into H2O (10.0 mL), extracted with dichloromethane (3 x 20.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum 221 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT ether: Ethyl acetate = 100: 0 to 9: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.60) to give the title compound (500 mg, 2.04 mmol, 81.0% yield) as off-white solid.1H NMR (400 MHz, CDCl3) δ 7.59 - 7.45 (m, 5H), 2.49 - 2.43 (m, 3H). (ESI+) m/z: 237.99 (M+H)+, (C9H8BrN3). [0718] D. 3-(5-(3-Methyl-1-phenyl-1H-1,2,4-triazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a siolution of 5-bromo-3-methyl-1-phenyl-1H-1,2,4-triazole (200 mg, 840 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (777 mg, 2.10 mmol, 2.50 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added K3PO4 (356 mg, 1.68 mmol, 2.00 eq), Ru-Phos-Pd-G3 (70.26 mg, 84.00 μmol, 0.10 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 19: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.50) and preparative-HPLC using a CD04-Welch Utimate C18 (150 x 25 x 7um) and gradient of 15-45% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give athe title compound (280 mg, 696 μmol, 82.9% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.74 (s, 1H), 7.72 - 7.68 (m, 1H), 7.53 - 7.47 (m, 3H), 7.47 - 7.44 (m, 1H), 7.42 - 7.36 (m, 2H), 5.15 - 5.08 (m, 1H), 4.46 - 4.28 (m, 2H), 2.97 - 2.84 (m, 1H), 2.63 - 2.55 (m, 1H), 2.41 (s, 3H), 2.40 - 2.31 (m, 1H), 2.05 - 1.96 (m, 1H). (ESI+) m/z: 402.15 (M+H)+, (C22H19N5O3). EXAMPLE 144 [0719] Synthesis of 3-(5-(5-cyclohexyl-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: [0720] A. tert-Butyl 5-amino-4-(5-(1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate: To a solution of 4-bromo-1,2-dimethyl-1H-imidazole (3.00 g, 17.1 mmol, 1.00 eq) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (8.38 g, 18.8 mmol, 1.10 eq) and K3PO4 (10.9 g, 51.4 mmol, 3.00 eq) in dioxane (50.0 mL) and H2O (2.50 mL) was added Ru-Phos-Pd-G3 222 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (1.43 g, 1.71 mmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 200: 1 to 20: 1, TLC: Dichloromethane : Methanol = 20: 1, Rf = 0.40) to give the title compound (5.20 g, 8.77 mmol, 51.1% yield, 69.6% purity in LCMS at 220 nm) as light yellow solid. (ESI+) m/z: 413.1 (M+H)+, (C22H28N4O4). [0721] B. tert-Butyl 5-amino-4-(5-(5-bromo-1,2-dimethyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1,2- dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (3.00 g, 7.27 mmol, 1.00 eq) in ACN (50.0 mL) was added NBS (1.36 g, 7.67 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (200 mL) and extracted with Ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (3 x 200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 200: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.45) to give the title compound (1.20 g, 2.10 mmol, 28.8% yield, 86.0% purity in LCMS at 220 nm) as light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.08 - 8.01 (m, 2H), 7.72 - 7.70 (m, 1H), 7.56 - 7.54 (m, 1H), 7.20 - 7.15 (m, 1H), 4.74 - 4.71 (m, 1H), 4.63 - 4.46 (m, 2H), 3.56 (s, 3H), 2.41 (s, 3H), 2.18 - 2.14 (m, 3H), 2.01 - 1.97 (m, 1H), 1.33 - 1.32 (m, 9H). (ESI+) m/z: 490.8 (M+H)+, (C22H27BrN4O4). [0722] C. tert-Butyl 5-amino-4-(5-(5-(cyclohex-1-en-1-yl)-1,2-dimethyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5- bromo-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (600 mg, 1.04 mmol, 1.00 eq), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280 mg, 1.35 mmol, 0.30 mL, 1.30eq) and K3PO4 (660 mg, 3.11 mmol, 3.00 eq) in dioxane (6.00 mL) and H2O (1.50 mL) was added Pd(dtbpf)Cl2 (135 mg, 207 μmol, 0.20 eq) under N2. The mixture was stirred at 65 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 18% - 48% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (400 mg, 812 μmol, 78.2% yield, 99.6% purity in HPLC at 220 nm) was obtained as light yellow oil.1H NMR (400 MHz, DMSO-d6): δ 7.84 – 7.82 (m, 2H), 7.79 - 7.70 (m, 1H), 7.68 - 7.61 (m, 1H), 7.22 – 7.20 (m, 1H), 6.10 – 6.08 (m, 1H), 4.76 – 4.73 (m, 1H), 4.68 – 4.50 (m, 2H), 3.59 (s, 3H), 2.64 (s, 3H), 2.21 – 2.13 (m, 5H), 2.07 – 2.02 (m, 3H), 1.71 – 1.69 (m, 4H), 1.30 (S, 9H). (ESI+) m/z: 493.4 (M+H)+, (C28H36N4O4). 223 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0723] D. tert-Butyl 5-amino-4-(5-(5-cyclohexyl-1,2-dimethyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of Pd/C (64.8 mg, 60.9 μmol, 10.0% purity, 0.10 eq) and tert-butyl 5-amino-4-(5-(5-(cyclohex-1-en-1-yl)-1,2-dimethyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 609 μmol, 1.00eq) in EtOH (6.00 mL) under N2.Then the reaction mixture was degassed purged with H2 for 3 times. Then the mixture was stirred at 25 °C for 12 h under H2 (30 psi). The reaction mixture was filtered through diatomite and the filtrate was concentrated under vacuum to give the title compound (260 mg, 518 μmol, 85.1% yield, 98.6% purity in LCMS at 220 nm) as yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.86 – 7.84 (m, 1H), 7.71 - 7.64 (m, 2H), 7.57 - 7.55 (m, 1H), 7.26 – 7.20 (m, 1H), 4.78 – 4.73 (m, 1H), 4.69 – 4.53 (m, 2H), 3.75 – 3.72 (m, 3H), 3.16 – 3.14 (m, 3H), 2.90 – 2.81 (m, 1H), 2.24 – 2.15 (m, 4H), 1.72 – 1.50 (m, 7H), 1.34 – 1.30 (m, 9H), 1.23 – 1.13 (m, 3H). (ESI+) m/z: 495.3 (M+H)+, (C28H38N4O4). [0724] E. 3-(5-(5-Cyclohexyl-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-cyclohexyl-1,2- dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 404 μmol, 1.00 eq) and TsOH (278 mg, 1.62 mmol, 4.00 eq) in ACN (10.0 mL) under N2. The mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 10% - 40% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (102 mg, 224 μmol, 59.0% yield, 98.2% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.91 - 7.89 (m, 1H), 7.72 - 7.70 (m, 1H), 7.61 – 7.59 (m, 1H), 5.18 – 5.13 (m, 1H), 4.58 – 4.40 (m, 2H), 3.76 (s, 3H), 2.93 – 2.87 (m, 2H), 2.64 – 2.60 (m, 4H), 2.41 – 2.37 (m, 1H), 2.07 - 2.06 (m, 1H), 1.76 – 1.70 (m, 4H), 1.68 – 1.50 (m, 3H), 1.33 – 1.30 (m, 2H), 1.17 – 1.09 (m, 1H). (ESI+) m/z: 421.1 (M+H)+, (C24H28N4O3). 224 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 145 [0725] Synthesis of 3-(5-(2-(3,3-difluorocyclobutyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0726] A. N-(2,2-Dimethoxyethyl)-3,3-difluoro-N-methylcyclobutane-1-carboxamide: A mixture of 3, 3-difluorocyclobutane-1-carboxylic acid (6.00 g, 44.0 mmol, 1.00 eq) in DMF (100 mL) was added 2, 2-dimethoxy-N-methylethan-1-amine (6.30 g, 52.9 mmol, 6.80 mL, 1.20 eq) and HOBt (7.15 g, 52.9 mmol, 1.20 eq) and then cooled to 0°C. EDCI (10.1 g, 52.9 mmol, 1.20 eq) was added into the mixture at 0 °C and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 h under N2. After the reaction was completed, the reaction mixture was quenched by H2O (500 mL) and extracted with dichloromethane 500 mL (3 x 500 mL). The combined organic layers were washed with brine 500 mL (3 x 500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate = 1:1) to give the title compound (9.80 g, 41.3 mmol, 67.3% yield) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 4.48 - 4.43 (m, 1H), 3.38 - 3.35 (m, 2H), 3.33 - 3.32 (m, 4H), 3.27 (s, 3H), 2.94 (s, 2H), 2.87 (s, 1H), 2.74 - 2.68 (m, 4H) . (ESI+) m/z: 238.1 (M+H)+, (C10H17F2NO3). [0727] B. 2-(3,3-Difluorocyclobutyl)-1-methyl-1H-imidazole: To a solution of N-(2, 2- dimethoxyethyl)-3, 3-difluoro-N-methylcyclobutane-1-carboxamide (9.00 g, 37.9 mmol, 1.00 eq) in AcOH (100 mL) was added acetic NH4OAc (29.2 g, 379 mmol, 10.0 eq). The mixture was stirred at 125 °C for 12 h. After the reaction was completed, the reaction mixture was quenched by H2O (100 mL) and extracted with dichloromethane 200 mL (3 x 200 mL). The combined organic layers were washed with brine 200 mL (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.24 (Petroleum ether: Ethyl acetate = 1:1)) to give the title compound (2.01 g, 11.4 mmol, 25.8% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.83 (s, 1H), 3.56 (s, 3H), 3.35 - 3.34 (m, 1H), 3.08 - 2.93 (m, 4H). (ESI+) m/z: 173.1 (M+H)+, (C8H10N2F2). 225 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0728] C. 4,5-Dibromo-2-(3,3-difluorocyclobutyl)-1-methyl-1H-imidazole: A mixture of 2-(3,3-difluorocyclobutyl)-1-methyl-1H-imidazole (500 mg, 2.90 mmol, 1.00 eq) in DMF (10.0 mL) was added NBS (1.14 g, 6.39 mmol, 2.20 eq) in DMF (5.00 mL). The mixture was stirred at 0°C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was quenched by H2O (20.0 mL) and extracted with ethyl acetate 50.0 mL (3 x 50.0 mL). The combined organic layers were washed with brine 50.0 mL (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100:0 to 10:1. TLC: Petroleum ether: Ethyl acetate=3:1, Rf =0.43) to give the title compound (800 mg, 2.33 mmol, 30.0% yield). (ESI+) m/z: 330.8 (M+H)+, (C8H8N2Br2F2). [0729] D. 4-Bromo-2-(3,3-difluorocyclobutyl)-1-methyl-1H-imidazole: A mixture of 4,5-dibromo-2-(3,3-difluorocyclobutyl)-1-methyl-imidazole (500 mg, 1.52 mmol, 1.00 eq) in THF (10.0 mL) at -78°C was added i-PrMgCl (2.00 M, 1.52 mL, 2.00 eq) under N2. The mixture was stirred at -78°C for 2 h. After the reaction was completed, the reaction mixture was quenched by H2O (20.0 mL) and extracted with ethyl acetate 50.0 mL (3 x 50.0 mL). The combined organic layers were washed with brine 50.0 mL (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1, Rf = 0.34) to give the title compound (380 mg, 1.50 mmol, 43.8% yield).1H NMR: (400 MHz, CDCl3) δ 3.80 (s, 1H), 3.54 (s, 3H), 3.30 - 3.03 (m, 1H), 2.96 - 2.09 (m, 4H). (ESI+) m/z: 250.9 (M+H)+, (C8H9N2BrF2). [0730] E. 3-(5-(2-(3,3-Difluorocyclobutyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 4-bromo-2-(3,3-difluorocyclobutyl)- 1-methyl-1H-imidazole (150 mg, 597 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL), then was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (663 mg, 1.79 mmol, 3.00 eq) and K3PO4 (380 mg, 1.79 mmol, 3.00 eq), and then was added Ru-Phos-Pd-G3 (49.9 mg, 59.7 μmol, 0.10 eq) under N2. The mixture was stirred at 100°C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The crude product was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500: 1 to 70: 1. TLC: Dichloromethane: Methanol = 15:1, Rf = 0.30) to give crude product. The residue was purified by preparative-HPLC using a CD04-Welch Utimate C18150 x 25 x 7 um and gradient of 3 - 33% acetonitrile in water containing 0.5% TFA over 10 min to give the title compound (119 mg, 283 μmol, 47.4% yield, 98.7% purity in HPLC at 226 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.00 – 7.98 (m, 1H), 7.94 - 7.93 (m, 1H), 7.91 - 7.89 (m, 1H), 7.79 - 7.77 (m, 1H), 5.15 - 5.10 (m, 1H), 4.53 - 4.36 (m, 2H), 3.68 (s, 3H), 3.13 - 3.06 (m, 5H), 2.92 - 2.76 (m, 1H), 2.63 - 2.59 (m, 1H), 2.44 - 2.41 (m, 1H), 2.04 - 2.02 (m, 1H). (ESI+) m/z: 415.1 (M+H)+, (C21H20O3N4F2). EXAMPLE 146 [0731] Synthesis of 3-(5-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0732] A. 5-(3,6-Dihydro-2H-pyran-4-yl)-1-methyl-1H-imidazole: To a solution of 5- bromo-1-methyl-1H-imidazole (3.00 g, 18.6 mmol, 1.00 eq) in dioxane (15.0 mL) and H2O (6.00 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.83 g, 37.2 mmol, 2.00 eq), Na2CO3 (3.95 g, 37.2 mmol, 2.00 eq) and Pd(dppf)Cl2 (1.36 g, 1.86 mmol, 0.100 eq) at 25 °C under N2, then the mixture was stirred at 80 °C for 4 h. It was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 24/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.31) to give the title compound (1.85 g, 10.70mmol, 57.4% yield, 95% purity LCMS at 220 nm) as a brown oil.1H NMR: (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 6.91 (s, 1H), 5.97 (s, 1H), 4.12 - 4.19 (m, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.65 (s, 3H), 2.34 - 2.33 (m, 2H). (ESI+) m/z: 165.1 (M+H)+, (C9H12N2O). [0733] B. 1-Methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of Pd/C (925 mg, 10% purity) in EtOH (18.5 mL) was added 5-(3,6-dihydro-2H-pyran-4-yl)-1- methyl-1H-imidazole (1.85 g, 10.7 mmol, 1.00 eq) under Ar at 18 °C. Degased under vacuum and purged with H2 three times. Then the mixture was stirred at 30 °C for 16 h under H2 (30 psi). The mixture was diluted with EtOH (30.0 mL), filtered through celite and the filter cake was washed with EtOH (3 x 30.0 mL) to collect the filtrate. The filtrate was concentrated under vacuum to give a residue at 40 °C to give the title compound (1.84 g, crude) as a brown oil.1H NMR: (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 6.64 (s, 1H), 3.91 - 3.87 (m, 2H), 3.56 (s, 3H), 3.45 - 3.39 (m, 2H), 2.84 - 2.78 (m, 1H), 1.78 - 1.75 (m, 2H), 1.58 - 1.50 (m, 2H). (ESI+) m/z: 167.2 (M+H)+, (C9H14N2O). 227 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0734] C. 4-Bromo-1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (1.74 g, 9.97 mmol, 1.00 eq) in THF (42.0 mL) was added NBS (1.77 g, 9.97 mmol, 1.00 eq) at -78°C, then the mixture was stirred at -78 °C for 2 h. It was poured into water (100 mL) and extracted with dichloromethane (3 x 60.0 mL) to collect the organic layer. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 1/1, TLC: Petroleum ether/Ethyl acetate = 0/1, Rf = 0.20) to give the title compound (1.10 g, 4.47 mmol, 44.8% yield, 99.5% purity LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 3.94 - 3.90 (m, 2H), 3.61 (s, 3H), 3.42 - 3.39 (m, 2H), 2.98 - 2.95 (m, 1H), 2.06 - 2.02 (m, 2H), 1.56 - 1.53 (m, 2H). (ESI+) m/z: 346.9 (M+2)+, (C9H13BrN2O). [0735] D. 3-(5-(1-Methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of4-bromo-1-methyl-5-(tetrahydro- 2H-pyran-4-yl)-1H-imidazole (300 mg, 1.22 mmol, 1.00 eq) in dioxane (12.0 mL) and H2O (0.600 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (1.13 g, 3.04 mmol, 2.50 eq), K3PO4 (516 mg, 2.44 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (101 mg, 121 μmol, 0.10 eq) at 25 °C, then the mixture was stirred at 80 °C for 3.5 h under N2. It was concentrated under vacuum. It was filtered and the filter was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 24/1, TLC: Dichloromethane/Methanol = 10/1, Rf = 0.35) The crude product was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 7 μm) and gradient of 0 - 29% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min give the title compound (59.2 mg, 144 μmol, 11.8% yield, 99.9% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO- d6) δ 11.0 (s, 1H), 8.94 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 5.16 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.57 - 4.40 (m, 2H), 3.91 (s, 3H), 3.88 - 3.84 (m, 2H), 3.40 - 3.35 (m, 2H), 3.20 - 3.17 (m, 1H), 2.95 - 2.92 (m, 1H), 2.65 - 2.64 (m, 1H), 2.43 - 2.41 (m, 1H), 2.07 - 2.05 (m, 1H), 1.77 - 1.65 (m, 4H). (ESI+) m/z: 409.2 (M+H)+, (C22H24N4O4). 228 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 147 [0736] Synthesis of 3-(5-(5-cyclopentyl-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0737] A. 5-(Cyclopent-1-en-1-yl)-1-methyl-1H-imidazole: To a solution of 5-bromo-1- methyl-1H-imidazole (1.00 g, 6.21 mmol, 1.00 eq) in dioxane (5.00 mL) and H2O (2.00 mL) was added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.45 g, 7.47 mmol, 1.20 eq), Na2CO3 (1.32 g, 12.4 mmol, 2.00 eq) and Pd(dppf)Cl2 (454 mg, 621 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 80/1, TLC: DCM/MeOH = 15/1, Rf = 0.40) to give the title compound (450 mg, 2.69 mmol, 43.2% yield, 88.5% purity in LCMS at 220 nm) as a brown oil.1H NMR: (400 MHz, CDCl3) δ 7.38 (s, 1H), 6.96 (s, 1H), 5.88 (s, 1H), 3.72 (s, 3H), 2.70 - 2.66 (m, 2H), 2.57 - 2.53 (m, 2H), 1.97 - 1.92 (m, 2H). (ESI+) m/z: 149.2 (M+H)+, (C9H12N2). [0738] B. 5-Cyclopentyl-1-methyl-1H-imidazole: To a solution of Pd/C (225 mg, 10% purity) in EtOH (4.50 mL) was added 5-(cyclopent-1-en-1-yl)-1-methyl-1H-imidazole (450 mg, 2.69 mmol, 1.00 eq) at 25 °C under Ar. Degassed under vacuum and purged with H2 three times. Then the mixture was stirred at 25 °C for 32 h under H2 (30 Psi). The mixture was filtered through celite and the filter cake was washed with EtOH (4 x 20.0 mL). The filtrate was concentrated under vacuum to give the title compound (340 mg, 2.08 mmol, 77.4% yield, 91.9% purity in LCMS at 220 nm) as a brown oil.1H NMR: (400 MHz, CDCl3) δ 7.35 (s, 1H), 6.77 (s, 1H), 3.57 (s, 3H), 2.97 - 2.90 (m, 1H), 2.05 - 2.02 (m, 2H), 1.79 - 1.77 (m, 2H), 1.67- 1.64 (m, 4H). (ESI+) m/z: 151.3 (M+H)+, (C9H14N2). [0739] C. 4-Bromo-5-cyclopentyl-1-methyl-1H-imidazole: To a solution of 5- cyclopentyl-1-methyl-1H-imidazole (300 mg, 1.84 mmol, 1.00 eq) in ACN (4.50 mL) was added a solution of NBS (163 mg, 917 μmol, 0.50 eq) in ACN (4.50 mL) at 0 °C. Then the mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water (50.0 mL) and extracted with EtOAc (2 x 50.0 mL) to get the organic layers, the organic layers was 229 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT washed with brine (50.0 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, PE/EtOAc = 100/0 to 0/1, TLC: PE/EtOAc = 1/1, Rf = 0.30) to give the title compound (170 mg, 726 μmol, 39.5% yield, 97.9% purity in LCMS at 220 nm) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.26 (s, 1H), 3.59 (s, 3H), 3.12 - 3.03 (m, 1H), 1.94 - 1.91 (m, 6H), 1.87 - 1.67 (m, 2H). (ESI+) m/z: 230.7 (M+H)+, (C9H13N2Br). [0740] D. 3-(5-(5-Cyclopentyl-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-5-cyclopentyl-1-methyl-1H-imidazole (150 mg, 640 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (830 mg, 2.24 mmol, 3.50 eq) in dioxane (7.00 mL) and H2O (0.350 mL) was added K3PO4 (272 mg, 1.28 mmol, 2.00 eq) and RuPhos Pd G3 (53.6 mg, 64.0 μmol, 0.100 eq) at 25 °C under N2. Then the mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered to get the filtrate, the filtrate was concentrated under vacuum to give a residue at 50 °C. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/1 to 40/1, TLC: DCM/MeOH = 10/1, Rf = 0.50) to get a residue. The residue was purified by preparative-HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 0-30% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min to give the title compound (41.0 mg, 93.1 μmol, 14.5% yield, 99.4% purity in HPLC at 220 nm, HCOOH) as a white solid.1H NMR: (400 MHz, DMSO- d6) δ 10.9 (s, 1H), 8.15 (s, 1H), 7.73 - 7.70 (m, 1H), 7.64 - 7.61 (m, 2H), 7.58 - 7.56 (m, 1H), 5.09 (dd, J = 5.2 Hz, J = 13.2 Hz, 1H), 4.50 - 4.32 (m, 2H), 3.67 (s, 3H), 3.44 - 3.42 (m, 1H), 2.93 - 2.89 (m, 1H), 2.62 - 2.58 (m, 1H), 2.45 - 2.37 (m, 1H), 1.93 - 1.91 (m, 1H),1.78 - 1.75 (m, 2H), 1.64 - 1.62 (m, 6H). (ESI+) m/z: 393.2 (M+H)+, (C22H24N4O3). EXAMPLE 148 [0741] Synthesis of 3-(5-(3-ethyl-1-phenyl-1H-1,2,4-triazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0742] A. N'-Phenylpropionohydrazide: To a solution of phenylhydrazine (5.00 g, 46.2 mmol, 1.00 eq) in pyridine (30.0 mL) was slowly added propanoyl chloride (4.71 g, 50.8 230 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mmol, 1.10 eq) at 0 °C, then the reaction mixture was stirred at 25 °C for 8 h. After 8 hours, H2O (100 mL) was added, the precipitate was collected, washed with H2O (3 x 20.0 mL). The reaction mixture was concentrated in vacuum to give the title compound (4.20 g, 25.2 mmol, 60.0% yield, 98.5% purity in LCMS at 220 nm) as off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.62 (s, 1H), 7.15 - 7.10 (m, 2H), 6.68 - 6.66 (m, 3H), 2.20 - 2.13 (m, 2H), 1.06 - 1.03 (m, 3H). m/z: 165.2 (M+H)+, (C9H12N2O). [0743] B. N-Phenylpropionohydrazonoyl chloride: To a solution of N'- phenylpropanehydrazide (2.90 g, 17.1 mmol, 1.00 eq) and PPh3 (5.39 g, 20.5 mmol, 1.20 eq) in ACN (30.0 mL) was added CCl4 (3.55 g, 23.1 mmol, 1.35 eq) at 20 °C and was stirred at 20 °C for 16 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 100: 1; TLC, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.90) to give the title compound (1.90 g, 10.4 mmol, 34.5% yield) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.21 - 7.12 (m, 4H), 6.79 - 6.77 (m, 1H), 2.64 - 2.59 (m, 2H), 1.19 - 1.16 (m, 3H). (ESI+) m/z: 183.1 (M+H)+, (C9H11ClN2). [0744] C. 3-Ethyl-1-phenyl-1H-1,2,4-triazole: To a solution of (1Z)-N- phenylpropanehydrazonoyl chloride (1.90 g, 10.4 mmol, 1.00 eq) in ACN (15.0 mL) was added NMI (2.14 g, 26.0 mmol, 2.50 eq) and then was stirred at 70 °C for 4 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 8: 1; TLC, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (480 mg, 2.76 mmol, 30.0% yield) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.81 - 7.79 (m, 2H), 7.54 - 7.50 (m, 2H), 7.39 - 7.35 (m, 1H), 2.74 - 2.69 (m, 2H), 1.28 - 1.24 (m, 3H). (ESI+) m/z: 174.0 (M+H)+, (C10H11N3). [0745] D. 5-Bromo-3-ethyl-1-phenyl-1H-1,2,4-triazole: To a solution of 3-ethyl-1- phenyl-1,2,4-triazole (480 mg, 2.77 mmol, 1.00 eq) in THF (20.0 mL) was added DBDMH (1.19 g, 4.16 mmol, 1.50 eq) and NaH (166 mg, 4.16 mmol, 60.0% purity, 1.50 eq) under N2 at 0 °C for 30 min, then the mixture was stirred at 25 °C for 16 h under N2. Upon completion, the reaction mixture was added with aq. HCl (1 N, 10.0 mL) to pH 7-8, diluted with water, and extracted with ethyl acetate (3 x 50.0 mL). The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 25: 1; TLC, Petroleum ether: Ethyl acetate = 3: 1 , Rf = 0.80) to give the title compound (160 mg, 634 μmol, 22.9% yield, 100% purity in LCMS at 220 nm) as yellow oil. 231 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H NMR (400 MHz, CDCl3) δ 7.56 - 7.49 (m, 5H), 2.84 -2.78 (m, 2H), 1.38 - 1.35 (m, 3H). (ESI+) m/z: 253.8 (M+H)+, (C10H10BrN3). [0746] E. 3-(5-(3-Ethyl-1-phenyl-1H-1,2,4-triazol-5-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-3-ethyl-1-phenyl-1,2,4-triazole (150 mg, 595 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (550 mg, 1.49 mmol, 2.50 eq), Ru-Phos-Pd-G3 (49.7 mg, 59.5 μmol, 0.10 eq) and K3PO4 (252 mg, 1.19 mmol, 2.00 eq) under N2, then the mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered through a pad of celite the pad or filter cake was washed with DCM (3 x 20.0 mL), the filtrate was concentrated to give residue. The crude product was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 100: 1; TLC, Dichloromethane: Methanol = 10: 1 , Rf = 0.50) and preparative-HPLC using a Welch Ultimate C18 (150 x 25mm x 7 μm) and gradient of 18 - 48% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (206 mg, 495 μmol, 83.2% yield, 99.6% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.75 (s, 1H), 7.71 - 7.69 (m, 1H), 7.50 - 7.48 (m, 3H), 7.40 (s, 1H), 7.39 - 7.37 (m, 2H), 5.13 - 5.08 (m, 1H), 4.47 - 4.29 (m, 2H), 2.90 - 2.80 (m, 1H), 2.78 - 2.74 (m, 2H), 2.61 - 2.59 (m, 1H), 2.40 - 2.37 (m, 1H), 2.01 - 2.00 (m, 1H), 1.34 - 1.30 (m, 3H). (ESI+) m/z: 416.2 (M+H)+, (C23H21N5O3). EXAMPLE 149 [0747] Synthesis of 3-(1-oxo-5-(3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)isoindolin-2-yl)piperidine-2,6-dione: [0748] A. 3-Iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine: To a solution of 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (4.00 g, 24.0 mmol, 1.00 eq) in DMF (15.0 mL) was added NIS (6.50 g, 28.8 mmol, 1.20 eq) and NaHCO3 (2.43 g, 28.8 mmol, 1.12 mL, 1.20 eq) at 25 °C. The mixture was stirred at 60 °C for 12 h. The mixture was poured into water (100 mL) and extracted with DCM (3 x 200 mL) to collect the organic 232 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT layer. The organic layer was dried over Na2SO4, filter and the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 1/0 to 20/1, TLC: Petroleum ether/Ethyl acetate= 5/1, Rf = 0.30) to give the title compound (4.50 g, 17.9 mmol, 74.5% yield, 98.9% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 249.0 (M+H)+ (C7H9N2I). [0749] B. 3-Phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine: To a solution of 3-iodo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.00 g, 4.03 mmol, 1.00 eq) and phenylboronic acid (983 mg, 8.06 mmol, 2.00 eq) in DMF (10.0 mL) and H2O (1.60 mL) was added K2CO3 (1.11 g, 8.06 mmol, 2.00 eq) and Pd(dppf)Cl2 (294 mg, 403 μmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 50 °C for 1 h. The mixture was poured into water (50.0 mL) and extracted with ethyl acetate (2 x 20.0 mL) to collect the organic layers. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filter and the filtrate was concentrated under reduced pressure to get residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 20/1, TLC:Petroleum ether/Ethyl acetate = 3/1, Rf = 0.28) to give the title compound (500 mg, 2.52 mmol, 62.5% yield, 100% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.41 - 7.36 (m, 4H), 7.25 – 7.20 (m, 1H), 4.21 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.10 - 2.07 (m, 2H),1.94 – 1.89 (m, 2H). (ESI+) m/z: 199.1 (M+H)+, (C13H14N2). [0750] C. 2-Bromo-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine: To a solution of 3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (100 mg, 504 μmol, 1.00 eq) in THF (3.00 mL) was added dropwise n-BuLi (2.50 M, 605 μL, 3.00 eq) at -78 °C under N2. The reaction mixture was stirred for additional 1 h, then 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (157 mg, 606 μmol, 1.20 eq) was added dropwise at -78 °C. Then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated NH4Cl solution (50.0 mL) at 0 °C under N2. Then the mixture was extracted with ethyl acetate (3 x 20.0 mL) to collect the organic layers. The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to get a residue. The crude product was purified by Prep-TLC (Petroleum ether/Ethyl acetate = 4/1, Rf = 0.37) to give the title compound (30.0 mg, 105 μmol, 20.9% yield, 97.4% purity in LCMS at 220 nm) as a yellow gum.1H NMR: (400 MHz,CDCl3) δ7.41 – 7.35 (m, 4H), 7.33 – 7.31 (m, 1H), 4.18 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.09 - 2.06 (m, 2H), 1.87 – 1.84 (m, 2H). (ESI+) m/z: 278.9 (M+H)+, (C13H13N2Br). [0751] D. 3-(1-Oxo-5-(3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl- 233 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (78.0 mg, 210 μmol, 2.00 eq) and 2-bromo-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (30.0 mg, 105 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.100 mL) was added RuPhos Pd G3 (8.82 mg, 10.5 μmol, 0.100 eq) and K3PO4 (44.7 mg, 210 μmol, 2.00 eq) at 25 °C under N2. The mixture was stirred for 3 h at 100 °C under N2. The crude product was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.31) to get a residue. The residue was purified by Preparative-HPLC using a CD01-Phenomenex luna (150 mm x 25 mm x 10 μm) and gradiente of 26 - 26% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min to give the title compound (28.1 mg, 63.6 μmol, 60.3% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.41 - 7.36 (m, 3H), 7.34 - 7.28 (m, 1H), 7.19 (d, J = 7.2 Hz, 2H), 5.11 - 5.06 (m, 1H), 4.45 - 4.25 (m, 2H), 4.19 (t, J = 6.4 Hz, 2H), 2.96 - 2.94 (m, 1H), 2.98 (t, J = 6.4 Hz, 2H), 2.62 - 2.61 (m, 1H), 2.39 - 2.32 (m, 1H), 2.03 - 1.99 (m, 3H), 1.84 - 1.80 (m, 2H). (ESI+) m/z: 441.1 (M+H)+, (C26H24N4O3). EXAMPLE 150 [0752] Synthesis of 3-(5-(1,2-dimethyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0753] A. tert-Butyl 5-amino-4-(5-(5-(3,6-dihydro-2H-pyran-4-yl)-1,2-dimethyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-[5-(5-bromo-1,2-dimethyl-imidazol-4-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (500 mg, 1.02 mmol, 1.00 eq) in dioxane (5.00 mL) was added H2O (1.25 mL), 2-(3,6-dihydro- 2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (256 mg, 1.22 mmol, 1.20 eq), Pd(dtbpf)Cl2 (66.3 mg, 101 μmol, 0.10 eq) and K3PO4 (647 mg, 3.05 mmol, 3.00 eq). The mixture was stirred at 70 °C for 12 h under N2 atmosphere. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 10: 0 to 10: 1, Rf = 0.43 (Dichloromethane: Methanol = 10: 1)) to give the title compound (450 mg, 736 μmol, 72.4% 234 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ = 7.83 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.17 (s, 1H), 5.98 (s, 1H), 4.72 (dd, J = 10.4, 4.0 Hz, 1H), 4.61 - 4.39 (m, 2H), 4.28 (d, J = 2.0 Hz, 2H), 3.85 (t, J = 5.2 Hz, 2H), 3.43 (s, 3H), 2.37 - 2.32 (s, 3H), 2.16 (s, 5H), 2.05 - 1.91 (m, 1H), 1.32 (s, 9H). (ESI+) m/z: 495 (M+H)+, (C27H34N4O5). [0754] B. tert-Butyl 5-amino-4-(5-(1,2-dimethyl-5-(tetrahydro-2H-pyran-4-yl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-[5-[5-(3,6-dihydro-2H-pyran-4-yl)-1,2-dimethyl-imidazol-4-yl]-1-oxo-isoindolin-2-yl]-5- oxo-pentanoate (300 mg, 606 μmol, 1.00 eq) in EtOH (10.0 mL) was added Pd/C (129 mg, 10.0% purity) and PtO2 (27.5 mg) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 50 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (260 mg, 523 μmol, 86.3% yield) as a yellow solid, which was used in the next step directly without further purification. (ESI+) m/z: 497 (M+H)+, (C27H36N4O5). [0755] C. 3-(5-(1,2-dimethyl-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-(1,2- dimethyl-5-tetrahydropyran-4-yl-imidazol-4-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (200 mg, 402 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (277 mg, 1.61 mmol, 4.00 eq). The mixture was stirred at 80 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and purified by preparative-HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 1 - 20% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25.0 mL/min to give the title compound (13.0 mg, 30.6 μmol, 7.60% yield, 99.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 13.2, 5.2 Hz, 1H), 4.52 - 4.32 (dd, J = 27.2, 8.4, 2H), 3.91 (dd, J = 10.8, 4.0 Hz, 2H), 3.58 (s, 3H), 3.41 (m, 2H), 3.14 (m, 1H), 2.93 (m, 1H), 2.64 - 2.59 (m, 1H), 2.40 (dd, J = 13.2, 4.4 Hz, 1H), 2.31 (s, 3H), 2.06 - 1.89 (m, 3H), 1.63 - 1.54 (m, 2H). (ESI+) m/z: 423.0 (M+H)+, (C23H26N4O4). 235 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 151 [0756] Synthesis of 3-(5-(1-methyl-4-(oxetan-3-yl)-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0757] A. 3-(1-Methyl-5-phenyl-1H-imidazol-4-yl)oxetan-3-ol: A mixture of 4-bromo- 1-methyl-5-phenyl-1H-imidazole (2.00 g, 8.44 mmol, 1.00 eq) in THF (20.0 mL) was degassed and purged with N2 for 3 times. Then the mixture was dropwise added iPrMgCl (2.00 M, 6.33 mL, 1.50 eq) at -15 °C and then the mixture was stirred at 10 °C for 2 h under N2 atmosphere. Then the mixture was dropwise added oxetan-3-one (911 mg, 12.6 mmol, 1.50 eq) in THF (5.00 mL) and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction was dropwise added into aq. NH4Cl (100 mL) at 0 °C under N2. The resulting mixture was extracted with DCM (3 x 30.0 mL). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 1: 0 to 1: 50, TLC: Dichloromethane: Methanol = 15: 1, Rf = 0.50) to give the title compound (400 mg, 1.74 mmol, 20.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.50 - 7.38 (m, 5H), 6.06 (s, 1H), 4.57 - 4.44 (m, 4H), 3.55 (s, 3H). (ESI+) m/z: 230.9 (M+H)+, (C13H14N2O2). [0758] B. 1-Methyl-4-(2H-oxet-3-yl)-5-phenyl-1H-imidazole: A mixture of 3-(1- methyl-5-phenyl-1H-imidazol-4-yl)oxetan-3-ol (50.0 mg, 217 μmol, 1.00 eq) in DCM (4.00 mL) was added TEA (65.9 mg, 651 μmol, 90.6 μL, 3.00 eq) in DCM (0.50 mL) at -15 °C for 5 min and purged with N2 for 3 times, and then the mixture was added Ms2O (75.6 mg, 434 μmol, 2.00 eq) in DCM (2.00 mL) at -15 °C. Then the mixture was stirred at -15 °C for 1 h under N2 atmosphere. The reaction mixture was combined six batches to work up. The reaction mixture was concentrated and aq. NaHCO3 (50.0 mL) was added to the residue. The resulting mixture was extracted with DCM (3 x 50.0 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The reaction mixture was concentrated directly to give the title compound (200 mg, 694 μmol, 53.3% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 236 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT δ 7.66 (s, 1H), 7.51 - 7.43 (m, 5H), 6.91 (s, 1H), 4.59 - 4.41 (m, 2H), 3.50 (s, 3H). (ESI+) m/z: 213.0 (M+H)+, (C13H12N2O). [0759] C. 1-Methyl-4-(oxetan-3-yl)-5-phenyl-1H-imidazole: A mixture of 1-methyl-4- (2H-oxet-3-yl)-5-phenyl-1H-imidazole (200 mg, 942 μmol, 1.00 eq) in MeOH (8.00 mL) was added Pd/C (100 mg, 10.0% purity) and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under H2 (15 psi) atmosphere.The reaction liquid is filtered to collect the filtrate and concentrated. The residue was purified by preparative-TLC (SiO2, DCM: MeOH = 10: 1, Rf = 0.51) to give the title compound (35.0 mg, 157 μmol, 16.7% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.50 - 7.27 (m, 5H), 4.77 - 4.67 (m, 4H), 4.16 - 4.08 (m, 1H), 3.52 (s, 3H). (ESI+) m/z: 215.0 (M+H)+, (C13H14N2O). [0760] D. 2-Bromo-1-methyl-4-(oxetan-3-yl)-5-phenyl-1H-imidazole: A mixture of 1- methyl-4-(oxetan-3-yl)-5-phenyl-1H-imidazole (30.0 mg, 140 μmol, 1.00 eq)in ACN (1.00 mL) at 0 °C was added NBS (24.9 mg, 140 μmol, 1.00 eq) in ACN (0.50 mL) and purged with N2 for 3 times, and then the mixture was stirred at -15 °C for 1 h under N2 atmosphere. Water (5.00 mL)was added to the residue.The resulting mixture was extracted with EtOAc(3 x 5.00 mL). The combined organic phase was washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified or by preparative-TLC (SiO2, DCM: MeOH = 10: 1, Rf = 0.58) to give the title compound (25.0 mg, 74.9 μmol, 53.5% yield) as a yellow oil.1H NMR (400 MHz, DMSO- d6) δ 7.52 - 7.44 (m, 3H), 7.33 - 7.28 (m, 2H), 4.72 - 4.67 (m, 4H), 4.12 - 4.04 (m, 1H), 3.44 (s, 3H). (ESI+) m/z: 292.9 (M+H)+, (C13H13BrN2O). [0761] E. 3-(5-(1-Methyl-4-(oxetan-3-yl)-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: A mixture of 2-bromo-1-methyl-4-(oxetan-3-yl)-5-phenyl-1H- imidazole (20.0 mg, 68.2 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (63.1 mg, 170 μmol, 2.50 eq), K3PO4 (28.9 mg, 136 μmol, 2.00 eq) and RuPhos Pd G3 (5.71 mg, 6.82 μmol, 0.10 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate. in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 5 – 35% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (10.2 mg, 22.2 μmol, 26.0% yield, 99.3% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.02 (s, 1H), 7.97 - 7.91 (m, 1H), 7.90 - 7.85 (m, 1H), 7.56 - 7.37 (m, 5H), 5.16 - 5.14 (m, 1H), 4.86 - 4.71 (m, 4H), 4.61 - 4.41 (m, 237 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2H), 4.26 - 4.16 (m, 1H), 3.60 (s, 3H), 3.00 - 2.88 (m, 1H), 2.66 - 2.58 (m, 1H), 2.46 - 2.42 (m, 1H), 2.09 - 2.00 (m, 1H). (ESI+) m/z: 457.2 (M+H)+, (C26H24N4O4). EXAMPLES 152-154 [0762] The compounds of Examples 152-154 were prepared according to Examples 100- 111. EXAMPLES 155-156 [0763] The compounds of Examples 155-156 were prepared according to Examples 131- 137. 238 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 157-178 [0764] The compounds of Examples 157-178 were prepared according to the following synthetic scheme: [0765] Experimental Procedure [0766] Step 1: To a vial containing a solution of 0022_A001 (71.7 mg, 150 µmol, 1.00 eq) and 0022_Bi (180 µmol, 1.20 eq) in Dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 µmol, 2.00 eq), Pd-118 (15.0 µmol, 0.10 eq) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas, then diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under nitrogen gas to give crude intermediates used for next step. (Note: For some compounds need do reduction, we purified intermediates by prep- HPLC.) 239 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0767] Step 2 (0022_Bi’s with double bond): To a solution of 0022_A001Bi_1 (150 µmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq, 50% in H2O) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediates used for next step. [0768] Step 3: [0769] Condition 1: To a vial containing a solution of 0022_A001Bi_1 (~150 µmol, 1.00 eq) in CH3CN (1.00 mL) was added TsOH·H2O (1.20 mmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. [0770] Condition 2: To a vial containing a solution of 0022_A001Bi_1 (~150 µmol, 1.00 eq) in CH3CN (1.00 mL) was added H2SO4 (con.) (200 µL). The mixture was stirred at 65 °C for 1 hr. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 240 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 241 1103861084\1\AMERICAS
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ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 179 [0771] Synthesis of 3-(1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [0772] A. 5-Phenyl-1-(trifluoromethyl)-1H-imidazole: To a solution of 5-phenyl-1H- imidazole (7.00 g, 48.6 mmol, 1.00 eq) in THF (120 mL) was added NaH (2.14 g, 53.4 mmol, 60.0% purity, 1.10 eq) at 0 °C under N2. The mixture was stirred at 50 °C for 30 min. CF3I (45.7 g, 58.3 mmol, 25.0% purity, 1.20 eq) was added under N2 and stirred at 50 °C for 1 h. Then CF3I (11.4 g, 58.3 mmol, 1.20 eq) was added to mixture under N2. The mixture was stirred at 50 °C for 18.5 h under N2. The mixture was poured into ice cold H2O (100 mL), extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 50: 1 to 1: 2; TLC: Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.40) and triturated with ethyl acetate (10.0 mL) at 25 °C for 10 min, then filtered to give crude product. The crude product was washed with ethyl acetate (10.0 mL), collected and dried to dryness in vacuum to give the title compound (2.50 g, 11.6 mmol, 24.0% yield) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.52 - 7.45 (m, 5H). (ESI+) m/z: 212.9 (M+H)+, (C10H7F3N2). [0773] B. 4-Bromo-5-phenyl-1-(trifluoromethyl)-1H-imidazole: To a solution of 55- phenyl-1-(trifluoromethyl)-1H-imidazole (1.00 g, 4.71 mmol, 1.00 eq) in THF (15.0 mL) was added NBS (880 mg, 4.95 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum and purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 3: 1; TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.60) to give the title compound (450 mg, 1.55 mmol, 32.8% yield) as a light yellow solid. (ESI+) m/z: 292.9 (M+H)+, (C10H6BrF3N2). [0774] C. 3-(1-Oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: A solution of 4-bromo-5-phenyl-1-(trifluoromethyl)-1H-imidazole (150 mg, 515 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (477 mg, 1.29 mmol, 2.50 eq) in dioxane (4.00 mL) 250 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT and H2O (0.20 mL) was added K3PO4 (218 mg, 1.03 mmol, 2.00 eq) and Pd(dtbpf)Cl2 (33.6 mg, 51.5 μmol, 0.10 eq) under N2. The reaction mixture was stirred at 65 °C for 2 h under N2. The reaction mixture was concentrated under vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 30: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.40) and preparative-HPLC (using a CD01- Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 30 - 60% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min B over 10 min) to give the title compound (20.0 mg, 43.0 μmol, 8.36% yield, 97.9% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.29 (s, 1H), 8.24 - 8.17 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.68 - 7.44 (m, 6H), 5.17 - 5.12 (m, 1H), 4.61 - 4.36 (m, 2H), 3.01 - 2.85 (m, 1H), 2.66 - 2.58 (m, 1H), 2.47 - 2.36 (m, 1H), 2.11 - 1.97 (m, 1H). (ESI+) m/z: 455.2 (M+H)+, (C23H17F3N4O3). EXAMPLE 180 [0775] Synthesis of 3-(1-oxo-5-(5-phenyl-2-(trifluoromethyl)thiazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: [0776] A. 3-(5-(1-Ethoxyvinyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (10.0 g, 30.9 mmol, 1.00 eq) and tributyl(1-ethoxyvinyl)stannane (27.9 g, 77.3 mmol, 26.1 mL, 2.50 eq) in dioxane (200 mL) was added Pd(PPh3)4 (2.86 g, 2.48 mmol, 0.08 eq) under N2. The reaction mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was added to sat. aq. NH4Cl (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with aq.KF (2 x 100 mL), drived over Na2SO4, filtered and concentrated in vacuumn to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give the title compound (4.00 g, 12.7 mmol, 41.1% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.83 (s, 1H), 7.80 - 7.65 (m, 2H), 5.12 - 5.10 (m, 1H), 4.92 (s, 1H), 4.90 - 4.35 (m, 3H), 4.00 - 3.95 (m, 2H), 3.00 - 2.65 (m, 1H), 2.60 - 2.55 (m, 1H), 2.41 - 2.30 251 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (m, 1H), 2.20 - 1.95 (m, 1H), 1.37 (t, J = 3.6 Hz, 3H). (ESI+) m/z: 315.1 (M+H)+, (C17H18N2O4). [0777] B. 3-(5-(2-Bromoacetyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(1-ethoxyvinyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.00 g, 3.18 mmol, 1.00 eq) in [Bmim]PF6 (10.0 mL) was added NBS (679 mg, 3.82 mmol, 1.20 eq) and TsOH (121 mg, 636 μmol, 0.20 eq). The reaction mixture was stirred at 25 °C for 16 h to give the title compound (1 g, crude) as a yellow solid. (ESI+) m/z: 364.9 (M+H)+, (C15H13BrN2O4). [0778] C. 3-(1-Oxo-5-(thiazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(2-bromoacetyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (3.00 g, 8.22 mmol, 1.00 eq) in 1-ethyl-3-methyl-imidazol-3-ium;hexafluorophosphate (30 mL) was added K2CO3 (1.47 g, 10.6 mmol, 1.30 eq) and thioformamide (1.20 g, 9.87 mmol, 1.20 eq). The mixture was stirred at 25 °C for 12 h. Then the reaction mixture was poured into 100 mL of water and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: EtOAc = 100: 1 to 1: 1, Rf = 0.70 (Dichloromethane: EtOAc = 0: 1)) to give the title compound (370 mg, 1.10 mmol, 11.9% yield, 97.1% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 328.1 (M+H)+, (C16H13N3O3S). [0779] D. 3-(5-(5-Bromothiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-thiazol-4-yl-isoindolin-2-yl)piperidine-2,6-dione (370 mg, 1.10 mmol, 1.00 eq) in DMF (4.00 mL) was added NBS (214 mg, 1.21 mmol, 1.10 eq). The mixture was stirred at 25 °C for 12 h. Then the reaction mixture was poured into 10.0 mL of water and extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: EtOAc = 100: 1 to 1: 1, Rf = 0.71 (Dichloromethane: EtOAc = 0: 1)) to give the title compound (300 mg, 682 μmol, 62.1% yield, 92.4% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.29 (s, 1H), 8.11 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 13.2, 5.2 Hz, 1H), 4.48 (dd, J = 54.0, 17.6 Hz, 2H), 2.98 - 2.87 (m, 1H), 2.65 - 2.58 (m, 1H), 2.48 - 2.35 (m, 1H), 2.08 - 2.00 (m, 1H). (ESI+) m/z: 405.9 (M+H)+, (C16H12N3O3SBr). [0780] 252 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0781] E. 3-(1-Oxo-5-(5-phenylthiazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(5-bromothiazol-4-yl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (300 mg, 682 μmol, 1.00 eq) and phenylboronic acid (249 mg, 2.05 mmol, 3.00 eq) in DMF (3.00 mL) was added Pd(dppf)Cl2 (99.8 mg, 136 μmol, 0.20 eq) and K3PO4 (434 mg, 2.05 mmol, 3.00 eq). The mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was poured into 10.0 mL of water and extracted with EtOAc (3 x 5.00 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: EtOAc = 100: 1 to 1: 1, Rf = 0.72 (Dichloromethane: EtOAc = 0: 1)) to give the title compound (220 mg, 545 μmol, 79.9% yield) as a yellow solid. (ESI+) m/z: 404.1 (M+H)+, (C22H17N3O3S). [0782] F. 3-(5-(2-Bromo-5-phenylthiazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione: To a solution of 3-[1-oxo-5-(5-phenylthiazol-4-yl)isoindolin-2-yl]piperidine-2,6- dione (200 mg, 495 μmol, 1.00 eq) in ACN (4.00 mL) and H2O (4.00 mL) was added Oxone (833 mg, 4.96 mmol, 10.0 eq) and KBr (589 mg, 4.96 mmol, 10.0 eq). The mixture was stirred at 50 °C for 12 h under N2. Then the reaction mixture was poured into 10.0 mL of water and extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: EtOAc = 100: 1 to 1: 1, Rf = 0.70 (Dichloromethane: EtOAc = 0: 1)) to give the title compound (80 mg, 106 μmol, 21.4% yield, 64.0% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 482.0 (M+H)+, (C22H16N3O3SBr). [0783] G. 3-(5-(2-((3,3-Difluorocyclobutyl)methyl)-1-methyl-5-phenyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(2-bromo-5-phenyl- thiazol-4-yl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (60.0 mg, 79.6 μmol, 1.00 eq) in DMF (1.00 mL) was added CuI (45.4 mg, 238 μmol, 3.00 eq) and methyl 2,2-difluoro-2- fluorosulfonyl-acetate (55.0 mg, 286 μmol, 36.4 μL, 3.60 eq). The mixture was stirred at 80 °C for 12 h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 25 mm 10 μm) and gradient of 42-72% acetonitrile in water containing 0.5% FA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (15.22 mg, 32.2 μmol, 40.4% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.53 - 7.45 (m, 6H), 5.11 (dd, J = 13.2, 4.8 Hz, 1H), 4.38 (dd, J = 53.6, 17.6 Hz, 2H), 2.96 - 253 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.45 - 2.35 (m, 1H), 2.05 - 1.97 (m, 1H). (ESI+) m/z: 472.1 (M+H)+, (C23H16N3O3F3S). EXAMPLE 181 [0784] Synthesis of 3-(5-(2-(cyclobutyldifluoromethyl)-1-methyl-5-phenyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0785] A. 1-Methyl-5-phenyl-1H-imidazole: To a solution of MeNH2^HCl (63.6 g, 942 mmol, 2.00 eq) in DMF (500 mL) was added PhCHO (50 g, 471 mmol, 47.6 mL, 1.00 eq) and DIEA (121 g, 942 mmol, 164 mL, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. Then K2CO3 (97.7 g, 707 mmol, 1.50 eq) and 1-((isocyanomethyl)sulfonyl)-4- methylbenzene (110 g, 565 mmol, 1.20 eq) was added to the mixture at 25 °C. The mixture was stirred at 50 °C for 12 h. The mixture was poured into water (500 mL) and brine (500 mL), extracted with ethyl acetate (3 x 1.00 L) to collect the organic layer, the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 100/5, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.38) to give the title compound (15.0 g, 94.1 mmol, 14.9% yield, 99.2% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 7.52 (s, 1H), 7.44 - 7.37 (m, 5H), 7.12 (s, 1H), 3.67 (s, 3H). (ESI+) m/z: 159.2 (M+1)+, (C10H10N2) [0786] B. 1-Methyl-5-phenyl-1H-imidazole-2-carbaldehyde: To a solution of 1-methyl- 5-phenyl-1H-imidazole (15.0 g, 94.1 mmol, 1.00 eq) in THF (150 mL) was slowly added n- BuLi (2.5 M, 56.4 mL, 1.50 eq) at -75°C - -65 °C under N2. The reaction mixture was stirred at -75 - -65 °C for 2 h under N2. Then slowly added DMF (13.8 g, 188 mmol, 14.5 mL, 2.00 eq) to the reaction mixture at -75 - -65 °C under N2. Then the mixture was warm to 25 °C and stirred at 25 °C for 16 h under N2. The reaction mixture was quenched with 200 mL of ice- water at 0 °C under N2. Then the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether /Ethyl acetate = 100/1 to 100/25, TLC: Petroleum ether/Ethyl acetate 254 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT = 1/1, Rf = 0.40) to give the title compound (12.0 g, 55.7 mmol, 69.1% yield, 86.4% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 9.85 (s, 1H), 7.51 - 7.47 (m, 3H), 7.43 - 7.41 (m, 2H), 7.34 (s, 1H), 3.98 (s, 3H). (ESI+) m/z: 187.1 (M+1)+, (C11H10N2O) [0787] C. Cyclobutyl(1-methyl-5-phenyl-1H-imidazol-2-yl)methanol: To a solution of 1-methyl-5-phenyl-imidazole-2-carbaldehyde (2.00 g, 9.78 mmol, 1.00 eq) in THF (24.0 mL) was added cyclobutylmagnesium bromide (0.50 M, 19.5 mL, 1.00 eq) at -70 °C under N2. The mixture was stirred at -70 °C for 2 h. The mixture was poured in NH4Cl (100 mL) solution and extracted with Ethyl acetate (3 x 100 mL ) to collecte the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/0 to 10/1, TLC: DCM/MeOH = 20/1, Rf = 0.30) to give the title compound (300 mg, 1.13 mmol, 11.5% yield, 91.0% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.47 - 7.41 (m, 4H), 7.38 - 7.36 (m, 1H), 6.88 (s, 1H), 5.32 (d, J = 6.4 Hz, 1H), 4.59 - 4.53 (m, 1H), 3.64 (s, 3H), 2.97 - 2.91 (m, 1H), 2.12 - 2.04 (m, 1H), 2.01 - 1.96 (m, 1H), 1.91 - 1.88 (m, 1H), 1.74 - 1.66 (m, 1H), 1.53 - 1.46 (m, 1H). (ESI+) m/z: 243.1 (M+H)+, (C15H18N2O). [0788] D. Cyclobutyl(1-methyl-5-phenyl-1H-imidazol-2-yl)methanone: To a solution of cyclobutyl-(1-methyl-5-phenyl-imidazol-2-yl)methanol (300 mg, 1.13 mmol, 1.00 eq) in THF (6.00 mL) was addded MnO2 (750 mg, 8.63 mmol, 7.66 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered through Celite® to collect the filtrate and the filtrate was concentrate under vacuum at 45 °C to get the compound (280 mg, 948 μmol, 84.1% yield, 81.4% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 241.6 (M+H)+, (C15H16N2O). [0789] E. 2-(Cyclobutyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of cyclobutyl-(1-methyl-5-phenyl-imidazol-2-yl)methanone (240 mg, 812 μmol, 1.00 eq) in TFADMA (117 mg, 812 μmol, 7.00 mL, 1.00 eq) at 25 °C.The mixture was stirred at 40 °C for 5 h. The mixture was poured in H2O (100 mL) and extracted with DCM (3 x 100 mL ) to collecte the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 30/1, TLC: DCM/MeOH = 20/1, Rf = 0.30) to get the compound (80.0 mg, 301 μmol, 37.0% yield, 98.7% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.50 - 255 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.43 (m, 3H), 7.40 - 7.37 (m, 2H), 7.02 (s, 1H), 3.77(s, 3H), 3.65 - 3.57 (m, 1H), 2.33 - 2.23 (m, 4H), 2.08 - 2.01 (m, 1H), 1.97 - 1.88 (m, 1H). (ESI+) m/z: 263.4 (M+H)+, (C15H16N2F2). [0790] F. 4-Bromo-2-(cyclobutyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-(cyclobutyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole (60.0 mg, 225 μmol, 1.00 eq) in ACN (1.20 mL) was added NBS (48.2 mg, 270 μmol, 1.20 eq) at 0°C. The mixture was stirred at 25 °C for 2 h. The mixture was poured in H2O (100 mL) solution and extracted with DCM (3 x 100 mL ) to collect the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 100/0 to 30/1, TLC: DCM/MeOH = 20/1, Rf = 0.30) to get residue (40.0 mg, 117 μmol, 51.9% yield, 100% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.50 - 7.47 (m, 3H), 7.40 - 7.37 (m, 2H), 3.69 (s, 3H), 3.65 - 3.52 (m, 1H), 2.30 - 2.19 (m, 4H), 2.09 - 1.99 (m, 1H), 1.94 - 1.86 (m, 1H). (ESI+) m/z: 343.2 (M/+H)+, (C15H15BrN2F2). [0791] G. 3-(5-(2-(Cyclobutyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2- (cyclobutyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole (40.0 mg, 117 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6- dione (108 mg, 293 μmol, 2.50 eq) in dioxane (1.20 mL) and H2O (0.06 mL) was added K3PO4 (49.7 mg, 234 μmol, 2.00 eq) and RuPhos-Pd-G3 (9.81 mg, 11.7 μmol, 0.10 eq) at 25 °C under N2.The mixture was stirred at 100 °C for 2.5 h. The mixture was filtered and the filtrate cake was concentrated under vacuum at 45 °C to get a residue. The residue was purified by preparative-TLC (DCM/MeOH = 15/1, Rf = 0.30) to give the residue. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 45% - 75% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) to give the title compound (26.1 mg, 51.7 μmol, 44.1% yield, 100% purity in HPLC at 220 nm) as a grey solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.56 - 7.53 (m, 5H), 7.47 - 7.45 (m, 2H), 7.41 - 7.39 (m, 1H), 5.09 - 5.04 (m, 1H), 4.38 - 4.18 (m, 2H), 3.69 - 3.59 (m, 1H), 3.56 (s, 3H), 2.98 - 2.81 (m, 1H), 2.59 - 2.54 (m, 1H), 2.40 - 2.32 (m, 1H), 2.26 - 2.19 (m, 4H), 2.07 - 2.03 (m, 1H), 1.98 - 1.94 (m, 1H), 1.90 - 1.82 (m, 1H). (ESI+) m/z: 505.2 (M/2+H)+, (C28H26N4F2O3). 256 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 182 [0792] Synthesis of 3-(5-(2-(1,1-difluoroethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0793] A. 1-Methyl-5-phenyl-1H-imidazole: To a solution of MeNH2^HCl (63.6 g, 942 mmol, 2.00 eq) in DMF (500 mL) was added PhCHO (50 g, 471 mmol, 47.6 mL, 1.00 eq) and DIEA (121 g, 942 mmol, 164 mL, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. Then K2CO3 (97.7 g, 707 mmol, 1.50 eq) and 1-((isocyanomethyl)sulfonyl)-4- methylbenzene (110 g, 565 mmol, 1.20 eq) was added to the mixture at 25 °C. The mixture was stirred at 50 °C for 12 h. The mixture was poured into water (500 mL) and brine (500 mL), extracted with ethyl acetate (3 x 1.00 L) to collect the organic layer, the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 100/5, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.38) to give the title compound (15.0 g, 94.1 mmol, 14.9% yield, 99.2% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 7.52 (s, 1H), 7.44 - 7.37 (m, 5H), 7.12 (s, 1H), 3.67 (s, 3H). (ESI+) m/z: 159.2 (M+1)+, (C10H10N2) [0794] B. 1-Methyl-5-phenyl-1H-imidazole-2-carbaldehyde: To a solution of 1-methyl- 5-phenyl-1H-imidazole (15.0 g, 94.1 mmol, 1.00 eq) in THF (150 mL) was slowly added n- BuLi (2.5 M, 56.4 mL, 1.50 eq) at -75°C - -65 °C under N2. The reaction mixture was stirred at -75 - -65 °C for 2 h under N2. Then slowly added DMF (13.8 g, 188 mmol, 14.5 mL, 2.00 eq) to the reaction mixture at -75 - -65 °C under N2. Then the mixture was warm to 25 °C and stirred at 25 °C for 16 h under N2. The reaction mixture was quenched with 200 mL of ice- water at 0 °C under N2. Then the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether /Ethyl acetate = 100/1 to 100/25, TLC: Petroleum ether/Ethyl acetate = 1/1, Rf = 0.40) to give the title compound (12.0 g, 55.7 mmol, 69.1% yield, 86.4% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 9.85 (s, 1H), 257 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.51 - 7.47 (m, 3H), 7.43 - 7.41 (m, 2H), 7.34 (s, 1H), 3.98 (s, 3H). (ESI+) m/z: 187.1 (M+1)+, (C11H10N2O) [0795] C. 1-(1-Methyl-5-phenyl-1H-imidazol-2-yl)ethan-1-ol: To a solution of 1- methyl-5-phenyl-1H-imidazole-2-carbaldehyde (2.00 g, 9.28 mmol, 1.00 eq) in THF (20.0 mL) was added MeMgBr (3 M, 6.19 mL, 2.00 eq) at -78 °C, then the mixture was stirred at - 78 °C for 5 h. It was poured into saturated NH4Cl (100 mL) solution and extracted with ethyl acetate (3 x 30.0 mL) to collect the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 10/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.43 ) to give the title compound (1.10 g, 5.42 mmol, 58.3% yield, 99.6% purity LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.45 - 7.36 (m, 5H), 6.88 (s, 1H), 5.42 (d, J = 5.6 Hz, 1H), 4.88 - 4.85 (m, 1H), 3.63 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H). (ESI+) m/z: 203.1 (M+H)+, (C12H14N2O). [0796] D. 1-(1-Methyl-5-phenyl-1H-imidazol-2-yl)ethan-1-one: To a solution of 1-(1- methyl-5-phenyl-1H-imidazol-2-yl)ethan-1-ol (660 mg, 3.25 mmol, 1.00 eq) in THF (16.5 mL) was added MnO2 (1.65 g, 18.9 mmol, 5.84 eq) at 20 °C, then the mixture was stirred at 80 °C for 3.5 h. It was filter and the filtrate was concentrated under vacuum to give the title compound (610 mg, 2.89 mmol, 89.0% yield, 95.0% purity LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.53 - 7.47 (m, 5H), 7.27 (s, 1H), 3.87 (s, 3H), 2.58 (s, 3H). (ESI+) m/z: 201.0 (M+H)+, (C12H12N2O). [0797] E. 2-(1,1-Difluoroethyl)-1-methyl-5-phenyl-1H-imidazole: A solution of 1-(1- methyl-5-phenyl-1H-imidazol-2-yl)ethan-1-one (200 mg, 948 μmol, 1.00 eq) in TFEDMA (5.00 mL) was stirred at 80 °C for 6 h. It was poured into water (20.0 mL) and extracted with ethyl acetate (3 x 20.0 mL) to collect the organic layers. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether/Ethyl acetate = 7/1, Rf = 0.58) to give the title compound (130 mg, 505 μmol, 53.2% yield, 86.4% purity LCMS at 220 nm) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.51 - 7.45 (m, 5H), 7.06 (s, 1H), 3.72 (s, 3H), 2.14 (t, J = 19.2 Hz, 3H). (ESI+) m/z: 223.0 (M+H)+, (C12H12F2N2). [0798] F. 4-Bromo-2-(1,1-difluoroethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-(1,1-difluoroethyl)-1-methyl-5-phenyl-1H-imidazole (110 mg, 427 μmol, 1.00 eq) in ACN (2.20 mL) was added NBS (79.9 mg, 449 μmol, 1.05 eq) at 0 °C, then the mixture was stirred at 20 °C for 2 h. The residue was purified preparative-TLC (SiO2, 258 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Petroleum ether/Ethyl acetate = 8/1, Rf = 0.60) to give the title compound (55.0 mg, 179 μmol, 42.0% yield, 98.4% purity LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.55 - 7.49 (m, 5H), 3.64 (s, 3H), 2.13 (t, J = 19.2 Hz, 3H). (ESI+) m/z: 300.8 (M+H)+, (C12H11BrF2N2). [0799] G. 3-(5-(2-(1,1-Difluoroethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(1,1-difluoroethyl)-1- methyl-5-phenyl-1H-imidazole (50.0 mg, 163 μmol, 1.00 eq) in dioxane (1.50 mL) and H2O (0.075 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (151 mg, 408 μmol, 2.50 eq), K3PO4 (69.3 mg, 326 μmol, 2.00 eq) and RuPhos-Pd-G3 (13.6 mg, 16.3 μmol, 0.10 eq) at 20°C under N2, then the mixture was stirred at 100 °C for 2 h. It was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, DCM/MeOH = 20/1, Rf = 0.30). The crude product was purified by preparative-HPLC (using a CD04-Welch Utimate C18 (150 mm x 25 mm x 7 μm) and gradient of 31 - 61% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min) give the title compound (40.9 mg, 87.9 μmol, 53.8% yield, 99.8% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.57 - 7.54 (m, 5H), 7.47 - 7.45 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.38 - 4.19 (m, 2H), 3.56 (s, 3H), 2.93 - 2.84 (m, 1H), 2.59 - 2.55 (m, 1H), 2.37 - 2.33 (m, 1H), 2.23 (t, J = 19.2 Hz, 3H), 1.98 - 1.93 (m, 1H). (ESI+) m/z: 465.2 (M+H)+, (C25H22F2N4O3). EXAMPLE 183 [0800] Synthesis of 3-(5-(2-(cyclopropylmethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: [0801] A. Cyclopropyl(5-phenyloxazol-2-yl)methanol: To a solution of 2-bromo-5- phenyloxazole (7.50 g, 33.4 mmol, 1.00 eq) in THF (105 mL) was added dropwise i- PrMgCl•LiCl (1.30 M, 51.5 mL, 2.00 eq) at -70 °C under N2. Then the mixture was stirred at -70 °C for 1h. Then a solution of cyclopropanecarbaldehyde (2.82 g, 40.1 mmol, 3.00 mL, 1.20 eq) in THF (150 mL) was added dropwise to the mixture at - 70°C. The mixture was 259 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT stirred at -70 °C for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution (300 mL) at 0 °C under N2. Then the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 5/1, TLC: Petroleum ether/Ethyl acetate = 2/1, Rf = 0.27) to give the title compound (1.12 g, 4.99 mmol, 14.9% yield, 95.9% purity LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.70 (d, J = 7.6 Hz, 2H), 7.59 (s, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 5.78 (d, J = 5.6 Hz, 1H), 4.11 - 4.08 (m, 1H), 1.35 - 1.29 (m, 1H), 0.56 - 0.43 (m, 3H), 0.34 - 0.31 (m, 1H). (ESI+) m/z: 216.1 (M+H)+, (C13H13NO2). [0802] B. 2-(Cyclopropylmethyl)-5-phenyloxazole: To a solution of cyclopropyl(5- phenyloxazol-2-yl)methanol (1.10 g, 4.90 mmol, 1.00 eq) in dichloromethane (11.0 mL) was added TFA (4.47 g, 39.2 mmol, 2.91 mL, 8.00 eq) and Et3SiH (3.42 g, 29.4 mmol, 4.70 mL, 6.00 eq) at 25 °C. The mixture was stirred at 50 °C for 16 h. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 1/1, TLC: Petroleum ether/Ethyl acetate = 5/1, Rf = 0.51) to give the title compound (1.00 g, 4.46 mmol, 90.9% yield, 88.8% purity LCMS at 220 nm) as a light yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.67(d, J = 7.6 Hz, 2H), 7.54 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 2.73 (d, J = 7.2 Hz, 2H), 1.17 - 1.10 (m, 1H), 0.59 - 0.47 (m, 2H), 0.28 - 0.24 (m, 2H). (ESI+) m/z: 200.0 (M+H)+, (C13H13NO). [0803] C. 4-Bromo-2-(cyclopropylmethyl)-5-phenyloxazole: To a solution of 2- (cyclopropylmethyl)-5-phenyloxazole (150 mg, 668 μmol, 1.00 eq) in DMF (3.00 mL) was added NBS (124 mg, 701 μmol, 1.05 eq) at 0 °C, then the mixture was stirred at 0 °C for 1h. It was poured into water (10.0 mL) and extracted with ethyl acetate (2 x 5.00 mL) to collect the organic layers, the combined layers were washed with brine (2 x 20.0 mL) to collect the organic layers dried over Na2SO4, and filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, Petroleum ether/Ethyl acetate=10/1, Rf = 0.43) to give the title compound (90 mg, 304 μmol, 45.5% yield, 94.1% purity LCMS at 220 nm) as a light yellow liquid.1H NMR: (400 MHz, DMSO-d6) δ 7.91 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 2.73 (d, J = 7.2 Hz, 2H), 1.21 - 1.17 (m, 1H), 0.64 - 0.60 (m, 2H), 0.34 - 0.30 (m, 2H). (ESI+) m/z: 277.9 (M+H)+, (C13H12BrNO). [0804] D. 3-(5-(2-(Cyclopropylmethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(cyclopropylmethyl)-5-phenyloxazole 260 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (60.0 mg, 202 μmol, 1.00 eq) in dioxane (1.50 mL) and H2O (0.075 mL) was added 3-(1-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (187 mg, 507 μmol, 2.50 eq), K3PO4 (86.1 mg, 405 μmol, 2.00 eq) and RuPhos-Pd-G3 (16.9 mg, 20.3 μmol, 0.10 eq) at 20 °C, then the mixture was stirred at 100 °C for 2.5 h under N2. It was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, Dichloromethane/Methanol = 20/1, Rf = 0.18). The crude product was purified by preparative-HPLC (using a CD04-Welch Utimate C18 (150 mm x 25 mm x 7 μm) and gradient of 35 - 65% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) give the title compound (47.9 mg, 108 μmol, 53.4% yield, 100% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.83 (s, 1H), 7.75 - 7.67 (m, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.49 - 7.43 (m, 3H), 5.12 (dd, J = 13.6 Hz, J = 5.2 Hz, 1H), 4.49 - 4.32 (m, 2H), 2.96 - 2.87 (m, 1H), 2.79 (d, J = 7.2 Hz, 2H), 2.62 - 2.57 (m, 1H), 2.41 - 2.37 (m, 1H), 2.03 - 1.99 (m, 1H), 1.20 - 1.16 (m, 1H), 0.59 - 0.54 (m, 2H), 0.33 - 0.29 (m, 2H). (ESI+) m/z: 442.2 (M+H)+, (C26H23N3O4). EXAMPLE 184 [0805] Synthesis of 3-(5-(2-(cyclobutylmethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0806] A. 2-(Cyclobutylidenemethyl)-5-phenyloxazole: To a solution of 2-bromo-5- phenyloxazole (1.00 g, 4.46 mmol, 1.00 eq) and 2-(cyclobutylidenemethyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.04 g, 5.36 mmol, 1.20 eq) in dioxane (20.0 mL) and H2O (5.00 mL) was added K3PO4 (2.84 g, 13.4 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (291 mg, 446 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 65 °C for 16 h under N2. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/0 to 100/20, TLC: Petroleum ether/Ethyl acetate = 5/1, Rf = 0.37) to give the title compound (580 mg, 2.70 mmol, 60.6% yield, 98.5% purity) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 7.56 - 7.54 (m, 2H), 7.37 - 7.34 (m, 2H), 7.28 - 7.21 (m, 2H), 6.11 (t, J = 2.4 Hz, 261 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 3.21 (t, J = 8.0 Hz, 2H), 2.93 - 2.89 (m, 2H), 2.16 -2.08 (m, 2H). (ESI+) m/z: 212.4 (M+H)+, (C14H13NO) [0807] B. 2-(Cyclobutylmethyl)-5-phenyloxazole: To a solution of 2- (cyclobutylidenemethyl)-5-phenyloxazole (400 mg, 1.87 mmol, 1.00 eq) in MeOH (11.0 mL) and ethyl acetate (4.00 mL) was added Pd/C (40.0 mg, 37.6 μmol, 10% purity) under N2 at 25 °C. Degassed under vacuum and purged with H2 three times. The mixture was stirred at 25 °C under H2 (15 Psi) for 16 h. The mixture was filtered through Celite® and the filter cake was washed with MeOH (2 x 10.0 mL). The filtrate was concentrated under vacuum to give a residue at 40 °C to give the title compound (300 mg, crude) as a colorless oil.1H NMR: (400 MHz, CDCl3-d6) δ 7.61 - 7.59 (m, 2H), 7.42 - 7.40 (m, 2H), 7.38 - 7.32 (m, 1H), 7.22 (s, 1H), 2.93 (t, J = 7.2 Hz, 2H), 7.84 - 7.82 (m, 1H), 2.19 - 2.17 (m, 2H), 1.92 - 1.83 (m, 4H). (ESI+) m/z: 214.1 (M+H)+, (C14H15NO) [0808] C. 4-Bromo-2-(cyclobutylmethyl)-5-phenyloxazole: To a solution of 2- (cyclobutylmethyl)-5-phenyloxazole (300 mg, 1.41 mmol, 1.00 eq) in ACN (7.50 mL) was added NBS (263 mg, 1.48 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum to get a residue at 25 °C. The residue was purified by preparative-TLC (SiO2, Petroleum ether/Ethyl acetate = 8/1, Rf = 0.52) to give the title compound (160 mg, 543 μmol, 38.6% yield, 99.2% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 7.91 - 7.90 (m, 1H), 7.90 - 7.89 (m, 1H), 7.47 - 7.43 (m, 2H), 7.38 - 7.37 (m, 1H), 2.91 (d, J = 7.6 Hz, 2H), 2.83 - 2.80 (m, 1H), 2.22 - 2.18 (m, 2H), 1.93 - 1.83 (m, 4H). (ESI+) m/z: 291.8 (M+H)+, (C14H14BrNO). [0809] D. 3-(5-(2-(Cyclobutylmethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(cyclobutylmethyl)-5-phenyloxazole (111 mg, 377 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (349 mg, 941 μmol, 2.50 eq) in dioxane (2.75 mL) and H2O (0.14 mL) was added K3PO4 (160 mg, 753 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (63.0 mg, 75.3 μmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 2.5 h under N2. The mixture was concentrated under vacuum to get a residue at 50 °C. The residue was purified by preparative-TLC (SiO2, Dichloromethane/Methanol = 20/1, Rf = 0.42) to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 45-75% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (80.9 mg, 178 μmol, 47.2% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.81 (s, 1H), 7.75 - 7.73 (m, 1H), 7.69 - 7.66 (m, 1H), 7.56 - 7.54 (m, 2H), 7.49 - 7.45 262 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (m, 3H), 5.15 - 5.10 (m, 1H), 4.50 - 4.32 (m, 2H), 2.96 (d, J = 7.6 Hz, 2H), 2.93 - 2.88 (m, 1H), 2.83 - 2.77 (m, 1H), 2.62 - 2.58 (m, 1H), 2.41 - 2.37 (m, 1H), 2.15 - 2.12 (m, 2H), 2.04 - 2.00 (m, 1H), 1.88 - 1.82 (m, 4H). (ESI+) m/z: 456.5 (M+H)+, (C27H25N3O4). EXAMPLE 185 [0810] Synthesis of 3-(5-(2-((3,3-difluorocyclobutyl)methyl)-5-phenyloxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0811] A. 2-((3,3-Difluorocyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane: 2,2,6,6-tetramethylpiperidine (3.16 g, 22.3 mmol, 3.80 mL, 1.20 eq) was dissolved in THF (35.0 mL) and cooled to -30 °C under N2 atmosphere. n-BuLi (2.50 M, 8.96 mL, 1.20 eq) was added dropwise, and the reaction mixture was stirred at -30 °C for 30 min. Next, the reaction was cooled to -78 °C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (5.00 g, 18.6 mmol, 1.00 eq) in THF (35.0 mL) was added dropwise. After stirring for 30 min, a solution of 3,3- difluorocyclobutanone (3.96 g, 37.3 mmol, 2.00 eq) in THF (70.0 mL) was added dropwise at -78 °C. The reaction mixture was allowed to slowly warm up to 25°C and stirred for 12 h under N2 atmosphere. Then the mixture was cooled to 0 °C, and aq. NH4Cl (150 mL) was added dropwise under N2 atmosphere. The mixture was extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 10: 1, Rf = 0.60 (Petroleum ether: EtOAc = 10: 1)) to give the title compound (2.00 g, crude) as colorless oil. (ESI+) m/z: 231.0 (M+H)+, (C11H17BO2F2). [0812] B. 2-((3,3-Difluorocyclobutylidene)methyl)-5-phenyloxazole: To a solution of 2-bromo-5-phenyl-oxazole (500 mg, 2.23 mmol, 1.00 eq) and 2-[(3,3- difluorocyclobutylidene)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 g, 4.46 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added Pd(dtbpf)Cl2 (145 mg, 223 μmol, 0.10 eq) and K3PO4 (1.42 g, 6.70 mmol, 3.00 eq). The mixture was stirred at 65 °C for 12 h under N2. Then the reaction mixture was filtered and the filtrate was concentrated in 263 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 5: 1, Rf = 0.50) to give the title compound (140 mg, crude) as brown oil. (ESI+) m/z: 248.0 (M+H)+, (C14H11NOF2). [0813] C. 2-((3,3-Difluorocyclobutyl)methyl)-5-phenyloxazole: To a solution of 2- [(3,3-difluorocyclobutylidene)methyl]-5-phenyl-oxazole (140 mg, 566 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (70.00 mg, 10% purity) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (20 Psi) at 25 °C for 12 h. Then the mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 25 mm 10 μm) and gradient of 42-72% acetonitrile in water containing 0.5% FA over 13 min at a flow rate of 25.0 mL/min) to give the title compound (60.0 mg, 235 μmol, 41.6% yield, 98.0% purity in LCMS at 220 nm) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.69 - 7.59 (m, 2H), 7.47 - 7.40 (m, 2H), 7.38 - 7.33 (m, 1H), 7.27 (s, 1H), 3.10 (d, J = 7.6 Hz, 2H), 2.90 - 2.79 (m, 2H), 2.76 - 2.67 (m, 1H), 2.50 - 2.40 (m, 2H). (ESI+) m/z: 250.0 (M+H)+, (C14H13NOF2). [0814] D. 4-Bromo-2-((3,3-difluorocyclobutyl)methyl)-5-phenyloxazole: To a solution of 2-[(3,3-difluorocyclobutyl)methyl]-5-phenyl-oxazole (50.0 mg, 196 μmol, 1.00 eq) in DMF (1.00 mL) was added NBS (38.4 mg, 216 μmol, 1.10 eq). The mixture was stirred at 25 °C for 1 h. Then the mixture was added into 2.00 mL of water and a white solid was separated out. The solid was collected and dried in vacuum to give the title compound (50.0 mg, 144 μmol, 73.4% yield, 94.8% purity in LCMS at 220 nm) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.93 - 7.85 (m, 2H), 7.49 - 7.43 (m, 2H), 7.42 - 7.36 (m, 1H), 3.02 (d, J = 7.2 Hz, 2H), 2.88 - 2.80 (m, 2H), 2.76 - 2.66 (m, 1H), 2.49 - 2.35 (m, 2H). (ESI+) m/z: 328.0 (M+H)+, (C14H12NOF2Br). [0815] E. 3-(5-(2-((3,3-Difluorocyclobutyl)methyl)-5-phenyloxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-[(3,3- difluorocyclobutyl)methyl]-5-phenyl-oxazole (50.0 mg, 144 μmol, 1.00 eq) and 3-[1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (133 mg, 361 μmol, 2.50 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added K3PO4 (91.9 mg, 433 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (24.1 mg, 28.8 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h. Then the mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 0: 1, Rf = 0.60) and then by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 30 mm 5 μm) and gradient of 44-74% acetonitrile in 264 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT water containing 0.5% FA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (37.8 mg, 76.5 μmol, 52.9% yield, 99.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.81 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.50 - 7.40 (m, 3H), 5.12 (dd, J = 13.6, 5.2 Hz, 1H), 4.41 (dd, J = 53.2, 18.0 Hz, 2H), 3.11 (d, J = 7.2 Hz, 2H), 2.97 - 2.86 (m, 1H), 2.85 - 2.75 (m, 2H), 2.68 - 2.57 (m, 2H), 2.49 - 2.31 (m, 3H), 2.06 - 1.98 (m, 1H). (ESI+) m/z: 492.3 (M+H)+, (C27H23N3O4F2). EXAMPLE 186 [0816] Synthesis of 3-(5-(4-(cyclobutylmethyl)-1-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0817] A. 2-(Cyclobutylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of tetramethyl-piperidine (24.2 g, 171 mmol, 1.20 eq) in THF (100 mL) was added n-BuLi (2.50 M, 68.4 mL, 1.20 eq) dropwise under an N2 atmosphere at -30°C and the mixture was stirred at -30°C for 0.5 h. The reaction was then cooled to -78 °C and a solution of bis (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (38.2 g, 142 mmol, 1.00 eq) in THF (300 mL) was added dropwise. The reaction mixture was stirred at -78°C for 0.5 h and a solution of cyclobutanone (10 g, 142 mmol, 10.6 mL, 1.00 eq) in THF (100 mL) was added dropwise. The reaction mixture was warmed to 25°C and stirred for an additional 12 h. The reaction mixture was slowly poured into 400 mL of saturated aqueous NH4Cl at 0°C and after stirring for 1 h, the solution was diluted with H2O (200 mL) and extracted with ethyl acetate (3 x 300 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (26.9 g, 138 mmol, 97.1% yield) as a brown oil.1H NMR (400 MHz, CDCl3) δ 5.08 - 5.04 (m, 1H), 2.93 - 2.86 (m, 2H), 2.78 - 2.71 (m, 2H), 1.93 (d, J = 7.9 Hz, 2H), 1.22 (s, 12H). (C11H19BO2). [0818] B. 4-(Cyclobutylidenemethyl)-1-phenyl-1H-imidazole: A mixture of 2- (cyclobutylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.60 g, 8.24 mmol, 1.00 eq), 4-bromo-1-phenyl-1H-imidazole (2.02 g, 9.07 mmol, 1.10 eq), K3PO4 (5.25 g, 24.7 mmol, 3.00 eq), Pd(dppf)Cl2 (603 mg, 824 μmol, 0.10 eq) in dioxane (16.0 mL) and H2O 265 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (4.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65°C for 12 h under N2 atmosphere. The reaction mixture was poured into H2O (80.0 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 3/1; TLC, Petroleum ether/Ethyl acetate = 3/1, Rf = 0.50) to give the title compound (1.03 g, 4.47 mmol, 54.3% yield) as a red oil. (ESI+) m/z: 211.1 (M+H)+, (C14H14N2). [0819] C. 4-(Cyclobutylmethyl)-1-phenyl-1H-imidazole: To a solution of 4- (cyclobutylidenemethyl)-1-phenyl-1H-imidazole (1.03 g, 4.90 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (0.500 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (20 psi) at 25°C for 16 h. The reaction mixture was filtered and the filter was concentrated to give the title compound (946 mg, 3.22 mmol, 65.7% yield) as a yellow oil. (ESI+) m/z: 213 (M+H)+, (C14H16N2). [0820] D. 2-Bromo-4-(cyclobutylmethyl)-1-phenyl-1H-imidazole: To a solution of 4- (cyclobutylmethyl)-1-phenyl-1H-imidazole (40.0 mg, 188 μmol, 1.00 eq) in THF (0.80 mL) was added n-BuLi (2.50 M, 113 μL, 1.50 eq) purged with N2 for 3 times at -78°C. The mixture was stirred at -78°C for 1 h and then 1,2-dibromo-1,1,2,2-tetrafluoroethane (53.8 mg, 207 μmol, 1.10 eq) in THF (0.40 mL) was added into the mixture and stirred at 25°C for 15 h under N2 atmosphere. The reaction mixture was poured into saturated NH4Cl aqueous solution (5.00 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 3/1, Rf = 0.70) to give the title compound (58.0 mg, 193.55 μmol, 20.5% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.49 (m, 3H), 7.47 - 7.41 (m, 2H), 7.24 (s, 1H), 2.57 (s, 3H), 2.12 - 1.99 (m, 2H), 1.87 - 1.77 (m, 2H), 1.74 - 1.63 (m, 2H). (ESI+) m/z: 292.9 (M+H)+, (C14H15BrN2). [0821] E. 3-(5-(4-(Cyclobutylmethyl)-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 2-bromo-4-(cyclobutylmethyl)-1-phenyl-1H- imidazole (50.0 mg, 171 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione (127 mg, 343 μmol, 2.00 eq), K3PO4 (72.9 mg, 343 μmol, 2.00 eq), Ru-Phos-Pd-G3 (14.3 mg, 17.1 μmol, 0.10 eq) in dioxane (0.500 mL) and H2O (0.025 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (20.0 266 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative-HPLC(using a CD01-Phenomenex luna C18150*25*10um) and gradiente of 15%-45% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (44.35 mg, 97.58 μmol, 56.83% yield, 99.91% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.56 - 7.48 (m, 3H), 7.42 (s, 3H), 5.11 (d, J = 18.4 Hz, 1H), 4.47 - 4.26 (m, 2H), 2.97 - 2.84 (m, 1H), 2.80 (d, J = 8.0 Hz, 2H), 2.75 - 2.65 (m, 1H), 2.62 - 2.56 (m, 1H), 2.41 - 2.31 (m, 1H), 2.20 - 2.08 (m, 2H), 2.06 - 1.95 (m, 1H), 1.93 - 1.83 (m, 2H), 1.82 - 1.72 (m, 2H). (ESI+) m/z: 455.2 (M+H)+, (C27H26N4O3). EXAMPLE 187 [0822] Synthesis of 3-(1-oxo-5-(1-phenyl-4-(trifluoromethyl)-1H-imidazol-2- yl)isoindolin-2-yl)piperidine-2,6-dione: [0823] A. 1-Phenyl-4-(trifluoromethyl)-1H-imidazole: To a solution of 4- (trifluoromethyl)-1H-imidazole (2.00 g, 14.7 mmol, 1.00 eq) and phenylboronic acid (1.79 g, 14.7 mmol, 1.00 eq) in ACN (50.0 mL) was added Cu(OAc)2 (2.67 g, 14.7 mmol, 1.00 eq) 4A MS and boric acid (908 mg, 14.70 mmol, 1.00 eq) .The mixture was stirred at 70 °C for 16 h. The mixture was poured into H2O (100 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with saturated NaCl aq. (3 x 100mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 50:1 to 5:1, TLC: Petroleum ether: Ethyl acetate = 5:1, Rf = 0.30) to give the title compound (1.50 g, 7.07 mmol, 48.0% yield, 99.5% purity in LCMS at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.44 - 8.49 (m, 2H), 7.71 - 7.76 (m, 2H), 7.53 - 7.59 (m, 2H), 7.42 - 7.47 (m, 1H). (ESI+) m/z: 213.1 (M+H)+, (C10H7F3N2). [0824] B. 2-Bromo-1-phenyl-4-(trifluoromethyl)-1H-imidazole: To a solution of 1- phenyl-4-(trifluoromethyl)-1H-imidazole (400 mg, 1.89 mmol, 1.00 eq) in THF (10.0 mL) was cooled to -70 °C, then n-BuLi (2.5 M, 1.51 mL, 2.00 eq) was dropwise to the mixture at - 267 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 70 °C under N2. Then the reaction mixture was stirred at -70 °C for 1 h, after that a solution of 1, 2-dibromo-1,1,2,2-tetrafluoroethane (979 mg, 3.77 mmol, 2.00 eq) in THF (10.0 mL) was added to the reaction mixture at -70 °C under N2. The mixture was stirred at 25 °C for 3 h under N2. The mixture was poured into NH4Cl (50.0 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with saturated NaCl aqueous (3 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by TLC (Petroleum ether: Ethyl acetate = 8:1,Rf = 0.30) to give the title compound (120 mg, 409 μmol, 21.7% yield, 99.4% purity in LCMS at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.58 – 7.55 (m, 5H). (ESI+) m/z: 292.8 (M+H)+, (C10H6BrF3N2). [0825] C. 3-(1-Oxo-5-(1-phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1-phenyl-4-(trifluoromethyl)-1H- imidazole (170 mg, 584 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (540 mg, 1.75 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (371 mg, 1.75 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (48.8 mg, 58.4 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 x 25 mm x 10 um) and gradient of 27.0% - 57.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (162 mg, 356 μmol, 61.0% yield, 100% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.32 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=7.60 Hz, 1H), 7.48 - 7.55 (m, 3H), 7.40 - 7.47 (m, 2H), 7.33 (d, J=8.00 Hz, 1H), 5.12 – 5.06 (m, 1H), 4.24 - 4.47 (m, 2H), 2.83 - 2.97 (m, 1H), 2.60 – 2.56 (m, 1H), 2.31 - 2.44 (m, 1H), 1.95 - 2.05 (m, 1H). (ESI+) m/z: 455.1 (M+H)+, (C23H17F3N4O3). 268 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 188 [0826] Synthesis of 3-(5-(2-(cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0827] A. 1-Methyl-5-phenyl-1H-imidazole: To a solution of MeNH2^HCl (63.6 g, 942 mmol, 2.00 eq) in DMF (500 mL) was added PhCHO (50 g, 471 mmol, 47.6 mL, 1.00 eq) and DIEA (121 g, 942 mmol, 164 mL, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. Then K2CO3 (97.7 g, 707 mmol, 1.50 eq) and 1-((isocyanomethyl)sulfonyl)-4- methylbenzene (110 g, 565 mmol, 1.20 eq) was added to the mixture at 25 °C. The mixture was stirred at 50 °C for 12 h. The mixture was poured into water (500 mL) and brine (500 mL), extracted with ethyl acetate (3 x 1.00 L) to collect the organic layer, the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 100/5, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.38) to give the title compound (15.0 g, 94.1 mmol, 14.9% yield, 99.2% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 7.52 (s, 1H), 7.44 - 7.37 (m, 5H), 7.12 (s, 1H), 3.67 (s, 3H). (ESI+) m/z: 159.2 (M+1)+, (C10H10N2) [0828] B. 1-Methyl-5-phenyl-1H-imidazole-2-carbaldehyde: To a solution of 1-methyl- 5-phenyl-1H-imidazole (15.0 g, 94.1 mmol, 1.00 eq) in THF (150 mL) was slowly added n- BuLi (2.5 M, 56.4 mL, 1.50 eq) at -75°C - -65 °C under N2. The reaction mixture was stirred at -75 - -65 °C for 2 h under N2. Then slowly added DMF (13.8 g, 188 mmol, 14.5 mL, 2.00 eq) to the reaction mixture at -75 - -65 °C under N2. Then the mixture was warm to 25 °C and stirred at 25 °C for 16 h under N2. The reaction mixture was quenched with 200 mL of ice- water at 0 °C under N2. Then the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether /Ethyl acetate = 100/1 to 100/25, TLC: Petroleum ether/Ethyl acetate = 1/1, Rf = 0.40) to give the title compound (12.0 g, 55.7 mmol, 69.1% yield, 86.4% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 9.85 (s, 1H), 269 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.51 - 7.47 (m, 3H), 7.43 - 7.41 (m, 2H), 7.34 (s, 1H), 3.98 (s, 3H). (ESI+) m/z: 187.1 (M+1)+, (C11H10N2O) [0829] C. Cyclopropyl(1-methyl-5-phenyl-1H-imidazol-2-yl)methanol: To a solution of 1-methyl-5-phenyl-1H-imidazole-2-carbaldehyde (2.00 g, 9.28 mmol, 1.00 eq) in THF (24.0 mL) was added bromo(cyclopropyl)magnesium (0.5 M, 37.1 mL, 2.0 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with NH4Cl, dropwise NH4Cl (50.0 mL) to the mixture at 0 - 20 °C under N2, and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 100/3, TLC: Dichloromethane /Methanol = 20/1, Rf = 0.21) to give the title compound (700 mg, 3.03 mmol, 32.7% yield, 98.8% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, CDCl3-d6) δ 7.74 - 7.72 (m, 2H), 7.39 - 7.35 (m, 3H), 6.97 (s, 1H), 4.20 (d, J = 8.0 Hz, 1H), 3.68 (s, 3H), 1.58 - 1.53 (m, 1H), 0.70 - 0.65 (m, 2H), 0.52 - 0.43 (m, 2H). (ESI+) m/z: 229.1 (M+H)+, (C14H16N2O). [0830] D. Cyclopropyl(1-methyl-5-phenyl-1H-imidazol-2-yl)methanone: To a solution of cyclopropyl(1-methyl-5-phenyl-1H-imidazol-2-yl)methanol (480 mg, 2.08 mmol, 1.00 eq) in THF (12.0 mL) was added MnO2 (1.08 g, 12.5 mmol, 6.00 eq) at 25 °C. The mixture was stirred at 80 °C for 4 h. The mixture was filtered through Celite® and the filter cake was washed with Dichloromethane (2 x 10.0 mL). The filtrate was concentrated under vacuum to give the title compound (460 mg, crude) as a light yellow solid.1H NMR: (400 MHz, DMSO-CDCl3) δ 7.50 - 7.46 (m, 3H), 7.42 - 7.40 (m, 2H), 7.27 (s, 1H), 3.95 (s, 3H), 3.40 - 3.34 (m, 1H), 1.23 - 1.21 (m, 2H), 1.11 - 1.07 (m, 2H). (ESI+) m/z: 227.4 (M+H)+, (C14H14N2O). [0831] E. 2-(Cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole: A mixture of 2-(cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole (200 mg, 884 μmol, 1.00 eq) in TFEDMA (1.28 g, 8.84 mmol, 10.0 eq) was stirred at 80 °C for 32 h. The mixture was poured into water (50.0 mL) and adjusted to pH = 7 with saturated solution of NaHCO3 (10.0 mL). The mixture was extracted with dichloromethane (3 x 50.0 mL) to collect the organic layers, the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/0 to 100/6, TLC: Petroleum ether/Ethyl acetate = 3/1, Rf = 0.31) to give the title compound (55.0 mg, 140 μmol, 7.89% 270 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT yield, 63.0% purity in LCMS at 220 nm) as a light yellow solid. (ESI+) m/z: 248.9 (M+H)+, (C14H14F2N2). [0832] F. 4-Bromo-2-(cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-(cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole (55.0 mg, 140 μmol, 1.00 eq) in ACN (1.50 mL) was added NBS (26.1 mg, 147 μmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give a residue at 25 °C. The residue was purified by preparative-TLC (SiO2, Petroleum ether/Ethyl acetate = 10/1, Rf = 0.46) to give the title compound (35.0 mg, 101 μmol, 72.5% yield, 94.6% purity in LCMS at 220 nm) as a light yellow solid. (ESI+) m/z: 329.0 (M+H)+, (C14H13BrF2N2). [0833] G. 3-(5-(2-(Cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2- (cyclopropyldifluoromethyl)-1-methyl-5-phenyl-1H-imidazole (33.0 mg, 95.4 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6- dione (88.3 mg, 239 μmol, 2.50 eq) in dioxane (0.83 mL) was added K3PO4 (40.5 mg, 191 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (7.98 mg, 9.54 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 100°C for 2.5 h. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The residue was purified by preparative-TLC (SiO2, Dichloromethane/Methanol = 20/1, Rf = 0.42) to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 34-64% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (20.5 mg, 41.8 μmol, 43.8% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.57 - 7.55 (m, 5H), 7.48 - 7.46 (m, 3H), 5.09 - 5.05 (m, 1H), 4.39 - 4.19 (m, 2H), 3.55 (s, 3H), 2.91 - 2.86 (m, 1H), 2.60 - 2.55 (m, 1H), 2.37 - 2.33 (m, 1H), 2.18 - 2.17 (m, 1H), 1.99 - 1.96 (m, 1H), 0.86 - 0.79 (m, 4H). (ESI+) m/z: 491.2 (M+H)+, (C27H24F2N4O3). 271 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 189 [0834] Synthesis of 3-(5-(2-((1-methylazetidin-3-yl)methyl)-5-phenyloxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0835] A. tert-Butyl 3-((5-phenyloxazol-2-yl)methylene)azetidine-1-carboxylate: To a solutuon of 2-bromo-5-phenyloxazole (1.00 g, 4.46 mmol, 1.00 eq), tert-butyl 3-((4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (2.63 g, 8.93 mmol, 2.00 eq) in dioxane (12.0 mL) and H2O (3.00 mL) was added Pd(dtbpf)Cl2 (291 mg, 446 μmol, 0.10 eq) , K3PO4 (1.89 g, 8.93 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 65 °C for 16 h. The reaction mixture was concentrated under vacuum and purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 80: 1 to 10: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (1.20 g, 4.95 mmol, 86.9% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.64 - 7.59 (m, 2H), 7.47 - 7.40 (m, 2H), 7.38 (s, 2H), 6.35 (s, 1H), 5.06 - 4.92 (m, 2H), 4.77 - 4.27 (m, 2H), 1.50 (s, 9H). (ESI+) m/z: 313.2 (M+H)+, (C18H20N2O3). [0836] B. tert-Butyl 3-((5-phenyloxazol-2-yl)methyl)azetidine-1-carboxylate: To a solution of tert-butyl 3-((5-phenyloxazol-2-yl)methylene)azetidine-1-carboxylate (1.00 g, 3.20 mmol, 1.00 eq) in MeOH (20.0 mL) was added Pd/C (200 mg, 188 μmol, 10.0% purity, 0.05 eq) under N2. The reaction mixture was degassed and purged with N2 for 3 times, then degassed and purged with H2 for 3 times. The reaction mixture was warmed to 25 °C and stirred at 15 psi under H2 for 5 h. The reaction mixture was filtered through diatomite. The filtrate was concentrated in vacuum to give the title compound (900 mg, crude) as black oil. 1H NMR: (400 MHz, CDCl3) δ 7.64 - 7.54 (m, 2H), 7.46 - 7.39 (m, 2H), 7.37 - 7.30 (m, 1H), 7.23 (s, 1H), 4.21 - 4.12 (m, 2H), 3.82 - 3.73 (m, 2H), 3.18 - 3.11 (m, 2H), 3.10 - 3.00 (m, 1H), 1.45 (s, 9H). (ESI+) m/z: 315.1 (M+H)+, (C18H22N2O3). [0837] C. 2-(Azetidin-3-ylmethyl)-5-phenyloxazole: To a soution of tert-butyl 3-((5- phenyloxazol-2-yl)methyl)azetidine-1-carboxylate (800 mg, 2.54 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (12.2 g, 107 mmol, 8.00 mL, 42.3 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to give the title 272 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT compound (1.00 g, crude) as a black oil.1H NMR: (400 MHz, CDCl3) δ 8.73 - 8.44 (m, 1H), 7.65 - 7.58 (m, 2H), 7.51 - 7.40 (m, 3H), 7.35 (s, 1H), 4.57 - 4.41 (m, 2H), 4.22 - 4.07 (m, 2H), 3.59 - 3.50 (m, 1H), 3.48 - 3.37 (m, 2H). (ESI+) m/z: 215.1 (M+H)+, (C13H14N2O). [0838] D. 2-((1-Methylazetidin-3-yl)methyl)-5-phenyloxazole: To a solution of 2- (azetidin-3-ylmethyl)-5-phenyloxazole (1.00 g, 3.05 mmol, 1.00 eq) in MeOH (10.0 mL) was added HCHO (2.47 g, 30.4 mmol, 2.27 mL, 37.0% purity, 10.0 eq) and AcOH (91.4 mg, 1.52 mmol, 87.2 μL, 0.50 eq) at 25 °C and stirred for 0.5 h, then NaBH3CN (574 mg, 9.14 mmol, 3.00 eq) was added at 0 °C. The reaction mixture was stirred at 25 °C for 15.5 h. The residue was diluted with H2O (20.0 mL) and extracted with ethyl acetate (3 x 50.0 mL), dried over drying Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 94: 6; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.30) to give the title compound (400 mg, 1.75 mmol, 57.5% yield) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.70 - 7.64 (m, 2H), 7.58 (s, 1H), 7.49 - 7.43 (m, 2H), 7.39 - 7.33 (m, 1H), 4.32 - 4.09 (m, 2H), 4.08 - 3.89 (m, 2H), 3.26 - 3.17 (m, 3H), 2.85 [0839] E. 4-Bromo-2-((1-methylazetidin-3-yl)methyl)-5-phenyloxazole: To a solution of 2-((1-methylazetidin-3-yl)methyl)-5-phenyloxazole (350 mg, 1.53 mmol, 1.00 eq) in ACN (5.00 mL) was added NBS (286 mg, 1.61 mmol, 1.05 eq). The reaction was stirred at 25 °C for 1 h. The reaction was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (180 mg, 568 μmol, 37.0% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.87 - 7.80 (m, 2H), 7.57 - 7.51 (m, 2H), 7.48 - 7.42 (m, 1H), 4.06 - 3.96 (m, 2H), 3.78 - 3.72 (m, 2H), 3.20 - 3.18 (m, 2H), 3.16 - 3.12 (m, 1H), 2.70 (s, 3H). (ESI+) m/z: 307.0 (M+H)+, (C14H15BrN2O). [0840] F. 3-(5-(2-((1-methylazetidin-3-yl)methyl)-5-phenyloxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-((1-methylazetidin-3- yl)methyl)-5-phenyloxazole (170 mg, 553 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (512 mg, 1.38 mmol, 2.50 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added Ru-Phos-Pd-G3 (46.3 mg, 55.3 μmol, 0.10 eq) and K3PO4 (235 mg, 1.11 mmol, 2.00 eq) under N2, the reaction mixture was stirred at 100 °C for 2 h under N2. The reaction was filtered and concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a CD04-Welch Utimate (C18 150 x 25 x 7 μm) and gradient of 10 - 40% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (129 mg, 213 μmol, 38.5% 273 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT yield, 96.2% purity in HPLC at 220 nm) as off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.82 - 7.74 (m, 2H), 7.72 - 7.65 (m, 1H), 7.59 - 7.53 (m, 2H), 7.51 - 7.42 (m, 3H), 5.15 - 5.10 (m, 1H), 4.52 - 4.36 (m, 2H), 4.35 - 4.29 (m, 1H), 4.23 - 4.04 (m, 2H), 4.01 - 3.89 (m, 1H), 3.28 - 3.26 (m, 2H), 2.89 - 2.84 (m, 2H), 2.66 - 2.57 (m, 1H), 2.54 (s, 3H), 2.42 - 2.29 (m, 1H), 2.07 - 1.95 (m, 1H). (ESI+) m/z: 471.0 (M+H)+, (C27H26N4O4). EXAMPLE 190 [0841] Synthesis of 3-(5-(4-(oxetan-3-ylmethyl)-1-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0842] A. 4,4,5,5-Tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane: 2,2,6,6-tetramethylpiperidine (8.22 g, 58.2 mmol, 9.88 mL, 1.20 eq) was dissolved in THF (100 mL) and cooled dwon to -30 °C, n-BuLi (2.5 M, 19.4 mL, 1.00 eq) was added dropwise under N2 and the reaction mixture was stirred at -30 °C for 30 min under N2. Next, the reaction was cooled dwon to -78 °C, and a solution of bis(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methane (13.0 g, 48.5 mmol, 1.00 eq) in THF (100 mL) was added dropwise under N2, After stirring for 30 min, a solution of oxetan-3-one (10.5 g, 145 mmol, 3.00 eq) in THF (100 mL) was added dropwise at -78 °C under N2. The reaction mixture was allowed to slowly warm up to 25 °C, and stirred for 10 h under N2. The reaction mixture was cooled dwon to 0 °C and aq. NH4Cl (100 mL) was added dropwise. After additional stirring for 1 h, the resulting mixture was filtered and the solvent was rotary evaporated. H2O (300 mL) was added to the obtained residue, and the aqueous layer was extracted with ethyl acetate (3 x 400 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give title compound (11.0 g, crude) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 5.39 - 5.33 (m, 2H), 5.29 - 5.24 (m, 2H), 5.21 - 5.16 (m, 1H), 1.25 (s, 12H). (ESI+) m/z: 197.1 (M+H)+, (C10H17BO3). [0843] B. 4-(Oxetan-3-ylidenemethyl)-1-phenyl-1H-imidazole: To a solution of 4,4,5,5- tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane (2.11 g, 10.7 mmol, 3.00 eq) and 4-bromo-1-phenyl-1H-imidazole (1.00 g, 3.59 mmol, 1.00 eq) in dioxane (12.0 mL) and H2O (3.00 mL) was added Pd(dtbpf)Cl2 (233 mg, 358 μmol, 0.10 eq) and K3PO4 (2.28 g, 10.7 274 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mmol, 3.00 eq) under N2. The reaction mixture was stirred at 65 °C for 16 h under N2. The reaction mixture was filtered and concentrated in vacuum to give a residue.The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 50: 1 to 1: 1; TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.40) to give the title compound (720 mg, 3.36 mmol, 93.6% yield) as a off-white solid.1H NMR: (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.52 - 7.46 (m, 2H), 7.42 - 7.33 (m, 3H), 7.04 (s, 1H), 6.14 - 6.07 (m, 1H), 5.65 - 5.59 (m, 2H), 5.42 - 5.35 (m, 2H). (ESI+) m/z: 213.0 (M+H)+, (C13H12N2O). [0844] C. 4-(Oxetan-3-ylmethyl)-1-phenyl-1H-imidazole: To a solution of 4-(oxetan-3- ylidenemethyl)-1-phenyl-imidazole (720 mg, 3.39 mmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (144 mg, 135 μmol, 10.0% purity, 0.05 eq) under N2. The reaction mixture was degassed and purged with N2 for 3 times, then degassed and purged with H2 for 3 times. The reaction mixture was warmed to 25 °C and stirred at 15 psi under H2 for 5 h. The reaction mixture was filtered through diatomite. The filtrate was concentrated in vacuum to give the title compound (770 mg, crude) as a light yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.52 - 7.45 (m, 2H), 7.41 - 7.33 (m, 3H), 7.01 (s, 1H), 4.90 - 4.84 (m, 2H), 4.56 - 4.50 (m, 2H), 3.47 - 3.37 (m, 1H), 3.09 - 3.00 (m, 2H). (ESI+) m/z: 215.0 (M+H)+, (C13H14N2O). [0845] D. 2-Bromo-4-(oxetan-3-ylmethyl)-1-phenyl-1H-imidazole: To a solution of 4- (oxetan-3-ylmethyl)-1-phenyl-1H-imidazole (270 mg, 1.26 mmol, 1.00 eq) in THF (5.00 mL) was added dropwise n-BuLi (2.5 M, 756 μL, 1.50 eq) at -78 °C under N2, the reaction mixture was stirred at -78 °C for 30 min. Then 1,2-dibromo-1,1,2,2-tetrafluoroethane (65.5 mg, 252 μmol, 0.20 eq) in THF (3.00 mL) was added to mixture dropwise at -78 °C. The reaction mixture was stirred at 25 °C for 16 h. To the mixture was added NH4Cl (8.00 mL) at 0 °C under N2, then extracted with ethyl acetate (3 x 20.0 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (450 mg, crude) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.58 - 7.49 (m, 3H), 7.47 - 7.41 (m, 2H), 7.32 (s, 1H), 4.74 - 4.62 (m, 2H), 4.42 - 4.27 (m, 2H), 3.26 - 3.21 (m, 1H), 2.87 - 2.81 (m, 2H). (ESI+) m/z: 295.0 (M+H)+, (C13H13BrN2O). [0846] E. 3-(5-(4-(Oxetan-3-ylmethyl)-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-4-(oxetan-3-ylmethyl)-1-phenyl-1H- imidazole (450 mg, 1.54 mmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione (1.42 g, 3.84 mmol, 2.50 eq) in dioxane (8.00 mL) and H2O (0.40 mL) was added Ru-Phos-Pd-G3 (128 mg, 153 μmol, 0.10 eq) and K3PO4 (651 mg, 3.07 mmol, 2.00 eq) under N2, the reaction was stirred at 100 °C for 2 h under N2. The reaction was filtered and concentrated in vacuum to give the residue. The residue was 275 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 20: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.40) and preparative-HPLC (using a CD04- Welch Utimate C18 (150 x 25 x 7 μm) and gradient of 8 - 38% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (19.4 mg, 39.7 μmol, 36.2% yield, 93.1% purity in HPLC at 220 nm) as off-white solid.1H NMR: (400 MHz, MeOD) δ 7.72 - 7.66 (m, 1H), 7.58 (s, 1H), 7.49 - 7.38 (m, 4H), 7.31 - 7.25 (m, 2H), 7.23 (s, 1H), 5.21 - 5.08 (m, 1H), 4.91 - 4.89 (m, 2H), 4.60 - 4.51 (m, 2H), 4.50 - 4.36 (m, 2H), 3.52 - 3.40 (m, 1H), 3.10 - 3.00 (m, 2H), 2.92 - 2.83 (m, 1H), 2.82 - 2.71 (m, 1H), 2.54 - 2.40 (m, 1H), 2.21 - 2.11 (m, 1H). (ESI+) m/z: 457.2 (M+H)+, (C26H24N4O4). EXAMPLES 191-192 [0847] The compounds of Example 191-192 were prepared according to Examples 100- 111. EXAMPLES 193-195 [0848] The compounds of Examples 193-195 were prepared according to Examples 131- 137. 276 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 196-203 [0849] The compounds of Examples 196-203 were prepared according to Examples 157- 178. 277 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 278 1103861084\1\AMERICAS
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ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 204-246 [0850] The compounds of examples 204-246 were prepared according to the following synthetic scheme: [0851] Experimental Procedure [0852] Step 1: [0853] To a vial containing a solution of 0023_A001 (69.4 mg, 150 µmol, 1.00 eq) and 0023_Bi (180 µmol, 1.20 eq) in Dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 µmol, 2.00 eq), Pd-118 (15.0 µmol, 0.10 eq) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas, then diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under nitrogen gas to give crude intermediates used for next step. (Note: For some compounds need do reduction, we purified intermediates by prep- HPLC.) [0854] Step 2 (BBs with double bond): To a solution of 0023_A001Bi_1 (150 µmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq, 50% in H2O) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. Spot checked by LCMS. The reaction mixture was concentrated under nitrogen gas to give crude intermediates used for next step. 281 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0855] Step 3: [0856] Condition 1: To a vial containing a solution of 0023_A001Bi_1 (~150 µmol, 1.00 eq) in CH3CN (1.00 mL) was added TsOH·H2O (1.20 mmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. [0857] Condition 2: To a vial containing a solution of 0023_A001Bi_1 (~150 µmol, 1.00 eq) in CH3CN (1.00 mL) was added H2SO4 (con.) (200 µL). The mixture was stirred at 65 °C for 1 hr. Spot checked by LCMS. The residue was concentrated under nitrogen gas and purified by prep-HPLC to give final product. 282 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 283 1103861084\1\AMERICAS
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ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 247 [0858] Synthesis of 3-(5-(2-(oxetan-3-ylmethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: [0859] A. 4,4,5,5-Tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane: 2,2,6,6-tetramethylpiperidine (8.22 g, 58.2 mmol, 9.88 mL, 1.20 eq) was dissolved in THF (100 mL) and cooled dwon to -30 °C, n-BuLi (2.5 M, 19.4 mL, 1.00 eq) was added dropwise under N2 and the reaction mixture was stirred at -30 °C for 30 min under N2. Next, the reaction was cooled dwon to -78 °C, and a solution of bis(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methane (13.0 g, 48.5 mmol, 1.00 eq) in THF (100 mL) was added dropwise under N2, After stirring for 30 min, a solution of oxetan-3-one (10.5 g, 145 mmol, 3.00 eq) in THF (100 mL) was added dropwise at -78 °C under N2. The reaction mixture was allowed to slowly warm up to 25 °C, and stirred for 10 h under N2. The reaction mixture was cooled dwon to 0 °C and aq. NH4Cl (100 mL) was added dropwise. After additional stirring for 1 h, the resulting mixture was filtered and the solvent was rotary evaporated. H2O (300 mL) was added to the obtained residue, and the aqueous layer was extracted with ethyl acetate (3 x 400 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give title compound (11.0 g, crude) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 5.39 - 5.33 (m, 2H), 5.29 - 5.24 (m, 2H), 5.21 - 5.16 (m, 1H), 1.25 (s, 12H). (ESI+) m/z: 197.1 (M+H)+, (C10H17BO3). [0860] B. 2-(Oxetan-3-ylidenemethyl)-5-phenyloxazole: To a solution of 4,4,5,5- tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane (1.05 g, 5.36 mmol, 1.20 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added 2-bromo-5-phenyl-oxazole (1.00 g, 4.46 mmol, 1.00 eq) ,di-tert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (290 mg, 446 μmol, 0.10 eq) and K3PO4 (2.84 g, 13.3 mmol, 3.00 eq) at 25 °C. The mixture was stirred at 65°C for 12 h. The mixture was poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3) to collect the organic layers. The combined organic layers was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 297 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 30/1 to 7/1, TLC: Petroleum ether/Ethyl acetate = 3/1, Rf = 0.20) to give the title compound (450 mg, 1.87 mmol, 41.8% yield, 88.4% purity in LCMS at 220 nm) as a gray solid. (ESI+) m/z: 214.1 (M+H)+ (C13H11NO2). [0861] C. 2-(Oxetan-3-ylmethyl)-5-phenyloxazole: To a solution of 2-(oxetan-3- ylidenemethyl)-5-phenyl-oxazole (350 mg, 1.45 mmol, 1.00 eq) in MeOH (3.00 mL) and EtOAc (3.00 mL) was added Pd/C (30.9 mg, 29.0 μmol, 10.0% purity, 0.02 eq) under N2 at 25 °C. Degassed under vacuum and purged with H2 three times. The mixture was stirred at 25 °C under H2 (15 Psi) for 5 h. The mixture was filtered through celite and the filter cake was washed with MeOH (300 mL x 2) . The filtrate was concentrated under vacuum to give the title compound (250 mg, 1.16 mmol, 70.7% yield, 88.4% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 216.1 (M+H)+, (C13H13NO2). [0862] D. 4-Bromo-2-(oxetan-3-ylmethyl)-5-phenyloxazole: To a solution of 2-(oxetan- 3-ylmethyl)-5-phenyl-oxazole (100 mg, 464 μmol, 1.00 eq) in DMF (5.00 mL) was added NBS (74.4 mg, 418 μmol, 0.90 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (2 x 10.0 mL) to collect the organic layers. The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by Preparative-TLC (Petroleum ether/Ethyl acetate = 2/1, Rf = 0.26) to give the title compound (42.0 mg, 139 μmol, 29.9% yield, 97.4% purity in LCMS at 220 nm) as a colorless gum.1H NMR: (400 MHz,CDCl3) δ7.91 - 7.87 (m, 2H), 7.47 - 7.38 (m, 3H), 4.93 (t, J = 6.4 Hz, 2H), 4.55 (t, J = 6.4 Hz, 2H), 3.50 - 3.55 (m, 1H), 3.24 - 3.22 (m, 2H). (ESI+) m/z: 294.2 (M+H)+, (C13H12NO2Br). [0863] E. 3-(5-(2-(Oxetan-3-ylmethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(oxetan-3-ylmethyl)-5-phenyl-oxazole (40.0 mg, 135 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (100 mg, 271 μmol, 2.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added RuPhos Pd G3 (11.3 mg, 13.6 μmol, 0.10 eq) and K3PO4 (57.7 mg, 271 μmol, 2.00 eq) at 25 °C under N2. The mixture was stirred for 3 h at 100 °C under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 30/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.31) to get a residue. The residue was purified by Preparative-HPLC (using a CD07- Daisogel SP-100-8-ODS-PK (150 mm x 25 mm x 10 μm) and gradient of 22 - 52% acetonitrile in water containing 0.05% NH4HCO3 over 15 min at a flow rate of 25 mL/min) to 298 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT give the title compound (33.8 mg, 73.9 μmol, 54.3% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.79 (s,1H), 7.75 - 7.65 (m, 1H), 7.34 - 7.28 (m, 1H), 7.55 - 7.44 (m, 5H), 5.14 - 5.09 (m, 1H), 4.78 - 4.75 (m, 2H), 4.45 - 4.25 (m, 4H), 3.52 - 3.49 (m, 1H), 2.26 (d, J = 7.6 Hz, 2H), 2.96 - 2.94 (m, 1H), 2.62 - 2.61 (m, 1H), 2.39 - 2.32 (m, 1H), 2.03 - 1.99 (m, 1H). (ESI+) m/z: 458.5 (M+H)+, (C26H23N3O5). EXAMPLE 248 [0864] Synthesis of 3-(4-fluoro-5-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0865] A. Methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate: To a solution of methyl 4-bromo-3-fluoro-2-methyl-benzoate (2.00 g, 8.10 mmol, 1.00 eq) in DCE (20.0 mL) was added NBS (1.73 g, 9.71 mmol, 1.20 eq) and AIBN (132 mg, 809 μmol, 0.10 eq). Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate =1/0 to 100/2, Rf = 0.50) to give the title compound (2.50 g, 7.67 mmol, 94.7% yield) as an off-white solid.1H NMR: (400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 5.01 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0866] B. 3-(5-Bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (1.26 g, 7.67 mmol, 1.00 eq, HCl) in ACN (50.0 mL) was added DIEA (2.48 g, 19.1 mmol, 3.34 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-3-fluoro-benzoate (2.50 g, 7.67 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was cooled down to 25 °C and filtered. The filter cake was washed with water (3 x 50.0 mL), ACN (3 x 50.0 mL), n-hexane (3 x 50.0 mL) and dried in vacuum to give the title compound (1.70 g, 4.98 mmol, 64.9% yield, 100% purity in LCMS at 220 nm) as a blue solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.90 - 7.84 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.2, 4.8 Hz, 1H), 4.53 (dd, J = 66.8, 17.6 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.64 - 2.57 (m, 1H), 2.47 - 2.37 (m, 1H), 2.05 - 1.96 (m, 1H). (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). 299 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0867] C. 1-Methyl-5-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole: To a solution of 4-bromo-1-methyl-5-phenyl-pyrazole (500 mg, 2.11 mmol, 1.00 eq) in dioxane (10.0 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.81 g, 14.1 mmol, 6.70 eq), TEA (533 mg, 5.27 mmol, 2.50 eq), Pd(CN)2Cl2 (27.3 mg, 105 μmol, 0.05) and Sphos (86.5 mg, 210 μmol, 0.10 eq) under N2, then the mixture was stirred at 80 °C for 16 h under N2. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 20/1; TLC, Petroleum ether/Ethyl acetate = 5/1, Rf = 0.40) to give the title compound (940 mg, crude) as a light yellow oil. (ESI+) m/z: 284.8 (M+H)+, (C16H21BN2O2). [0868] D. 3-(4-Fluoro-5-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 1-methyl-5-phenyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (312 mg, 1.10 mmol, 2.50 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added 3-(5-bromo-4-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (150 mg, 439 μmol, 1.00 eq), K3PO4 (186 mg, 879 μmol, 2.00 eq) and Pd(dtbpf)Cl2 (28.6 mg, 43.9 μmol, 0.10 eq) under N2, then the mixture was stirred at 80 °C for 4 h under N2. The mixture was filtered through a pad of celite, the filter cake was washed with ethyl acetate (3 x 20.0 mL), the filtrate was concentrated in vacuum to give residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100: 1 to 0/1; TLC, Petroleum ether/Ethyl acetate = 0/1, Rf = 0.50) and preparative-HPLC (using a CD05- Phenomenex luna C18 (150 x 40 mm x 10 μm) and gradient of 18 - 48% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 75.0 mL/min) to give the title compound (139 mg, 332 μmol, 75.7% yield, 99.7% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.78 (s, 1H), 7.47 - 7.46 (m, 3H), 7.41 (d, J = 7.6 Hz, 1H), 7.37 - 7.35 (m, 2H), 7.17 - 7.16 (m, 1H), 5.11 - 5.06 (m, 1H), 4.52 - 4.30 (m, 2H), 3.78 (s, 3H), 2.91 - 2.85 (m, 1H), 2.60 - 2.56 (m, 1H), 2.43 - 2.38 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 419.2 (M+H)+, (C23H19FN4O3). 300 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 249-262 [0869] The compounds of Examples 249-262 were prepared according to Examples 100- 111. 301 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 302 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 263 [0870] The compound of Example 263 was prepared according to Examples 131-137. EXAMPLES 264-280 [0871] The compounds of Examples 264-280 were prepared according to Examples 157- 178. 303 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 304 1103861084\1\AMERICAS
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ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 281-291 [0872] The compounds of Examples 281-291 were prepared according to Examples 204- 246. 310 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 311 1103861084\1\AMERICAS
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ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 292 [0873] Synthesis of 3-(6-fluoro-5-(1-isopropyl-5-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0874] A. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0875] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0876] C. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf 315 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0877] D. 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0878] E. 3-Iodo-1-isopropyl-5-phenyl-1H-pyrazole: To a solution of 3-iodo-5-phenyl- 1H-pyrazole (2.00 g, 7.41 mmol, 1.00 eq) and 2-bromopropane (1.82 g, 14.8 mmol, 2.00 eq) in DMF (20.0 mL) was added CsCO3 (4.83 g, 14.80 mmol, 2.00 eq) at 20 °C The mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered through diatomite and the filtrate was concentrated under vacuum to give a residue. The residue was purified by TLC (Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.60) to give the title compound (200 mg, 571 μmol, 7.7% yield, 89.3% purity in LCMS at 220 nm) as light yellow oil.1H NMR (400 MHz, DMSO-d6) δ.7.47 - 7.55 (m, 3H), 7.42 (d, J = 6.00 Hz, 2H), 6.51 (s, 1H), 4.52 - 4.42 (m, 1H), 1.35 (d, J=6.40 Hz, 6H). (ESI+) m/z: 313.0 (M+H)+, (C12H13IN2). [0879] F. 3-(6-Fluoro-5-(1-isopropyl-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 3-iodo-1-isopropyl-5-phenyl-1H-pyrazole (180 mg, 576 μmol, 1.00 eq) and 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (447 mg, 1.15 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (367 mg, 1.73 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (48.2 mg, 57.6 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 42.0% - 72.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (69.9 mg, 155 μmol, 27.0% yield, 99.4% purity in HPLC at 220 nm) was obtained as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.24 (d, J = 6.40 Hz, 1H), 7.67 (s, 1H), 7.47 - 7.59 (m, 5H), 6.77 (d, J = 4.00 Hz, 1H), 5.14 (m, 1H), 4.57 - 4.65 (m, 1H), 4.37 - 4.56 (m, 2H), 2.87 - 2.99 (m, 316 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 2.64 -2.59 (m, 1 H), 2.37 - 2.46 (m, 1H), 1.99 - 2.09 (m, 1H), 1.46 (d, J = 6.40 Hz, 6 H). (ESI+) m/z: 447.2 (M+H)+, (C25H23FN4O3). EXAMPLE 293 [0880] Synthesis of 3-(5-(1,4-dimethyl-5-phenyl-1H-pyrazol-3-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0881] A. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0882] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0883] C. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The 317 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0884] D. 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0885] E. 1,4-Dimethyl-5-phenyl-1H-pyrazole: A mixture of 4-bromo-1-methyl-5- phenyl-pyrazole (400 mg, 1.69 mmol, 1.00 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.12 g, 8.44 mmol, 2.36 mL, 5.00 eq), K3PO4 (1.07 g, 5.06 mmol, 3.00 eq), Pd(dppf)Cl2 (123 mg, 168 μmol, 0.10 eq) in dioxane (4.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (20.0 mL) and extracted with EA (3 x 50.0 mL).The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 3:1) (Rf= 0.40) to give the title compound (183 mg, 986 μmol, 58.5% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.48 (m, 2H), 7.47 - 7.37 (m, 3H), 7.32 (s, 1H), 3.69 (s, 3H), 1.95 (s, 3H). (ESI+) m/z: 173 (M+H)+, (C11H12N2). [0886] F. 3-Bromo-1,4-dimethyl-5-phenyl-1H-pyrazole: A mixture of 1,4-dimethyl-5- phenyl-pyrazole (150 mg, 870 μmol, 1.00 eq), NBS (162 mg, 914 μmol, 1.05 eq) in ACN (1.50 mL) was degassed and purged with N2 for 3 times at 0°C, and then the mixture was stirred at 20°C for 16 h under N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1) (Rf= 0.60) to give the title compound (129 mg, 508 μmol, 58.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.57 - 7.47 (m, 3H), 7.44 (d, J = 7.6 Hz, 2H), 3.68 (s, 3H), 1.89 (s, 3H). (ESI+) m/z: 252.9 (M+H)+, (C11H11BrN2). [0887] G. 3-(5-(1,4-Dimethyl-5-phenyl-1H-pyrazol-3-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-bromo-1,4-dimethyl-5-phenyl-pyrazole (119 mg, 318 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 473 μmol, 1.00 eq), 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (367 mg, 947 μmol, 2.00 eq), K3PO4 (201 mg, 947 μmol, 2.00 eq), Ru-Phos-Pd-G3 (39.6 mg, 47.3 μmol, 0.100 eq) in dioxane (1.20 mL) and H2O (0.060 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 h under N2 atmosphere. The reaction mixture was concentrated under vacuum. The crude product was purified by preparative-HPLC (using a CD04-Welch Utimate C18150 x 25 x 7 um) and gradient of 30%-60% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 25 mL/min) to give the title compound (35.48 mg, 81.00 μmol, 17.0% yield, 98.7% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 11.01 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.53 - 7.45 (m, 3H), 5.15 (d, J = 17.6 Hz, 1H), 4.54 - 4.34 (m, 2H), 3.80 (s, 3H), 3.00 - 2.85 (m, 1H), 2.69 - 2.57 (m, 1H), 2.44 - 2.32 (m, 1H), 2.12 - 2.00 (m, 1H), 1.94 (s, 3H). (ESI+) m/z: 433.2 (M+H)+, (C24H21FN4O3). EXAMPLE 294 [0888] Synthesis of 3-(6-fluoro-5-(2-methyl-1-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0889] A. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0890] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was 319 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0891] C. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0892] D. 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0893] E. 3-(6-Fluoro-5-(2-methyl-1-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-methyl-1-phenyl-1H-imidazole (150 mg, 617 μmol, 1.00 eq) in dioxane (3.00 mL) and H2O (0.15 mL) was added 3-(6-fluoro-1- oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (599 mg, 1.54 mmol, 2.50 eq), K3PO4 (262 mg, 1.23 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (51.6 mg, 61.7 μmol, 0.10 eq) at 20 °C, then the mixture was stirred at 100 °C for 2 h under N2. It was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 25/1, TLC: Dichloromethane/Methanol = 15/1, Rf = 0.33). The crude product was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and 320 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT gradient of 8 - 38% acetonitrile in water containing 0.05% FA over 16 min at a flow rate of 25 mL/min) to give the title compound (77.0 mg, 182 μmol, 29.6% yield, 99.3% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.32 (d, J = 6.4 Hz, 1H), 7.74 (d, J = 4.4 Hz, 1H), 7.60 - 7.56 (m, 5H), 7.53 - 7.49 (m, 1H), 5.13 (dd, J = 13.2 Hz, J = 5.6 Hz, 1H), 4.52 - 4.35 (m, 2H), 2.96 - 2.87 (m, 1H), 2.63 - 2.59 (m, 1H), 2.42 - 2.40 (m, 1H), 2.37 (s, 3H), 2.04 - 2.01 (m, 1H). (ESI+) m/z: 419.2 (M+H)+, (C23H19FN4O3). EXAMPLE 295 [0894] Synthesis of 3-(5-(4-(benzo[d]thiazol-6-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0895] A. 6-(3-Methyl-4H-1,2,4-triazol-4-yl)benzo[d]thiazole: A mixture of acetohydrazide (1.63 g, 21.9 mmol, 1.10 eq) in ACN (20.0 mL) was added DMF-DMA (2.62 g, 21.9 mmol, 2.92 mL, 1.10 eq) and purged with N2 for 3 times at 50 °C for 0.5 h, and then the mixture was added benzo[d]thiazol-6-amine (3.00 g, 19.9 mmol, 1.00 eq) and AcOH (5.00 mL) in ACN (5.00 mL), then the mixture was stirred at 120 °C for 4 h under N2 atmosphere. The reaction mixture was concentrated directly in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 1: 0 to 3: 100, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.54) to give the title compound (1.60 g, 7.31 mmol, 36.5% yield) as a red solid.1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.75 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.69 - 7.67 (m, 1H), 2.38 (s, 3H). (ESI+) m/z: 217.0 (M+H)+, (C10H8N4S). [0896] B. 6-(3-Bromo-5-methyl-4H-1,2,4-triazol-4-yl)benzo[d]thiazole: A mixture of 6-(3-methyl-4H-1,2,4-triazol-4-yl)benzo[d]thiazole (1.00 g, 4.62 mmol, 1.00 eq) in DCM (10.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was added NBS (658 mg, 3.70 mmol, 0.80 eq) in DCM (5.00 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated directly in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: 321 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Methanol = 1: 0 to 1: 80, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.48) to give the title compound (260 mg, 847 μmol, 18.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.42 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 2.27 (s, 3H). (ESI+) m/z: 295.1 (M+H)+, (C10H7BrN4S). [0897] C. 3-(5-(4-(Benzo[d]thiazol-6-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 6-(3-bromo-5-methyl-4H-1,2,4- triazol-4-yl)benzo[d]thiazole (230 mg, 779 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (721 mg, 1.95 mmol, 2.50 eq), K3PO4 (330 mg, 1.56 mmol, 2.00 eq) and RuPhos Pd G3 (65.1 mg, 77.9 μmol, 0.10 eq) degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 5 - 35% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (35.7 mg, 74.4 μmol, 9.55% yield, 95.3% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.55 (s, 1H), 8.39 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.64 - 7.58 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 5.09 - 5.05 (m, 1H), 4.44 - 4.22 (m, 2H), 2.95 - 2.82 (m, 1H), 2.61 - 2.54 (m, 1H), 2.38 - 2.31 (m, 1H), 2.30 (s, 3H), 2.03 - 1.92 (m, 1H). (ESI+) m/z: 459.1 (M+H)+, (C23H18N6O3S). EXAMPLE 296 [0898] Synthesis of 3-(5-(4-(benzofuran-5-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione [0899] A. 4-(Benzofuran-5-yl)-3-methyl-4H-1,2,4-triazole: To a solution of acetohydrazide (556 mg, 7.51 mmol, 1.00 eq) and DMF-DMA (894 mg, 7.51 mmol, 997 μL, 1.00 eq) in ACN (20.0 mL). The mixture was stirred at 50 °C for 30 min. Then a solution of AcOH (1.75 g, 29.1 mmol, 1.67 mL, 3.88 eq) and benzofuran-5-amine (1.00 g, 7.51 mmol, 322 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1.00 eq) in ACN (5.00 mL) was added into the mixture. Then the mixture was stirred at 120 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane : Methanol=50/1 to 10/1, Rf = 0.35) to give the title compound (230 mg, 1.15 mmol, 15.2% yield, 99.3% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.82 - 7.78 (m, 2H), 7.43 - 7.41 (m, 1H), 7.06 (s, 1H), 2.32 (s, 3H). (ESI+) m/z: 119.2 (M+H)+ (C11H9N3O). [0900] B. 4-(Benzofuran-5-yl)-3-bromo-5-methyl-4H-1,2,4-triazole: To a solutiono f 4- (benzofuran-5-yl)-3-methyl-1,2,4-triazole (1.00 g, 5.02 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (893 mg, 5.02 mmol, 1.00 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (10.0 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by Preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradiente of 0 - 30% acetonitrile in water containing 0.05% FA over 4 min at a flow rate of 25 mL/min) to give the title compound (200 mg, 682 μmol, 13.6% yield, 94.9% purity in LCMS at 220 nm) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.84 - 7.82 (m, 2H), 7.42 -7.39 (m, 1H), 7.12 (s, 1H), 2.23 (s, 3H). (ESI+) m/z: 278 (M+H)+ (C11H8BrN3O). [0901] C. 3-(5-(4-(Benzofuran-5-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To as solutuon of 4-(benzofuran-5-yl)-3-bromo-5-methyl-1,2,4- triazole (200 mg, 682 μmol, 1.00 eq), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (303 mg, 818 μmol, 1.20 eq) and K3PO4 (434 mg, 2.05 mmol, 3.00 eq) in DMF (3.00 mL) was added RuPhos Pd G3 (57.0 mg, 68.2 μmol, 0.10 eq) under N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into H2O (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by Preparative- HPLC (using a CD05-Phenomenex luna C18 (150 mm x 40 mm x 10 μm) and gradiente of 5 - 35% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (16.0 mg, 34.3 μmol, 5.03% yield, 94.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.15 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.67 (s, 1H), 7.62 (d, J = 8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 5.09 - 5.04 (m, 1H), 4.42 - 4.22 (m, 2H), 2.89 - 2.85 (m, 1H), 2.60 - 2.59 (m, 1H), 2.33 - 2.32 (m, 1H), 2.25 (s, 3H), 2.10 - 1.95 (m, 1H). (ESI+) m/z: 442.1 (M+H)+, (C24H19N5O4). 323 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 297 [0902] Synthesis of 3-(5-(7-benzyl-2-hydroxy-7-azaspiro[3.5]nonan-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0903] A. 2-((3,3-Difluorocyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane: 2,2,6,6-tetramethylpiperidine (3.16 g, 22.3 mmol, 3.80 mL, 1.20 eq) was dissolved in THF (35.0 mL) and cooled to -30 °C under N2 atmosphere. n-BuLi (2.50 M, 8.96 mL, 1.20 eq) was added dropwise, and the reaction mixture was stirred at -30 °C for 30 min. Next, the reaction was cooled to -78 °C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (5.00 g, 18.6 mmol, 1.00 eq) in THF (35.0 mL) was added dropwise. After stirring for 30 min, a solution of 3,3- difluorocyclobutanone (3.96 g, 37.3 mmol, 2.00 eq) in THF (70.0 mL) was added dropwise at -78 °C. The reaction mixture was allowed to slowly warm up to 25°C and stirred for 12 h under N2 atmosphere. Then the mixture was cooled to 0 °C, and aq. NH4Cl (150 mL) was added dropwise under N2 atmosphere. The mixture was extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 10: 1, Rf = 0.60 (Petroleum ether: EtOAc = 10: 1)) to give the title compound (2.00 g, crude) as colorless oil. (ESI+) m/z: 231.0 (M+H)+, (C11H17BO2F2). [0904] B. 4-((3,3-Difluorocyclobutylidene)methyl)-1-phenyl-1H-imidazole: A mixture of 4-bromo-1-phenyl-1H-imidazole (1.00 g, 4.48 mmol, 1.00 eq) in dioxane (20.0 mL) and H2O (5.00 mL) was added 2-((3,3-difluorocyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.24 g, 5.38 mmol, 1.20 eq), K3PO4 (2.85 g, 13.5 mmol, 3.00 eq) and Pd(dtbpf)Cl2, (292 mg, 448 μmol, 0.10 eq) under N2. The mixture was stirred at 65 °C for 16 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1, Rf = 0.30 (Petroleum ether: Ethyl acetate = 3:1)) to give the title compound (0.17 g, 676 μmol, 16.5% yield, 98% 324 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT purity)) as colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.57 - 7.46 (m, 2H), 7.45 - 7.35 (m, 3H), 7.18 - 7.05 (m, 1H), 6.45 (s, 1H), 3.66 - 3.33 (m, 4H). (ESI+) m/z: 247.1 (M+H)+, (C14H12F2N2). [0905] C. 4-((3,3-Difluorocyclobutyl)methyl)-1-phenyl-1H-imidazole: A mixture of 4- [(3,3-difluorocyclobutylidene)methyl]-1-phenyl-imidazole (150 mg, 624 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (65.4 mg, 61.5 μmol, 10% purity, 0.10 eq) under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The mixture was filtered with 50.0 mL EtOH and then concentrated under vacuum to give the title compound (135 mg, 558 μmol, 91.3% yield, 98% purity) as a yellow oil. (ESI+) m/z: 249.0 (M+H)+, (C14H14F2N2). [0906] D. 2-Bromo-4-((3,3-difluorocyclobutyl)methyl)-1-phenyl-1H-imidazole: A mixture of 4-((3,3-difluorocyclobutyl)methyl)-1-phenyl-1H-imidazole (100 mg, 402 μmol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.5 M, 241 μL, 1.50 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. Then a solution of 1,2-dibromo-1,1,2,2- tetrafluoroethane (126 mg, 483 μmol, 1.20 eq) in THF (1.00 mL) was added into the mixture at -78 °C under N2. The mixture was stirred at -78°C for 2 h under N2. After the reaction was completed, the mixture was poured into H2O (20.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with brine (3 x 30.0 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (50.0 mg, 137 μmol, 48.7% yield, 90% purity) as a yellow oil. (400 MHz, CDCl3) δ 10.99 (s, 1H), 7.56 - 7.44 (m, 3H), 7.40 - 7.32 (m, 2H), 2.79 (d, J = 7.6 Hz, 2H), 2.76 - 2.65 (m, 2H), 2.62 - 2.50 (m, 1H), 2.38 - 2.23 (m, 2H). (ESI+) m/z: 328.9 (M+H)+, (C14H13F2N2Br). [0907] E. 3-(5-(4-((3,3-Difluorocyclobutyl)methyl)-1-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 2-bromo-4-((3,3- difluorocyclobutyl)methyl)-1-phenyl-1H-imidazole (50.0 mg, 152 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.20 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (141 mg, 382 μmol, 2.50 eq), K3PO4 (97.3 mg, 458 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (9.96 mg, 15.2 μmol, 0.10 eq) under N2. The mixture was stirred at 100°C for 2 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum. The crude product was pre- purified by column chromatography followed by preparative-HPLC (using a CD04-Welch Utimate C18150 x 25 x 7 um and gradient of 15 - 45% acetonitrile in water containing 0.5% TFA over 10 min) to give the title compound (29.4 mg, 59.8 μmol, 39.1% yield, 99.8% purity 325 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.76 - 7.69 (m, 1H), 7.68 - 7.62 (m, 2H), 7.51 (s, 3H), 7.44 - 7.35 (m, 3H), 5.11 (dd, J = 4.4, 12.8 Hz, 1H), 4.47 - 4.24 (m, 2H), 2.88 (d, J = 8.0 Hz, 3H), 2.83 - 2.71 (m, 2H), 2.62 - 2.56 (m, 1H), 2.45 (d, J = 1.6 Hz, 1H), 2.44 - 2.31 (m, 3H), 2.05 - 1.96 (m, 1H). (ESI+) m/z: 491.2 (M+H)+, (C27H24O3N4F2). EXAMPLE 298 [0908] Synthesis of 3-[5-(1-cyclopropyl-5-phenyl-pyrazol-3-yl)-6-fluoro-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: [0909] A. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0910] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0911] C. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) 326 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0912] D. 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0913] E. 3-[5-(1-Cyclopropyl-5-phenyl-pyrazol-3-yl)-6-fluoro-1-oxo-isoindolin-2- yl]piperidine-2,6-dione: To a solution of 1-cyclopropyl-3-iodo-5-phenyl-pyrazole (200 mg, 644 μmol, 1.00 eq) in dioxane (4.00 mL) was added H2O (0.20 mL), 3-[6-fluoro-1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (625 mg, 1.61 mmol, 2.50 eq), K3PO4 (410 mg, 1.93 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (107 mg, 128 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 35 - 65% acetonitrile in water containing 0.5% FA over 10 min at a flow rate of 25.0 mL/min) to give the title compound (44.0 mg, 97.0 μmol, 15.0% yield, 98% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 9.6 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.49 (m, 1H), 6.88 (d, J = 4.0 Hz, 1H), 5.14 (dd, J = 13.2, 5.2 Hz, 1H), 4.55 - 4.34 (dd, J = 25.2, 8.8 Hz, 2H), 3.90 - 3.82 (m, 1H), 2.97 - 2.86 (m, 1H), 2.63 (m, 1H), 2.41 (m, 1H), 2.09 - 1.99 (m, 1H), 1.08 (d, J = 3.6 Hz, 2H), 1.01 (d, J = 6.8 Hz, 2H). (ESI+) m/z: 445.0 (M+H)+, (C25H21FN4O3). 327 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 299 [0914] Synthesis of 3-(6-fluoro-5-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0915] A. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0916] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0917] C. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf 328 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0918] D. 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0919] E. 3-(6-Fluoro-5-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-5-phenyl-pyrazole (100 mg, 421 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-[6-fluoro-1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (327 mg, 843 μmol, 2.00 eq), K3PO4 (179 mg, 843 μmol, 2.00 eq) and Pd(dtbpf)Cl2 (27.5 mg, 42.2 μmol, 0.10 eq) under N2.The mixture was stirred at 80 °C for 2 h under N2. The mixture was filtered through a pad of celite, the filter cake was washed with DCM (3 x 20.0 mL), the filtrate was concentrated in vacuum to give residue. The residue was purified by preparative- HPLC (using a CD04-Welch Utimate C18 (150 x 25 mm x 7 μm) and gradient of 22 - 52% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 30.0 mL/min) to give the title compound (91.3 mg, 216 μmol, 51.6% yield, 99.3% purity in HPLC at 220 nm) as brown solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.76 (s, 1H), 7.47 - 7.45 (m, 4H), 7.34 - 7.33 (m, 3H), 5.10 - 5.05 (m, 1H), 4.34 - 4.16 (m, 2H), 3.79 (s, 3H), 2.93 - 2.84 (m, 1H), 2.59 - 2.55 (m, 1H), 2.37 - 2.33 (m, 1H), 1.99 - 1.96 (m, 1H). (ESI+) m/z: 419.0 (M+H)+, (C23H19FN4O3). 329 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 300 [0920] Synthesis of 3-(5-(5-(4-((dimethylamino)methyl)phenyl)-1-methyl-1H-pyrazol- 4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0921] A. 5-Bromo-4-iodo-1-methyl-1H-pyrazole: To a solution of 4-iodo-1-methyl-1H- pyrazole (4.00 g, 19.2 mmol, 1.00 eq) in THF (30.0 mL) was added LDA (2 M, 10.5 mL, 1.10 eq) dropwise at -70 °C under N2, the mixture was stirred at -70 °C for 30 min. Then CBr4 (7.65 g, 23.0 mmol, 1.20 eq) in THF (20.0 mL) was added dropwise. The reaction mixture was stirred at -70 °C for 1 h. The mixture was quenched with NH4Cl (80.0 mL), extracted with ethyl acetate (3 x 100 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 9: 1; TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.50) to give the title compound (3.00 g, 10.4 mmol, 54.3% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 3.89 (s, 3H). (ESI+) m/z: 257.1 (M+H)+, (C4H4BrIN2). [0922] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0923] C. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified 330 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0924] D. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0925] E. Preparation of 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0926] F. 3-(5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-4-iodo-1-methyl-1H-pyrazole (300 mg, 1.05 mmol, 1.00 eq), 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (487 mg, 1.25 mmol, 1.20 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added K3PO4 (443 mg, 2.09 mmol, 2.00 eq), Pd(dppf)Cl2 (76.5 mg, 104 μmol, 0.10 eq) under N2. The reaction was stirred at 60 °C for 2 h under N2. The reaction was filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Methanol: Dichloromethane = 100: 0 to 80: 1; TLC: Methanol: Dichloromethane = 20: 1, Rf = 0.40) to give the title compound (180 mg, 427 μmol, 24.3% yield) was obtained as a yellow solid. (ESI+) m/z: 421.0 (M+H)+, (C17H14BrFN4O3). 331 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0927] G. 3-(5-(5-(4-((Dimethylamino)methyl)phenyl)-1-methyl-1H-pyrazol-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(5-bromo-1- methyl-pyrazol-4-yl)-6-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (65.0 mg, 154 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added N,N-dimethyl-1-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (80.6 mg, 308 μmol, 2.00 eq), Pd(dtbpf)Cl2 (10.1 mg, 15.4 μmol, 0.10 eq) and K3PO4 (65.5 mg, 308 μmol, 2.00 eq) under N2, the reaction was stirred at 65 °C for 16 h under N2. The mixture was filtered through a pad of celite. The filter cake was washed with EtOAc (3 x 20.0 mL), the filtrate was concentrated to give residue. The residue was purified by preparative-HPLC (using a CD20-Waters Xbidge BEH C18 (250 mm x 25 mm x 10 μm) and gradient of 11 - 45% acetonitrile in water containing 0.05% NH4HCO3 over 10 min at a flow rate of 30.0 mL/min) to give the title compound (27.4 mg, 56.2 μmol, 36.9% yield, 97.6% purity in HPLC at 220 nm) as off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 4.0 Hz, 1H), 7.45 (d, J = 12.0 Hz, 1H), 7.37 - 7.35 (m, 2H), 7.32 - 7.30 (m, 1H), 7.29 - 7.27 (m, 2H), 5.10 - 5.05 (m, 1H), 4.32 - 4.15 (m, 2H), 3.78 (s, 3H), 3.41 (s, 2H), 2.93 - 2.84 (m, 1H), 2.59 - 2.54 (m, 1H), 2.40 - 2.30 (m, 1H), 2.14 (s, 6H), 2.01 - 1.96 (m, 1H). (ESI+) m/z: 476.2 (M+H)+, (C26H26FN5O3). EXAMPLE 301 [0928] Synthesis of 3-(5-(5-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-1-methyl-1H- pyrazol-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0929] A. 5-Bromo-4-iodo-1-methyl-1H-pyrazole: To a solution of 4-iodo-1-methyl-1H- pyrazole (4.00 g, 19.2 mmol, 1.00 eq) in THF (30.0 mL) was added LDA (2 M, 10.5 mL, 1.10 eq) dropwise at -70 °C under N2, the mixture was stirred at -70 °C for 30 min under N2. Then CBr4 (7.65 g, 23.0 mmol, 1.20 eq) in THF (20.0 mL) was added dropwise. The reaction mixture was stirred at -70 °C for 1 h under N2. The mixture was quenched with NH4Cl (80.0 mL), extracted with ethyl acetate (3 x 100 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column 332 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 9: 1; TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.50) to give the title compound (3.00 g, 10.4 mmol, 54.3% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 3.89 (s, 3H). (ESI+) m/z: 257.1 (M+H)+, (C4H4BrIN2). [0930] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [0931] C. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc =1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0932] D. 3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0933] E. 3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 333 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0934] F. 3-(5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-4-iodo-1-methyl-1H-pyrazole (300 mg, 1.05 mmol, 1.00 eq), 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (487 mg, 1.25 mmol, 1.20 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added K3PO4 (443 mg, 2.09 mmol, 2.00 eq), Pd(dppf)Cl2 (76.5 mg, 104 μmol, 0.10 eq) under N2. The reaction was stirred at 60 °C for 2 h under N2. The reaction was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Methanol: Dichloromethane = 100: 0 to 80: 1; TLC: Methanol: Dichloromethane = 20: 1, Rf = 0.40) to give the title compound (180 mg, 427 μmol, 20.4% yield) as a yellow solid. (ESI+) m/z: 421.0 (M+H)+, (C17H14BrFN4O3). [0935] G. 3-(5-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-methyl-1H-pyrazol-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1- methyl-1H-pyrazol-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 196 μmol, 1.00 eq), (2,2-difluorobenzo[d][1,3]dioxol-5-yl)boronic acid (47.6 mg, 235 μmol, 1.20 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added Pd(dtbpf)Cl2 (12.8 mg, 19.6 μmol, 0.10 eq), K3PO4 (125 mg, 589 μmol, 3.00 eq) under N2. The reaction was stirred at 65 °C for 16 h under N2. The reaction was filtered and concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a CD04-Welch Utimate C18 (150 x 25 x 7 μm) and gradient of 28 - 58% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (40.2 mg, 80.3 μmol, 40.8% yield, 99.6% purity in HPLC at 220 nm) as off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.80 - 7.74 (m, 1H), 7.63 - 7.57 (m, 1H), 7.53 - 7.45 (m, 2H), 7.43 - 7.37 (m, 1H), 7.14 - 7.08 (m, 1H), 5.13 - 5.05 (m, 1H), 4.41 - 4.18 (m, 2H), 3.80 (s, 3H), 2.96 - 2.83 (m, 1H), 2.62 - 2.55 (m, 1H), 2.42 - 2.30 (m, 1H), 2.04 - 1.94 (m, 1H). (ESI+) m/z: 499.1 (M+H)+, (C24H17F3N4O5). 334 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 302 [0936] Synthesis of 3-(5-(5-(1,1-difluoroethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0937] A. 4-Phenyl-4H-1,2,4-triazole-3-carbaldehyde: To a solution POCl3 (21.1 g, 137 mmol, 12.8 mL, 5.00 eq) in DMF (40.0 mL) at 0 °C under N2 and was stirred 2 h. Then a solution of 4-phenyl-4H-1,2,4-triazole (4.00 g, 27.5 mmol, 1.00 eq) in DMF (40.0 mL) was added into the mixture at 0°C. The mixture was stirred at 0 °C for 2 h. Then allowed warmed to 25 °C for about 12 h. The reaction mixture was quenched with H2O (200 mL). Then the mixture was diluted with Na2CO3 (200 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500:1 to 10: 1, Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (2.10 g, 11.6 mmol, 42.3% yield, 96% purity).1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 8.41 (s, 1H), 7.56 (d, J = 5.6 Hz, 3H), 7.41 - 7.30 (m, 2H). (ESI+) m/z: 174.1 (M+H)+, (C9H7ON3). [0938] B. 1-(4-Phenyl-4H-1,2,4-triazol-3-yl)ethan-1-ol: A mixture of 4-phenyl-4H- 1,2,4-triazole-3-carbaldehyde (1.90 g, 10.9 mmol, 1.00 eq) in THF (40.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was added dropwise MeMgBr (3.00 M, 7.31 mL, 2.00 eq) at -30 °C. The resulting mixture was stirred at 25°C for 2 h under N2 atmosphere. The reaction mixture was quenched with 100 mL of Saturated NH4Cl solution at 0 °C under N2 and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500: 1 to 80: 1, Dichloromethane : Methanol = 15 : 1, Rf = 0.40) to give the title compound (1.70 g, 8.63 mmol, 78.6% yield, 96% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.63 - 7.52 (m, 3H), 7.50 - 7.40 (m, 2H), 4.94 (q, J = 6.8 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). (ESI+) m/z: 190.1 (M+H)+. (C10H11ON3). 335 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0939] C. 1-(4-Phenyl-4H-1,2,4-triazol-3-yl)ethan-1-one: A mixture of 1-(4-phenyl-4H- 1,2,4-triazol-3-yl)ethan-1-ol (1.70 g, 8.98 mmol, 1.00 eq) in DCM (40.0 mL) was added MnO2 (7.81 g, 89.8 mmol, 10.0 eq) under N2. The mixture was stirred at 25°C for 12 h. The reaction mixture was filtered and concentrated in vacuum to give residue. The crude product was purified by column chromatography (SiO2, Dichloromethane : Methanol = 500:1 to 50:1, TLC: Dichloromethane : Methanol = 10:1, Rf = 0.50) to give the title compound (1.40 g, 7.10 mmol, 79.0% yield, 95.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.59 - 7.46 (m, 3H), 7.27 (s, 2H), 2.79 (s, 3H). (ESI+) m/z: 188.0 (M+H)+, (C10H9N3O). [0940] D. 3-(1,1-Difluoroethyl)-4-phenyl-4H-1,2,4-triazole: A mixture of 1-(4-phenyl- 4H-1,2,4-triazol-3-yl)ethan-1-one (1.40 g, 7.48 mmol, 1.00 eq) in TFEDMA (25.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was diluted with H2O (50.0 mL), quenched by addition NaHCO3 solution (100 mL) at 0 °C and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 500: 1 to 10: 1, Petroleum ether : Ethyl acetate = 1: 1, Rf = 0.40) to give the title compound (240 mg, 1.09 mmol, 14.5% yield, 95% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.60 - 7.49 (m, 3H), 7.41 (d, J = 6.0 Hz, 2H), 2.23 (t, J = 19.6 Hz, 3H). (ESI+) m/z: 210.0 (M+H)+, (C10H9F2N3). [0941] E. 3-Bromo-5-(1,1-difluoroethyl)-4-phenyl-4H-1,2,4-triazole: A mixture of 3- (1,1-difluoroethyl)-4-phenyl-4H-1,2,4-triazole (100 mg, 478 μmol, 1.00 eq) in ACN (5.00 mL) was added a solution of NBS (102 mg, 573 μmol, 1.20 eq) in ACN (2.00 mL) at 0°C under N2. The mixture was stirred at 25 °C for 2 h. The mixture was poured into H2O (5.00 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with brine (3 x 20.0 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate=1: 1, Rf = 0.60) to give the title compound (40.0 mg, 138 μmol, 29.0% yield, 100% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.64 - 7.51 (m, 3H), 7.31 (d, J = 7.2 Hz, 2H), 2.17 (J = 18.8 Hz, 3H). (ESI+) m/z: 289.9 (M+H)+, (C10H8BrN3F2). [0942] F. 3-(5-(5-(1,1-Difluoroethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: A mixture of 3-bromo-5-(1,1-difluoroethyl)-4-phenyl-4H-1,2,4- triazole (40.0 mg, 138 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 3- (1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione 336 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (128 mg, 347 μmol, 2.50 eq), K3PO4 (88.4 mg, 416 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (9.05 mg, 13.8 μmol, 0.10 eq) under N2. The mixture was stirred at 80°C for 2 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The product was pre-purified by preparative-HPLC (using a CD04-Welch Utimate C18150 x 25 x 7 um and gradient of 25 - 55% acetonitrile in water containing 0.5% TFA over 10 min) to give the title compound (18.77 mg, 41.5 μmol, 29.9% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.72 - 7.64 (m, 2H), 7.53 (s, 5H), 7.44 (d, J = 8.4 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.22 (m, 2H), 2.96 - 2.83 (m, 1H), 2.60 (s, 1H), 2.40 - 2.30 (m, 1H), 2.14 (t, J = 19.2 Hz, 3H), 2.05 - 1.94 (m, 1H). (ESI+) m/z: 452.1 (M+H)+, (C23H19O3N5F2). EXAMPLE 303 [0943] Synthesis of 3-(5-(4-(1H-indol-6-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0944] A. 6-(3-Methyl-4H-1,2,4-triazol-4-yl)-1H-indole: To a solution of acetohydrazide (1.68 g, 22.7 mmol, 1.00 eq) and DMF-DMA (2.70 g, 22.7 mmol, 3.02 mL, 1.00 eq) in ACN (20.0 mL). The mixture was stirred at 50 °C for 30 min. Then a solution of AcOH (5.00 mL) and 1H-indol-6-amine (3.00 g, 22.7 mmol, 1.00 eq) in ACN (5.00 mL) was added into the mixture. Then the mixture was stirred at 120 °C for 3 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100:1 to 20:1, TLC: Dichloromethane: Methanol = 20:1, Rf = 0.30) to give the title compound (2.80 g, 14.0 mmol, 62.0% yield, 99.7% purity in LCMS at 220 nm) as yellow solid.1H NMR (400 MHz, DMSO- d6) δ 11.42 (s, 1H), 8.63 (s, 1H), 7.69 (d, J = 8.40 Hz, 1H), 7.46 - 7.52 (m, 2H), 7.05 – 7.03 (m, 1 H), 6.55 (s, 1H), 2.32 (s, 3H). (ESI+) m/z: 199.0 (M+H)+, (C11H10N4). [0945] B. 6-(3-Methyl-4H-1,2,4-triazol-4-yl)-1-tosyl-1H-indole: To a solution of 6-(3- methyl-4H-1,2,4-triazol-4-yl)-1H-indole (500 mg, 2.52 mmol, 1.00 eq) in THF (10.0 mL) was added NaH (151 mg, 3.78 mmol, 60% purity, 1.50 eq) at 0 °C under N2.The mixture was 337 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT stirred at 0 °C for 20 min under N2.Then TsCl (721 mg, 3.78 mmol, 1.50 eq) was added at 0 °C under N2.The mixture was stirred at 0 °C for 3 h under N2. The reaction mixture was quenched with H2O (50.0 mL) at 0 °C under N2 and extracted with ethyl acetate (3 x 100 mL) to get the organic layers, the organic layers was washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100:1 to 20:1, TLC: Dichloromethane: Methanol = 20:1, Rf = 0.40) to give the title compound (460 mg, 1.13 mmol, 44.9% yield, 86.8% purity in LCMS at 220 nm) as brown oil.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.93 - 8.01 (m, 4H), 7.78 (d, J = 8.00 Hz, 1H), 7.34 - 7.43 (m, 3H), 6.94 (d, J = 3.60 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H). (ESI+) m/z: 353.0 (M+H)+, (C18H16N4O2S). [0946] C. 6-(3-Bromo-5-methyl-4H-1,2,4-triazol-4-yl)-1-tosyl-1H-indole: To a solution of 6-(3-methyl-4H-1,2,4-triazol-4-yl)-1-tosyl-1H-indole (440 mg, 1.25 mmol, 1.00 eq) in DCM (10.0 mL) was added NBS (244 mg, 1.37 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 25:1, Rf=0.60) to give the title compound (160 mg, 312 μmol, 25.0% yield, 84.2% purity in LCMS at 220 nm) as brown solid.1H NMR (400 MHz, DMSO- d6) δ 8.09 (s, 1H), 7.98 (d, J = 7.20 Hz, 3H), 7.80 (d, J = 8.40 Hz, 1H), 7.40 (d, J = 8.00 Hz, 2H), 7.33 (d, J = 8.00 Hz, 1H), 6.95 (d, J = 3.20 Hz, 1H), 2.32 (s, 3H), 2.19 (s, 3H). (ESI+) m/z: 432.9 (M+H)+, (C18H15BrN4O2S). [0947] D. 6-(3-Bromo-5-methyl-4H-1,2,4-triazol-4-yl)-1H-indole: To a solution of 6-(3- bromo-5-methyl-4H-1,2,4-triazol-4-yl)-1-tosyl-1H-indole (160 mg, 370 μmol, 1.00 eq) in dioxane (5.00 mL) was added NaOH (5 M, 1.48 mL, 20.0 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Dichloromethane: Methanol = 25:1, Rf = 0.40) to give the title compound (40.0 mg, 114 μmol, 30.0% yield in LCMS at 220 nm) as light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 7.72 (d, J = 8.40 Hz, 1H), 7.48 - 7.56 (m, 2H), 6.99 – 6.95 (m, 1H), 6.57 (s, 1H), 2.23 (s, 3H). (ESI+) m/z: 276.9 (M+H)+, (C11H9BrN4). [0948] E. 3-(5-(4-(1H-indol-6-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 6-(3-bromo-5-methyl-4H-1,2,4-triazol-4-yl)-1H- 338 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT indole (80.0 mg, 288 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione (320 mg, 866 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (183 mg, 866 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (24.1 mg, 28.8 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 10.0% - 40.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (10.7 mg, 23.7 μmol, 8.22% yield, 97.6% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.35 - 11.43 (m, 1H), 10.94 - 11.00 (m, 1H), 7.66 - 7.74 (m, 2H), 7.61 (d, J = 8.80 Hz, 1H), 7.44 - 7.52 (m, 2H), 7.38 (d, J = 7.60 Hz, 1H), 7.00 (d, J = 7.60 Hz, 1H), 6.55 (s, 1H), 5.04 - 5.10 (m, 1H), 4.20 - 4.42 (m, 2H), 2.81 - 2.94 (m, 1H), 2.62 - 2.69 (m, 1H), 2.33 (s, 1H), 2.27 (s, 3H), 1.92 - 2.00 (m, 1H). (ESI+) m/z: 441.1 (M+H)+, (C24H20N6O3). EXAMPLE 304 [0949] Synthesis of 3-(5-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0950] A. 3-(5-Nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of methyl 2-(bromomethyl)-4-nitrobenzoate (10.0 g, 36.4 mmol, 1.00 eq) and 3-aminopiperidine-2,6- dione (6.61 g, 40.1 mmol, 1.10 eq, HCl) in DMF (100 mL) was added K2CO3 (15.1 g, 109 mmol, 3.00 eq). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated in vacuum to give residue. To the resulting residue, water (10.0 mL) was added and the mixture stirred at 25 °C for 30 min. The resultant solid was filtered, washed with ethyl acetate (2 x 10.0 mL) and concentrated in vacuum to give the title compound (5.00 g, 17.2 mmol, 47.3% yield) as a gray solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.53 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 5.18 - 5.14 (m, 1H), 4.62 - 4.46 (m, 2H), 2.95 - 2.88 (m, 1H), 2.63 - 2.50 (m, 1H), 2.45 - 2.40 (m, 1H), 2.10 - 2.00 (m, 1H). (ESI+) m/z: 290.1 (M+H)+, (C13H11N3O5). 339 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [0951] B. 3-(5-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5- nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.00 g, 17.3 mmol, 1.00 eq) and 4-(4- pyridyl)pyridine (135 mg, 864 μmol, 0.05 eq) in THF (50.0 mL) was added hypoboric acid (4.95 g, 55.3 mmol, 3.20 eq) slowly at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered to give residue, then residue was washed with THF (3 x 10.0 mL) and concentrated in vacuum to give the title compound (3.50 g, 12.5 mmol, 90.4% yield, 92.7% purity in LCMS at 220 nm) as a gray solid. (ESI+) m/z: 260.1 (M+H)+, (C13H13N3O3). [0952] C. 3-(5-Hydrazineyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione: A solution of 3- (5-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (3.50 g, 13.5 mmol, 1.00 eq) in conc. HCl (50.0 mL) was added a solution of NaNO2 (931 mg, 13.5 mmol, 1.00 eq) in H2O (25.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then to the mixture was added solution of SnCl2•2H2O (6.09 g, 27.0 mmol, 2.00 eq) in conc. HCl (50.0 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to give the title compound (10.0 g, crude) as a black brown solid. (ESI+) m/z: 275.1 (M+H)+, (C13H14N4O3). [0953] D. 3-(5-(3-Methyl-5-phenyl-1H-pyrazol-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: A solution of 4-phenylbut-3-yn-2-one (100 mg, 693 μmol, 1.00 eq) and 3-(5- hydrazineyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (228 mg, 832 μmol, 1.20 eq) in ACN (5.00 mL) was stirred at 25 °C for 1 h. Then to the reaction mixture was added Cu(OAc)2 (12.6 mg, 69.3 μmol, 0.10 eq). The reaction mixture was stirred at 80 °C for 11 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. The product was pre-purified by preparative-HPLC (using a CD04-Welch Utimate C18150 x 25 x 7 um and gradient of 20 - 50% acetonitrile in water containing 0.5% TFA over 10 min) to give the title compound (49.52 mg, 124 μmol, 17.9% yield, 99.8% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.42 - 7.34 (m, 3H), 7.28 - 7.20 (m, 3H), 6.51 (s, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.26 (m, 2H), 2.96 - 2.84 (m, 1H), 2.63 - 2.56 (m, 1H), 2.38 (dd, J = 4.4, 13.2 Hz, 1H), 2.30 (s, 3H), 2.06 - 1.96 (m, 1H). (ESI+) m/z: 401.1 (M+H)+. (C23H20O3N4). 340 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 305 [0954] Synthesis of 3-(5-(3-ethyl-5-phenyl-1H-pyrazol-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [0955] A. 5-Phenyl-3-vinyl-1H-pyrazole: To a solution of 3-iodo-5-phenyl-1H-pyrazole (0.70 g, 2.59 mmol, 1.00 eq) in dioxane (8.00 mL) , H2O (2.00 mL) was added potassium;trifluoro(vinyl)boranuide (416 mg, 3.11 mmol, 1.20 eq) , ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (337 mg, 518 μmol, 0.20 eq), K3PO4 (1.65 g, 7.78 mmol, 3.00 eq) under N2, The mixture was stirred at 65°C for 16 h. The reaction mixture was quenched with H2O (50.0 mL) and extracted with EA (50.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=30/1 to 1/1, Rf = 0.4) to give the title compound (200 mg, 1.14 mmol, 44.1% yield, 97.4% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 13.2 - 13.0 (m, 1H), 7.80 - 7.73 (m, 2H), 7.44 - 7.41 (m, 3H), 7.28 - 6.63 (m, 2H), 5.84 - 5.80 (m, 1H), 5.35 - 5.25 (m, 1H), (ESI+) m/z: 171.1 (M+H)+, (C11H10N2). [0956] B. 3-Ethyl-5-phenyl-1H-pyrazole: To a solution of 5-phenyl-3-vinyl-1H-pyrazole (0.20 g, 1.18 mmol, 1.00 eq) in MeOH (2.00 mL) was added Pd/C (0.20 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 at 25 °C for 2h. The reaction mixture was filtrated to give a filtrate, the filtrate was concentrated to give a residue under vacuum to give the title compound (0.18 g, 967 μmol, 82.3% yield, 92.6% purity) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 13.2 - 12.5 (m, 1H), 7.5 - 7.73 (m, 2H), 7.39 - 7.34 (m, 3H), 6.46 (s, 1H), 2.64 - 2.59 (m, 2H), 1.21 (t, J = 4 Hz, 3H), (ESI+) m/z: 173.1 (M+H)+, (C11H12N2). [0957] C. 5-Amino-4-(5-(3-ethyl-5-phenyl-1H-pyrazol-1-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoic acid: To a solution of 3-ethyl-5-phenyl-1H-pyrazole (150 mg, 797 μmol, 1.00 eq) in DMF (2.00 mL), H2O (0.20 mL) was added tert-butyl 5-amino-4-(5-bromo-1-oxo- isoindolin-2-yl)-5-oxo-pentanoate (316 mg, 797 μmol, 1.00 eq) quinolin-8-ol (3.47 mg, 23.9 μmol, 4.14 μL, 0.03 eq) , CuI (4.56 mg, 23.9 μmol, 0.03 eq) , Cs2CO3 (1.04 g, 3.19 mmol, 341 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 4.00 eq) under N2, The mixture was stirred at 150°C for 2h under N2. The reaction mixture was quenched with H2O (50.0 mL) and extracted with EA (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (using a Phenomenex Luna C18 (200 x 40mm x 10μm) and gradient of 0%- 25.0% acetonitrile in water containing 0.1% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (260 mg, 330 μmol, 5.18% yield, 55% purity) was obtained as a yellow solid. (ESI+) m/z: 443.1 (M+H)+, (C24H24N4O4). [0958] D. 3-(5-(3-Ethyl-5-phenyl-1H-pyrazol-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of 5-amino-4-[5-(3-ethyl-5-phenyl-pyrazol-1-yl)-1-oxo-isoindolin- 2-yl]-5-oxo-pentanoic acid (50.0 mg, 63.59 μmol, 1.00 eq) in ACN (1 mL)was added CDI (41.2 mg, 254 μmol, 4.00 eq) , The mixture was stirred at 80°C for 2h. The reaction mixture was quenched with H2O (20.0 mL) and extracted with EA (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (using a Daisogel SP ODS RPS 150 x 25mm x 5μm and gradient of 33.0% - 63.0% acetonitrile in water containing 10 mmol/L NH4HCO3 over 10 min at a flow rate of 25 mL/min).to give the title compound (21.1 mg, 48.8 μmol, 76.8% yield, 95.7% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.76 - 7.66 (m, 2H), 7.37 - 7.24 (m, 6H), 6.65 (s, 1H), 5.12 - 5.08 (m, 1H), 4.46 - 4.28 (m, 2H), 2.95 - 2.90 (m, 1H), 2.70 - 2.61 (m, 3H), 2.40 - 2.37 (m, 1H), 2.02 - 2.01 (m, 1H), 1.27 (t, J = 4 Hz, 3H), (ESI+) m/z: 415.1 (M+H)+, (C24H22N4O3). EXAMPLE 306 [0959] Synthesis of 3-(5-(5-(4-((dimethylamino)methyl)phenyl)-1-methyl-1H-pyrazol- 4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [0960] A. Methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate: To a solution of methyl 4-bromo-3-fluoro-2-methyl-benzoate (2.00 g, 8.10 mmol, 1.00 eq) in DCE (20.0 mL) was added NBS (1.73 g, 9.71 mmol, 1.20 eq) and AIBN (132 mg, 809 μmol, 0.10 eq). Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate 342 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate =1/0 to 100/2, Rf = 0.50) to give the title compound (2.50 g, 7.67 mmol, 94.7% yield) as an off-white solid.1H NMR: (400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 5.01 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [0961] B. 3-(5-Bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (1.26 g, 7.67 mmol, 1.00 eq, HCl) in ACN (50.0 mL) was added DIEA (2.48 g, 19.1 mmol, 3.34 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-3-fluoro-benzoate (2.50 g, 7.67 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was cooled down to 25 °C and filtered. The filter cake was washed with water (3 x 50.0 mL), ACN (3 x 50.0 mL), n-hexane (3 x 50.0 mL) and dried in vacuum to give the title compound (1.70 g, 4.98 mmol, 64.9% yield, 100% purity in LCMS at 220 nm) as a blue solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.90 - 7.84 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.2, 4.8 Hz, 1H), 4.53 (dd, J = 66.8, 17.6 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.64 - 2.57 (m, 1H), 2.47 - 2.37 (m, 1H), 2.05 - 1.96 (m, 1H). (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [0962] C. 3-(4-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-4-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (500 mg, 1.45 mmol, 1.00 eq) in DMF (10.0 mL)was added BPD (1.10 g, 4.34 mmol, 3.00 eq), KOAc (426 mg, 4.34 mmol, 3.00 eq) and Pd(dppf)Cl2 (211 mg, 289 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 20.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with ethyl acetate until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (350 mg, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [0963] D. 5-Bromo-4-iodo-1-methyl-1H-pyrazole: To a solution of 4-iodo-1-methyl-1H- pyrazole (4.00 g, 19.2 mmol, 1.00 eq) in THF (30.0 mL) was added LDA (2 M, 10.5 mL, 1.10 eq) dropwise at -70 °C under N2, the mixture was stirred at -70 °C for 30 min. Then CBr4 (7.65 g, 23.0 mmol, 1.20 eq) in THF (20.0 mL) was added dropwise. The reaction mixture was stirred at -70 °C for 1 h. The mixture was quenched with NH4Cl (80.0 mL), extracted with ethyl acetate (3 x 100 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column 343 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/0 to 9/1; TLC: Petroleum ether/Ethyl acetate = 5/1, Rf = 0.50) to give the title compound (3.00 g, 10.4 mmol, 54.3% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 3.89 (s, 3H). (ESI+) m/z: 257.1 (M + H)+, (C4H4BrIN2). [0964] E. 3-(5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-4-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 5-bromo-4-iodo-1-methyl-1H-pyrazole (200 mg, 697 μmol, 1.00 eq), 3-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (324. mg, 836 μmol, 1.20 eq) in dioxane (8.00 mL), H2O (0.40 mL) was added K3PO4 (295 mg, 1.39 mmol, 2.00 eq) and Pd(dppf)Cl2 (51.0 mg, 69.7 μmol, 0.10 eq) under N2. The reaction mixture was stirred at 80 °C for 2 h under N2. The reaction was filtered and concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane/Methanol = 15/1; TLC: Dichloromethane/Methanol = 20/1, Rf = 0.50) to give the title compound (60.0 mg, 142 μmol, 20.4% yield) as a yellow solid. (ESI+) m/z: 421.0 (M +H)+, (C17H14BrFN4O3). [0965] F. 3-(5-(5-(4-((Dimethylamino)methyl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1- methyl-1H-pyrazol-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60.0 mg, 142 μmol, 1.00 eq) N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)methanamine (74.4 mg, 284 μmol, 2.00 eq) in dioxane (4.00 mL) H2O (0.20 mL) was added Pd(dtbpf)Cl2 (9.28 mg, 14.2 μmol, 0.10 eq) and K3PO4 (60.4 mg, 284 μmol, 2.00 eq) under N2. The reaction was stirred at 65 °C under N2 for 16 h. The reaction was filtered and concentrated in vacuum to give a residue. The reaction was purified by preparative- HPLC (using a CD07-Daisogel SP-100-8-ODS-PK (150 x 25 mm x 10μm) and gradient of 12 - 42% acetonitrile in water containing 0.05% NH4HCO3 over 10 min at a flow rate of 25 mL/min) to give the title compound (30.0 mg, 63.0 μmol, 14.0 % yield, 96.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.33 - 7.27 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 5.13 - 5.05 (m, 1H), 4.55 - 4.29 (m, 2H), 3.78 (s, 3H), 3.42 (s, 2H), 2.97 - 2.83 (m, 1H), 2.61 - 2.56 (m, 1H), 2.44 - 2.38 (m, 1H), 2.15 (s, 6H), 2.03 - 1.94 (m, 1H). (ESI+) m/z: 476.1 (M+H)+, (C26H26FN5O3). 344 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 307 [0966] Synthesis of 3-(5-(5-(1H-indol-6-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0967] A. tert-Butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a suspension of tert-butyl 4,5-diamino-5-oxo-pentanoate (10.0 g, 41.8 mmol, 1.00 eq, HCl) in ACN (120 mL) at 0 °C was added DIEA (19.3 g, 149 mmol, 26.0 mL, 3.57 eq). After stirring for 15 min, the reaction mixture was treated with methyl 4-bromo-2-(bromomethyl)benzoate (14.8 g, 48.1 mmol, 1.15 eq) as a solid in several portions over 15 min. The reaction mixture was stirred at 0 °C for 30 min and then at 25 °C for 3 h. The reaction mixture was warmed to 60 °C in an oil bath under 90 °C condenser and hold at that temperature for 12 h. To the resulting residue, 500 mL water was added and the mixture stirred at 25 °C for 30 min. The resultant solid was filtered and washed with 200 mL EtOAc. The solid was dried under vacuum filtration to afford the residue to give the title compound (52.0 g, 130 mmol, 78.1% yield) as a yellow solid. (ESI+) m/z: 397 (M+H)+, (C17H21BrN2O4). [0968] B. tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)pentanoate: A mixture of tert-butyl 5-amino-4-(5- bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (25.0 g, 62.9 mmol, 1.00 eq), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.1 g, 75.5 mmol, 1.20 eq), AcOK (18.5 g, 188 mmol, 3.00 eq), Pd(dppf)Cl2 (2.30 g, 3.15 mmol, 0.05 eq) in dioxane (250 mL) was degassed and purged with N2 for 3 times at 20 °C, and then the mixture was stirred at 60 °C for 16 h under N2 atmosphere. The reaction solution was filtered out with suction over kieselguhr. The kieselguhr was washed twice with EtOAc (2 x 200 mL). The mother liquid was concentrated. The crude product was triturated with EtOAc (250 mL) at 25oC for 30 min to give the title compound (29.5 g, 63.9 mmol, 50.8% yield, 96.3% purity) as a gray solid. (ESI+) m/z: 445.2 (M+H)+, (C23H33BN2O6). [0969] C. tert-Butyl 5-amino-4-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate: To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole (5.00 g, 30.9 mmol, 1.00 eq) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- 345 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (16.5 g, 37.0 mmol, 1.20 eq) in dioxane (500 mL) and H2O (50.0 mL) was added K3PO4 (13.1 g, 61.7 mmol, 2.00 eq) and CataCXium A Pd G3 (2.25 g, 3.09 mmol, 0.10 eq) at 25 °C under N2. The mixture was stirred at 60 °C for 4 h under N2. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 15/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.30) to give the title compound (5.80 g, 14.4 mmol, 46.6% yield, 99.0% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.08 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.20 (s, 1H), 4.76 (d, J = 4.0 Hz, 1H), 4.74 - 4.63 (m, 1H), 4.54 - 4.50 (m, 1H), 4.12 (s, 3H), 2.17 (s, 3H), 2.01 - 1.99 (m, 1H), 1.33 (s, 9H). (ESI+) m/z: 400.4 (M+H)+, (C20H25N5O4) [0970] D. tert-Butyl 4-(5-(5-(1H-indol-6-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 1.24 mmol, 1.00 eq) and tert-butyl 6-bromo-1H-indole-1-carboxylate (1.10 g, 3.72 mmol, 3.00 eq) in NMP (12.5 mL) was added tetrabutylammonium acetate (1.49 g, 4.96 mmol, 1.51 mL, 4.00 eq) and Pd(PPh3)2Cl2 (87.0 mg, 124 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 120 °C for 16 h. The mixture was poured water (100 mL) and extracted with ethyl acetate (3 x 100 mL) to collect the organic layers, The organic layer were washed with brine (2 x 100 mL ), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum at 45 °C to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane/Methanol = 20/1, Rf = 0.26) to give a residue. The residue was purified by preparative-HPLC (using a Welch Ultimate XB-Diol (250 mm x 50 mm x 10 μm) and gradient of 15-45% Hexane in EtOH over 15 min at a flow rate of 90 mL/min) to give the title compound (130 mg, 245 μmol, 19.8% yield, 97.1% purity in LCMS at 220 nm) as a light yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.57 - 7.48 (m, 5H), 7.16 (s, 1H), 7.03 - 7.00 (m, 1H), 6.53 (s, 1H), 4.70 - 4.67 (m, 1H), 4.60 - 4.42 (m, 2H), 3.91 (s, 3H), 2.15 - 2.10 (m, 3H), 1.95 - 1.93 (m, 1H), 1.31 (s, 9H). (ESI+) m/z: 515.2 (M+H)+, (C28H30N6O4). [0971] E. 3-(5-(5-(1H-Indol-6-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 4-(5-(5-(1H-indol-6-yl)-1-methyl-1H- 1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (110 mg, 208 μmol, 1.00 eq) in ACN (2.20 mL) was added TsOH (143 mg, 830 μmol, 4.00 eq) at 25 °C. The mixture was stirred at 80 °C for 4 h. The mixture was dissolved with Dichloromethane/Methanol = 346 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 10/1 (2.00 mL). The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 100/5, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.27). The residue was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 17-47% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (30.7 mg, 68.1 μmol, 32.8% yield, 97.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 11.0 (s, 1H), 7.77 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 - 7.50 (m, 3H), 7.06 - 7.03 (m, 1H), 6.55 (s, 1H), 5.10 - 5.06 (m, 1H), 4.42 - 4.22 (m, 2H), 3.92 (s, 3H), 2.93 - 2.85 (m, 1H), 2.59 - 2.54 (m, 1H), 2.40 - 2.31 (m, 1H), 1.99 - 1.95 (m, 1H). (ESI+) m/z: 441.1 (M+H)+, (C24H20N6O3). EXAMPLE 308 [0972] Synthesis of 3-(5-(5-(benzo[d]thiazol-6-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0973] A. tert-Butyl 5-amino-4-(5-(5-(benzo[d]thiazol-6-yl)-1-methyl-1H-1,2,3-triazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 1.24 mmol, 1.00 eq) and 6-bromobenzo[d]thiazole (796 mg, 3.72 mmol, 3.00 eq) in NMP (12.5 mL) was added tetrabutylammonium;acetate (1.49 g, 4.96 mmol, 1.51 mL, 4.00 eq), Pd(PPh3)2Cl2 (87.0 mg, 124 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 120 °C for 12 h under N2. The mixture was poured water (100 mL) and extracted with ethyl acetate (3 x 100 mL) to collect the organic layer, The organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under vacuum at 45 °C to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane/Methanol = 20/1, Rf = 0.26) to give a residue. The residue was purified by preparative-HPLC (using a Welch Ultimate XB-Diol (250 mm x 50 mm x 10 μm) and gradient of 15-45% Hexane in EtOH:MeOH = 4:1 over 20 min at a flow rate of 90 mL/min) to give the title compound (140 mg, 257 μmol, 20.7% yield, 97.8% purity in LCMS at 220 nm) as a light yellow solid.1H 347 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT NMR: (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.40 - 8.39 (m, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.61 - 7.59 (m, 2H), 7.53 (s, 1H), 7.47 - 7.45 (m, 1H), 7.16 (s, 1H), 4.71 - 4.68 (m, 1H), 4.55 - 4.38 (m, 2H), 3.95 (s, 3H), 2.13 (s, 3H), 1.98 - 1.93 (m, 1H), 1.31 (s, 9H). (ESI+) m/z: 533.0 (M+H)+, (C27H28N6O4S) [0974] B. 3-(5-(5-(Benzo[d]thiazol-6-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5- (benzo[d]thiazol-6-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (120 mg, 220 μmol, 1.00 eq) in ACN (2.40 mL) was added TsOH (152 mg, 881 μmol, 4.00 eq) at 25 °C. The mixture was stirred at 80 °C for 3 h. The mixture was dissolved with Dichloromethane/Methanol = 10/1 (2.00 mL). The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 100/1 to 100/5, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.33) to give a residue. The residue was triturated with Petroleum ether (10.0 mL) at 25 °C for 30 min. Filtered and the filter cake was concentrated under reduce pressure to get a residue at 45-50 °C. The residue was freeze- drying. to give the title compound (27.0 mg, 58.0 μmol, 26.3% yield, 98.3% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.55 (s, 1H), 8.42 - 8.41 (m, 1H), 8.26 (d, J = 8.00 Hz, 1H), 7.74 (s, 1H), 7.65 - 7.60 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.42 - 4.23 (m, 2H), 3.96 (s, 3H), 2.93 - 2.88 (m, 1H), 2.59 - 2.55 (m, 1H), 2.37 - 2.33 (m, 1H), 1.99 - 1.96 (m, 1H). (ESI+) m/z: 459.1 (M+H)+, (C23H18N6O3S). EXAMPLE 309 [0975] Synthesis of 3-(5-(5-(1,1-difluoroethyl)-1-phenyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [0976] A. 5-Iodo-1-phenyl-1H-1,2,3-triazole: To a solution of 2,2,6,6- tetramethylpiperidine (11.1 g, 79.2 mmol, 13.4 mL, 2.30 eq) in THF (125 mL) was added n- BuLi (2.50 M, 31.6 mL, 2.30 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 15 min, then ZnCl2•TMEDA (6.96 g, 27.5 mmol, 0.80 eq) was added to the mixture at 0 °C and stirred for 15 min, then 1-phenyltriazole (5.00 g, 34.4 mmol, 1.00 eq) was added to the mixture. The mixture was stirred at 25 °C for 2 h. The mixture was poured into cool Na2S2O3 348 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (500 mL) and extracted with DCM (3 x 500 mL). The combined organic layer was washed with bine (500 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 1/0 to 20/1, TLC: Petroleum ether/Ethyl acetate= 3/1, Rf = 0.43) to give the title compound (3.60 g, 12.5 mmol, 36.5% yield, 94.7% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.58 - 7.53 (m, 5H). (ESI+) m/z: 272.1 (M+H)+, (C8H6IN3). [0977] B. 5-(1-Ethoxyvinyl)-1-phenyl-1H-1,2,3-triazole: To a solution of 5-iodo-1- phenyl-1H-1,2,3-triazole (1.50 g, 5.53 mmol, 1.00 eq) in toluene (15.0 mL) was added Pd(PPh3)4 (319.74 mg, 276.69 μmol, 0.05 eq) at 25 °C under N2. Then tributyl(1- ethoxyvinyl)stannane (3.68 g, 10.19 mmol, 3.44 mL, 1.84 eq) was dropwise into the mixture at 25 °C under N2. The mixture was stirred at 100 °C for 16 h under N2. The mixture was cool down to 25 °C. The mixture was poured into ice-water (100 mL) and extracted with EtOAc (3 x 50.0 mL) to collect the organic layers. The organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered and the filtrated was concentrated under vacuum at 45 °C to get a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 20/1, TLC: Petroleum ether/Ethyl acetate = 3/1, Rf = 0.37) to give the title compound (300 mg, 1.21 mmol, 21.8% yield, 86.6% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 216.1 (M+H)+, (C12H13N3O). [0978] C. 1-(1-Phenyl-1H-1,2,3-triazol-5-yl)ethan-1-one: To a solution of 5-(1- ethoxyvinyl)-1-phenyl-triazole (300 mg, 1.21 mmol, 1.00 eq) in THF (3.00 mL) was added HCl (1.00 M, 4.83 mL, 4.00 eq) at 20 °C. Then the mixture was stirred at 20 °C for 1 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (2 x 10.0 mL) to collect the organic layers. The combined organic layers was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (200 mg, 1.03 mmol, 85.5% yield, 96.6% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.54 - 7.42 (m, 5H), 2.57 (s, 3H),. (ESI+) m/z: 188.1 (M+H)+ (C10H9N3O). [0979] D. 5-(1,1-Difluoroethyl)-1-phenyl-1H-1,2,3-triazole: To a solution of 1-(1- phenyl-1H-1,2,3-triazol-5-yl)ethan-1-one (200 mg, 1.07 mmol, 1.00 eq) in DCM (2.50 mL) was added DAST (3.44 g, 21.37 mmol, 2.82 mL, 20.0 eq) at 0 °C. The mixture was stirred at 50 °C for 24 h. The mixture was poured into water (10.0 mL) and adjust to pH = 8 with saturated NaHCO3 solution (10.0 mL), the mixture was extracted with DCM (2 x 10.0 mL) to collect the organic layers. The combined organic layers were dried over anhydrous Na2SO4, 349 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 50/1 to 5/1, TLC: Petroleum ether/Ethyl acetate = 3/1, Rf = 0.40) to give the title compound (110 mg, 472 μmol, 44.2% yield, 89.8% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.58 - 7.54 (m, 5H), 1.86 (t, J = 18.0 Hz, 3H). (ESI+) m/z: 210.1 (M+H)+, (C10H9F2N3). [0980] E. 4-Bromo-5-(1,1-difluoroethyl)-1-phenyl-1H-1,2,3-triazole: To a solution of 5- (1,1-difluoroethyl)-1-phenyl-1H-1,2,3-triazole (60.0 mg, 286 μmol, 1.00 eq) in THF (0.50 mL) was added dropwise n-BuLi (2.50 M, 344 μL, 3.00 eq) at -78 °C under N2. The reaction mixture was stirred for additional 1 h, then a solution of 1,2-dibromo-1,1,2,2-tetrafluoro- ethane (149 mg, 573 μmol, 2.00 eq) in THF (0.5 mL) was added dropwise at -78 °C. Then the reaction mixture was stirred at 25 °C for 11 h. The mixture was poured into NH4Cl (aq., 10.0 mL) and extracted with ethyl acetate (3 x 5.00 mL). The combined organic layers were washed with saturated NaCl aqueous (10.0 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (60.0 mg, 204 μmol, 71.1% yield, 98.0% purity in LCMS at 220 nm) as a yellow gum.1H NMR: (400 MHz,CD3CN) δ 7.65 - 7.50 (m, 5H), 1.98 (s, 1H), 1.94 (s, 1H), 1.89 (s, 1H). (ESI+) m/z: 287.9 (M+H)+, (C10H8F2N3Br). [0981] F. 3-(5-(5-(1,1-Difluoroethyl)-1-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (151 mg, 408 μmol, 2.00 eq) and 4- bromo-5-(1,1-difluoroethyl)-1-phenyl-1H-1,2,3-triazole (60.0 mg, 204 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (17.0 mg, 20.4 μmol, 0.10 eq) and K3PO4 (86.6 mg, 408 μmol, 2.00 eq) at 25 °C under N2. The mixture was stirred for 3 h at 100 °C under N2. The mixture was concentrated under reduced pressure to get a residue. The crude product was purified by column chromatography (SiO2, Dichloromethane/Methanol = 0/1 to 50/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.33) and concentrated under reduced pressure to get a residue. The residue was purified by Preparative-HPLC (using a CD01-Phenomenex luna (150 mm x 25 mm x 10 μm) and gradiente of 25%-55% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) to give the title compound (28.5 mg, 62.8 μmol, 30.8% yield, 99.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.88 - 7.86 (m, 2H), 7.78 - 7.75 (m, 1H), 7.70 - 7.65 (m, 5H), 5.11 - 5.06 (m, 1H), 4.45 - 4.25 (m, 2H), 2.96 - 2.94 (m, 1H), 2.62 - 2.61 (m, 1H), 2.45 - 2.41 (m, 1H), 2.07 - 2.05 (m, 1H), 1.82 (t, J = 19.2 Hz, 3H), (ESI+) m/z: 452.2 (M+H)+, (C23H19F2N5O3). 350 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLES 310-312 [0982] The compound of Examples 310-312 were prepared according to Examples 100- 111. EXAMPLE 313 [0983] Synthesis of 3-{5-[5-(1-Acetylpiperidin-4-yl)-2-methyl-1,3-oxazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [0984] A. tert-Butyl 4-(5-(5-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyloxazol- 4-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(5-bromo-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (71.7 mg, 150 umol, 1.00 eq.) and 1-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (45.2 mg, 180 umol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), 351 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Pd-118 (9.76 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen gas, then diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 523.3 (M+H)+, (C28H34N4O6). [0985] B. tert-Butyl 4-(5-(5-(1-acetylpiperidin-4-yl)-2-methyloxazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a solution of tert-butyl 4-(5-(5-(1-acetyl- 1,2,3,6-tetrahydropyridin-4-yl)-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5- oxopentanoate (~150 umol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 525.3 (M+H)+, (C28H36N4O6). [0986] C.3-{5-[5-(1-Acetylpiperidin-4-yl)-2-methyl-1,3-oxazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 4-(5-(5-(1-acetylpiperidin-4-yl)-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5- oxopentanoate (~150 umol, 1.00 eq.) in CH3CN (1.00 mL) was added H2SO4 (con.) (200 uL). The mixture was stirred at 65 °C for 1 hr. The mixture was concentrated under nitrogen gas to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18150 * 25mm * 5um and gradient of 9% - 39% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (12.49 mg, 27.7 μmol, 18.4% yield, 99.6% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 451.3 (M+H)+, (C24H26N4O5). 352 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 314 [0987] Synthesis of 3-{5-[2-Methyl-5-(1-methylpiperidin-4-yl)-1,3-oxazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [0988] A. tert-Butyl 5-amino-4-(5-(2-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(5-bromo-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (71.6 mg, 150 μmol, 1.00 eq.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (40.2 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd-118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 495.3 (M+H)+, (C27H34N4O5). [0989] B. tert-Butyl 5-amino-4-(5-(2-methyl-5-(1-methylpiperidin-4-yl)oxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(2-methyl-5- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 497.3 (M+H)+, (C27H36N4O5). [0990] C.3-{5-[2-Methyl-5-(1-methylpiperidin-4-yl)-1,3-oxazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-methyl-5-(1-methylpiperidin-4-yl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (crude, ~150 umol, 1.00 eq.) in CH3CN (1.00 mL) was added H2SO4 (con.) (200 uL). The mixture was stirred at 65 °C for 1 hr. The mixture was concentrated under nitrogen gas to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 0% - 22% acetonitrile in water 353 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT containing 0.225% FA over 12 mins at a flow rate of 25 mL/min to give final product (6.95 mg, 16.4 μmol, 10.9% yield, 96.8% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 423.3 (M+H)+, (C23H26N4O4). EXAMPLE 315 [0991] Synthesis of 3-[5-(5-cyclohexyl-2-methyl-1,3-oxazol-4-yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]piperidine-2,6-dione: [0992] A. tert-Butyl 5-amino-4-(5-(5-(cyclohex-1-en-1-yl)-2-methyloxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 4-(5-(5-bromo-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (71.6 mg, 150 μmol, 1.00 eq.) and cyclohex-1-en-1-ylboronic acid (22.7 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd-118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 480.2 (M+H)+, (C27H33N3O5). [0993] B. tert-Butyl 4-(5-(5-(1-acetylpiperidin-4-yl)-2-methyloxazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5- (cyclohex-1-en-1-yl)-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 482.7 (M+H)+, (C27H35N3O5). [0994] C.3-[5-(5-Cyclohexyl-2-methyl-1,3-oxazol-4-yl)-1-oxo-2,3-dihydro-1H-isoindol- 2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 4-(5-(5-(1- acetylpiperidin-4-yl)-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (crude, ~150 umol, 1.00 eq.) in CH3CN (1.00 mL) was added H2SO4 (con.) (200 uL). The mixture was stirred at 65 °C for 1 hr. The mixture was concentrated under nitrogen gas to 354 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18 (150 * 25 mm * 5 um) and gradient of 30% - 60% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (7.25 mg, 17.8 μmol, 11.8% yield, 99.9% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 408.3 (M+H)+, (C23H25N3O4). EXAMPLE 316 [0995] Synthesis of 3-[5-(5-Cyclopentyl-2-methyl-1,3-oxazol-4-yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]piperidine-2,6-dione: [0996] A. tert-Butyl 5-amino-4-(5-(5-(cyclopent-1-en-1-yl)-2-methyloxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 4-(5-(5-bromo-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (71.6 mg, 150 μmol, 1.00 eq.) and cyclopent-1-en-1-ylboronic acid (20.1 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd- 118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 466.2 (M+H)+, (C26H31N3O5). [0997] B. tert-Butyl 5-amino-4-(5-(5-cyclopentyl-2-methyloxazol-4-yl)-1-oxoisoindolin- 2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5-(cyclopent-1-en-1-yl)-2- methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 468.2 (M+H)+, (C26H33N3O5). [0998] C.3-[5-(5-Cyclopentyl-2-methyl-1,3-oxazol-4-yl)-1-oxo-2,3-dihydro-1H- isoindol-2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- 355 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (5-(5-cyclopentyl-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (228 mg, 1.20 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Welch Ultimate C18 (150 * 25 mm * 5 um) and gradient of 26% - 56% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (9.71 mg, 24.6 μmol, 16.4% yield, 99.9% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 394.1 (M+H)+, (C22H23N3O4). EXAMPLE 317 [0999] Synthesis of 3-{5-[2-Methyl-5-(propan-2-yl)-1,3-oxazol-4-yl]-1-oxo-2,3-dihydro- 1H-isoindol-2-yl}piperidine-2,6-dione: [1000] A. tert-Butyl 5-amino-4-(5-(2-methyl-5-(prop-1-en-2-yl)oxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 4-(5-(5-bromo-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (71.6 mg, 150 μmol, 1.00 eq.) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (30.3 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd-118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 440.2 (M+H)+, (C24H29N3O5). [1001] B. tert-Butyl 5-amino-4-(5-(5-isopropyl-2-methyloxazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(2-methyl-5-(prop-1-en-2- yl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 442.2 (M+H)+, (C24H31N3O5). 356 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1002] C.3-{5-[2-Methyl-5-(propan-2-yl)-1,3-oxazol-4-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(5-isopropyl-2-methyloxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (228 mg, 1.20 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 20% - 40% acetonitrile in water containing 0.225% FA over 15 mins at a flow rate of 25 mL/min to give final product (4.77 mg, 13.0 μmol, 8.67% yield, 98.8% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 368.2 (M+H)+, (C20H21N3O4). EXAMPLE 318 [1003] Synthesis of 3-{1-Oxo-5-[5-(piperidin-3-yl)-1,3-oxazol-4-yl]-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: [1004] A. tert-Butyl 5-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1- oxoisoindolin-5-yl)oxazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(5-bromooxazol-4-yl)-1-oxoisoindolin-2-yl)- 5-oxopentanoate (69.5 mg, 150 μmol, 1.00 eq.) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (55.6 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 μmol, 2.00 eq.), Pd- 118 (9.78 mg, 15.0 μmol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 567.2 (M+H)+, (C30H38N4O7). [1005] B. tert-Butyl 3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1- oxoisoindolin-5-yl)oxazol-5-yl)piperidine-1-carboxylate: To a solution of tert-butyl 5-(4- (2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)oxazol-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. 357 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 569.3 (M+H)+, (C30H40N4O7). [1006] C.3-{1-Oxo-5-[5-(piperidin-3-yl)-1,3-oxazol-4-yl]-2,3-dihydro-1H-isoindol-2- yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 3-(4-(2-(1-amino-5- (tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)oxazol-5-yl)piperidine-1- carboxylate (crude, ~150 umol, 1.00 eq.) in CH3CN (1.00 mL) was added H2SO4 (con.) (200 uL). The mixture was stirred at 65 °C for 1 hr. The mixture was concentrated under nitrogen gas to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 0% - 22% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (5.42 mg, 13.7 μmol, 9.14% yield, 95.0% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 395.2 (M+H)+, (C21H22N4O4). EXAMPLE 319 [1007] Synthesis of 3-{5-[5-(4,4-Dimethylcyclohexyl)-1,3-oxazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1008] A. tert-Butyl 5-amino-4-(5-(5-(4,4-dimethylcyclohex-1-en-1-yl)oxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 4-(5-(5-bromooxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (69.5 mg, 150 μmol, 1.00 eq.) and 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (42.5 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd-118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 494.3 (M+H)+, (C28H35N3O5). [1009] B. tert-Butyl 5-amino-4-(5-(5-(4,4-dimethylcyclohexyl)oxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5-(4,4- 358 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT dimethylcyclohex-1-en-1-yl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 496.3 (M+H)+, (C28H37N3O5). [1010] C.3-{5-[5-(4,4-Dimethylcyclohexyl)-1,3-oxazol-4-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(5-(4,4-dimethylcyclohexyl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (228 mg, 1.20 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Waters Xbridge C18 (150 * 25 mm * 10 um) and gradient of 40% - 70% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (12.4 mg, 29.3 μmol, 19.5% yield, 95.8% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 422.3 (M+H)+, (C21H27N3O4). EXAMPLE 320 [1011] Synthesis of 3-{5-[5-(4-Methoxycyclohexyl)-1,3-oxazol-4-yl]-1-oxo-2,3-dihydro- 1H-isoindol-2-yl}piperidine-2,6-dione: [1012] A. tert-Butyl 5-amino-4-(5-(5-(4-methoxycyclohex-1-en-1-yl)oxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 4-(5-(5-bromooxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (69.5 mg, 150 μmol, 1.00 eq.) and 2-(4-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (42.9 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd-118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL), and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and 359 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 496.2 (M+H)+, (C27H33N3O6). [1013] B. tert-Butyl 5-amino-4-(5-(5-(4-methoxycyclohexyl)oxazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5-(4- methoxycyclohex-1-en-1-yl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 498.3 (M+H)+, (C27H35N3O6). [1014] C.3-{5-[5-(4-Methoxycyclohexyl)-1,3-oxazol-4-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(5-(4-methoxycyclohexyl)oxazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~150 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (228 mg, 1.20 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 22% - 42% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (7.40 mg, 17.4 μmol, 11.6% yield, 99.8% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 424.3 (M+H)+, (C23H25N3O5). EXAMPLE 321 [1015] Synthesis of 3-(1-Oxo-5-{5-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1,3-oxazol-4- yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: [1016] A. tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(5-(1-(2,2,2-trifluoroethyl)-1,2,3,6- tetrahydropyridin-4-yl)oxazol-4-yl)isoindolin-2-yl)pentanoate: To a vial containing a solution of tert-butyl 5-amino-4-(5-(5-bromooxazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (69.5 mg, 150 μmol, 1.00 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 360 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2-yl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine (52.4 mg, 180 μmol, 1.20 eq.) in dioxane (1.50 mL) and H2O (0.30 mL) was added K2CO3 (41.4 mg, 300 umol, 2.00 eq.), Pd- 118 (9.78 mg, 15.0 umol, 0.10 eq.) under protection of N2. The mixture was stirred at 100 °C for 1 hr under microwave. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL), and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 549.2 (M+H)+, (C27H31F3N4O5). [1017] B. tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(5-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)oxazol-4-yl)isoindolin-2-yl)pentanoate: To a solution of tert-butyl 5-amino-5-oxo-4-(1- oxo-5-(5-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)oxazol-4-yl)isoindolin-2- yl)pentanoate (crude, ~150 μmol, 1.00 eq.) in MeOH (1.50 mL) was added Pd/C (60.0 mg, 0.30 eq., 10%) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hrs. The reaction mixture was concentrated under nitrogen gas to give crude intermediate which was used for next step directly. (ESI+) m/z: 551.2 (M+H)+, (C27H33F3N4O5). [1018] C.3-(1-Oxo-5-{5-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1,3-oxazol-4-yl}-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxazol-4-yl)isoindolin- 2-yl)pentanoate (crude, ~150 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (228 mg, 1.20 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 12% - 42% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (5.82 mg, 12.2 μmol, 8.13% yield, 95.7% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 477.3 (M+H)+, (C23H23F3N4O4). 361 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 322 [1019] Synthesis of 3-(1-Oxo-5-(4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3- yl)isoindolin-2-yl)piperidine-2,6-dione: [1020] A. Benzene-1,3,5-triyl triformate: A mixture of Ac2O (18.2 g, 178 mmol, 16.7 mL, 4.00 eq) and HCOOH (10.7 g, 222 mmol, 5.00 eq) was stirred at 60 °C for 2 h under N2 atmosphere. And then the mixture was added benzene-1,3,5-triol (5.62 g, 44.5 mmol, 1.00 eq) and NaOAc (1.83 g, 22.2 mmol, 0.50 eq). Then the mixture was stirred at 25 °C for 30 h under N2 atmosphere. Tol. (200 mL) was added to the residue. The resulting mixture was extracted with H2O (2 x 100 mL). The combined organic phase was cooled to 0 °C 2 h. The reaction mixture was filtered. The filter cake was concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 1: 10, TLC, PE: EtOAc = 1: 1, Rf = 0.75) to give the title compound (8.00 g, 38.0 mmol, 42.7% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.28 (s, 3H), 7.00 (s, 3H), (C9H6O6). [1021] B. (E)-2,2,2-Trifluoro-N-phenylacetimidoyl chloride: A mixture of TEA (33.3 g, 329 mmol, 45.8 mL, 3.00 eq) and PPh3 (57.5 g, 219 mmol, 2.00 eq) in CCl4 (43.0 mL) was dropwise added TFA (13.8 g, 121 mmol, 9.00 mL, 1.10 eq) and purged with N2 for 3 times at 0 °C for 15 min, and then the mixture was added aniline (10.2 g, 109 mmol, 10.0 mL, 1.00 eq) in CCl4 (43.0 mL) at 0 °C. Then the mixture was stirred at 85 °C for 30 h under N2 atmosphere. The reaction mixture was filtered quickly, repeated wash the filter cake using hot petroleum ether until in the filtrate without solid by-products precipitation. The reaction mixture was concentrated directly to give the title compound (4.0 g, crude) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.25 - 7.19 (m, 1H), (C8H5ClF3N). [1022] C.4-Phenyl-3-(trifluoromethyl)-4H-1,2,4-triazole: A mixture of (E)-2,2,2- trifluoro-N-phenylacetimidoyl chloride (2.00 g, 9.64 mmol, 1.00 eq) and benzene-1,3,5-triyl triformate (4.04 g, 19.28 mmol, 2.00 eq) in Tol. (40.0 mL), and then the mixture was added N2H4·H2O (3.01 g, 48.0 mmol, 2.92 mL, 80% purity, 5.00 eq) and TFA (1.09 g, 9.64 mmol, 362 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 712 μL, 1.00 eq) at 20 °C and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated directly at 40 °C. The residue was purified by by preparative -TLC (SiO2, Petroleum ether: Ethyl acetate = 4: 1, Rf = 0.26) to give the title compound (150 mg, 703 μmol, 7.3% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.63 - 7.56 (m, 3H), 7.38 (d, J = 7.2 Hz, 2H), (C9H6F3N3). [1023] D.3-Bromo-4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazole: A mixture of 4- phenyl-3-(trifluoromethyl)-4H-1,2,4-triazole (150 mg, 703 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (125 mg, 703 μmol, 1.00 eq) in ACN (0.50 mL) at 0 °C and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated directly in vacuum to give residue. The residue was purified by preparative -TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.36) to give the title compound (80.0 mg, 114 μmol, 38.9% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 7.69 - 7.58 (m, 3H), 7.32 (d, J = 7.2 Hz, 2H), (C9H5BrF3N3). [1024] E.3-(1-Oxo-5-(4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)isoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-bromo-4-phenyl-5-(trifluoromethyl)-4H-1,2,4- triazole (50.0 mg, 171 μmol, 1.00 eq), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (126 mg, 342 μmol, 2.00 eq), RuPhos Pd G3 (14.3 mg, 17.1 μmol, 0.10 eq), K3PO4 (72.6 mg, 342 μmol, 2.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 5 μm) and gradiente of 23 - 53% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (24.0 mg, 52.0 μmol, 30.4% yield, 98.3% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 6.4 Hz, 2H), 7.60 - 7.53 (m, 3H), 7.47 (d, J = 8.4 Hz, 1H), 5.11 - 5.07 (m, 1H), 4.49 - 4.25 (m, 2H), 2.96 - 2.83 (m, 1H), 2.64 - 2.59 (m, 1H), 2.38 - 2.34 (m, 1H), 2.04 - 1.94 (m, 1H). (ESI+) m/z: 456.0 (M+H)+, (C22H16F3N5O3). 363 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 323 [1025] Synthesis of 3-(5-(5-(benzofuran-5-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1026] A. tert-Butyl 5-amino-4-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate: To a solution of 4-bromo-1-methyl-1H-1,2,3-triazole (5.00 g, 30.9 mmol, 1.00 eq) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) isoindolin-2-yl) pentanoate (16.5 g, 37.0 mmol, 1.20 eq) in dioxane (500 mL) and H2O (50.0 mL) was added K3PO4 (13.1 g, 61.7 mmol, 2.00 eq) and CataCXium A Pd G3 (2.25 g, 3.09 mmol, 0.10 eq) at 25 °C under N2. The mixture was stirred at 60 °C for 4 h under N2. The mixture was filtered and the filtrate was concentrated under vacuum to get a residue at 50 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 15: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.30) to give the title compound (5.80 g, 14.4 mmol, 46.6% yield, 99.0% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.08 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.20 (s, 1H), 4.76 (d, J = 4.0 Hz, 1H), 4.74 - 4.63 (m, 1H), 4.54 - 4.50 (m, 1H), 4.12 (s, 3H), 2.17 (s, 3H), 2.01 - 1.99 (m, 1H), 1.33 (s, 9H). (ESI+) m/z: 400.4 (M+H)+, (C20H25N5O4) [1027] B. tert-Butyl 5-amino-4-(5-(5-(benzofuran-5-yl)-1-methyl-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl tert-butyl 5-amino-4- (5-(1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (600 mg, 1.49 mmol, 1.00 eq) and 5-bromobenzofuran (879 mg, 4.46 mmol, 3.00 eq) in NMP (14.0 mL) was added tetrabutylammonium;acetate (1.79 g, 5.95 mmol, 1.81 mL, 4.00 eq), dichloropalladium;triphenylphosphane (104 mg, 149 μmol, 0.10 eq). The mixture was degassed and purged with N2 for 3 times at 25 °C then was stirred at 120 °C for 16 h under N2. The reaction mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated the filtrate under vacuum at 45 °C to get a residue. The residue was purified by preparative- TLC (SiO2, Dichloromethane: Methanol = 18: 1 Rf = 0.35). The residue was purified by Prep- 364 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT HPLC (using a Welch Ultimate XB-Diol (250 mm x 50 mm x 10 μm) and gradient of 14% - 44% Hexane in EtOH over 15 min at a flow rate of 90 mL/min) to give the title compound to give the title compound (170 mg, crude) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.14 (d, J = 2.0 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.74 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.36 (m, 1H), 7.19 - 7.13 (m, 1H), 7.06 - 7.03 (m, 1H), 4.69 (br dd, J = 4.2, 10.4 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.44 - 4.35 (m, 1H), 3.91 (s, 3H), 2.16 - 2.10 (m, 3H), 1.97 - 1.88 (m, 1H), 1.33 - 1.29 (m, 9H). (ESI+) m/z: 516.3 (M+H)+, (C28H29N5O5) [1028] C.3-(5-(5-(Benzofuran-5-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(benzofuran-5-yl)-1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (100 mg, 151 μmol, 1.00 eq) in ACN (2.50 mL) was added TsOH (104 mg, 605 μmol, 4.00 eq), the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purification by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 100: 3 Dichloromethane: Methanol = 16: 1, Rf = 0.40). The solution was concentrated under vacuum to get a residue at 50 °C. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 5 μm) and gradiente of 15 - 25% acetonitrile in water containing 0.05% FA over 18 min at a flow rate of 25 mL/min) to give the title compound (20.2 mg, 41.0 μmol, 15.9% yield, 99.1% purity, FA) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.04 - 10.88 (m, 1H), 8.52 (br s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.87 - 7.77 (m, 2H), 7.73 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 8.4 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 5.08 (dd, J = 5.2, 13.4 Hz, 1H), 4.44 - 4.20 (m, 2H), 3.92 (s, 3H), 2.96 - 2.82 (m, 1H), 2.57 (br dd, J = 2.4, 15.6 Hz, 1H), 2.35 (dd, J = 4.4, 13.2 Hz, 1H), 2.02 - 1.93 (m, 1H). (ESI+) m/z: 442.1 (M+H)+, (C24H19N5O4) 365 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 324 [1029] Synthesis of 3-(1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [1030] A.3-(1-Oxo-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)piperidine-2,6-dione: To solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30.0 g, 92.8 mmol, 1.00 eq) and ethynyltrimethylsilane (45.5 g, 464 mmol, 64.3 mL, 5.00 eq) in THF (600 mL) was added CuI (3.54 g, 18.5 mmol, 0.20 eq), Pd(dppf)Cl2 (13.5 g, 18.5 mmol, 0.20 eq), TEA (18.7 g, 185 mmol, 25.8 mL, 2.00 eq) under N2. The reaction mixture was stirred at 70 °C for 5 h under N2. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 20: 1, TLC: Dichloromethane: Methanol = 15: 1, Rf = 0.41). The crude product was triturated with Dichloromethane (50.0 mL) to give the title compound (20.0 g, 54.9 mmol, 59.1% yield, 93.5% purity in LCMS at 220 nm) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 - 7.69 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.47 - 4.30 (m, 2H), 2.93 - 2.87 (m, 1H), 2.61 - 2.57 (m, 1H), 2.41 - 2.37 (m, 1H), 2.02 - 1.99 (m, 1H), 0.25 (s, 9H). (ESI+) m/z: 341.1 (M+H)+, (C18H20O3N2Si). [1031] B.3-(5-Ethynyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1- oxo-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)piperidine-2,6-dione (20.0 g, 54.9 mmol, 1.00 eq) in THF (396 mL) was added TBAF (1.00 M, 54.9 mL, 1.00 eq) at 20 °C, then the mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to 25 °C and filtered. The residue was washed THF (150 mL) and filter and the filter cake was washed with H2O (100 mL) and concentrated to give the title compound (4.00 g, 14.4 mmol, 26.3% yield, 97.0% purity in LCMS at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.73 - 7.71 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.48 - 4.31 (m, 3H), 2.93 - 2.87 (m, 1H), 2.62 - 2.57 (m, 1H), 2.41 - 2.38 (m, 1H), 2.02 - 2.01 (m, 1H). (ESI+) m/z: 269.0 (M+H)+, (C15H12O3N2). [1032] C. ((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)copper: To a solution of CuI (1.14 g, 5.96 mmol, 2.00 eq) in EtOH (9.00 mL) and NH3•H2O (15.0 mL) 366 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was added 3-(5-ethynyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (800 mg, 2.98 mmol, 1.00 eq) at 20 °C, then the mixture was stirred at 20 °C for 5 h under N2. It was filtered and the filter cake was wased with water (20.0 mL) and EtOH (20.0 mL) and Petroleum ether (20.0 mL), then collect the filter cake and concentrated under vacuum to give the title compound (1 g, crude) as a yellow solid. [1033] E. Azidotrifluoromethane: To a solution of CsF (1.85 g, 12.1 mmol, 1.20 eq) in DMF (22.0 mL) was added dropwise trimethyl(trifluoromethyl)silane (1.73 g, 12.1 mmol, 1.20 eq) and a solution of 4-methylbenzenesulfonyl azide (2.00 g, 10.1 mmol, 1.00 eq) in DMF (3.00 mL) at -60 °C, then the mixture was stirred at -60 °C to -30 °C for 6 h under N2 to give the title compound used to the next step. [1034] F.3-(1-Oxo-5-(1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)ethynyl)copper (1.00 g, 3.02 mmol, 1.00 eq) in DMF (5.00 mL) was added I2 (767 mg, 3.02 mmol, 608 μL, 1.00 eq) at 20 °C, then a solution of CF3N3 (674 mg, 6.08 mmol, 2.01 eq) in DMF (15.0 mL) and TEA (685 mg, 6.77 mmol, 942 μL, 2.24 eq) was aaded to the mixture at 0 °C under N2, then the mixture was stirred at 20 °C for 4 h. under N2. It was poured into water (30.0 mL) and extracted with Ethyl acetate (3 x 20.0 mL). The organic layers were washed with brine (3 x 20.0 mL) and dried over anhydrous Na2SO4 filtered and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 26 - 56% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) give the title compound (120 mg, 313 μmol, 10.3% yield, 99.1% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.67 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.58 - 4.41 (m, 2H), 2.97 - 2.91 (m, 1H), 2.63 - 2.59 (m, 1H), 2.45 - 2.42 (m, 1H), 2.05 - 2.03 (m, 1H). (ESI+) m/z: 379.8 (M+H)+, (C16H12N5F3O3). [1035] G.3-(1-Oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione (90.0 mg, 235 μmol, 1.00 eq) in NMP (2.25 mL) was added iodobenzene (143 mg, 705 μmol, 78.6 μL, 3.00 eq) , Pd(OAc)2 (5.28 mg, 23.5 μmol, 0.10 eq) and Tetrabutylammonium acetate (283 mg, 940 μmol, 286 μL, 4.00 eq) at 20 °C, then the mixture was stirred at 80 °C for 8 h under N2. It was diluted with DMSO (0.50 mL) The crude product was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 30 - 60% acetonitrile in water containing 0.05% 367 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT FA over 16 min at a flow rate of 25 mL/min) give the title compound (35.1 mg, 75.1 μmol, 31.9% yield, 97.5% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.65 - 7.59 (m, 5H), 7.49 (d, J = 8.8 Hz, 1H), 5.09 (dd, J = 13.2 Hz, J = 4.8 Hz, 1H), 4.45 - 4.26 (m, 2H), 2.91 - 2.86 (m, 1H), 2.60 - 2.55 (m, 1H), 2.39 - 2.34 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 456.1(M+H)+, (C22H16O3N5F3). EXAMPLE 325 [1036] Synthesis of 3-(1-Oxo-5-(5-phenyl-3-(2,2,2-trifluoroethyl)-1H-pyrazol-1- yl)isoindolin-2-yl)piperidine-2,6-dione: [1037] A.2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindoline-5-diazonium: To a solution of 3- (5-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.93 mmol, 1.00 eq) in H2O (4.00 mL) was added trifluoroborane;hydrofluoride (706 mg, 3.86 mmol, 500 μL, 48% purity, 2.00 eq) at 0 °C. The mixture was stirred at 0 °C for 10 mins. And then NaNO2 (133 mg, 1.93 mmol, 1.00 eq) in H2O (1.00 mL) was added above mixture, the mixture was stirred at 0 °C for 50 mins. The reaction mixture was filtered and the filter cake was dissolved into acetone (5.00 mL). Then tert-butyl methyl ether (10.0 mL) was added until the recrystallized product precipitated completely. The precipitated was filtered and the filter cake was concentrated in vacuum to give the title compound (566 mg, 1.58 mmol, 82.0% yield) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.95 (s, 1H), 8.80 (dd, J = 1.2, 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 5.21 (dd, J = 5.2, 13.2Hz, 1H), 4.76 - 4.57 (m, 2H), 2.98 - 2.87 (m, 1H), 2.63 (br d, J = 17.2 Hz, 1H), 2.47 - 2.37 (m, 1H), 2.12 - 2.04 (m, 1H). [1038] B.3-(1-Oxo-5-(5-phenyl-3-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 1-phenylbut-3-en-1-one (216 mg, 1.48 mmol, 1.00 eq) in ACN (4.00 mL) was added AgNO3 (90.0 mg, 530 μmol, 3.59e-1 eq), 2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindoline-5-diazonium (566 mg, 1.58 mmol, 1.07 eq) and sodium;trifluoromethanesulfinate (461 mg, 2.96 mmol, 461 μL, 2.00 eq). The mixture was degassed and purged with N2 for 3 times, and then was added H2O2 (330 mg, 2.91 mmol, 280 μL, 30.0% purity, 1.97 eq) and stirred at 80 °C for 2 h under N2 atmosphere. The reaction 368 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture was diluted with ethyl acetate (20.0 mL) and washed with saturated NaHCO3 solution (10.0 mL), followed by water (10.0 mL) and brine solution (10.0 mL). The organic layer was dried on Na2SO4 and solvents were removed under reduced pressure. The crude product was purified by Prep-HPLC (using a CD05-Phenomenex luna C18150 x 40 x 10um) and gradient of 27 - 57% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) to give the title compound (47.7 mg, 1011 μmol, 6.83% yield, 100% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.42 - 7.37 (m, 3H), 7.30 - 7.25 (m, 3H), 6.71 (s, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.30 (m, 2H), 3.79 (q, J = 11.4 Hz, 2H), 2.95 - 2.85 (m, 1H), 2.59 (br d, J = 18.4 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.05 - 1.98 (m, 1H). (ESI+) m/z: 468.9 (M+1)+, (C24H19F3N4O3). EXAMPLE 326 [1039] Synthesis of 3-(1-Oxo-5-(1-phenyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [1040] A.3-(1-Oxo-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)piperidine-2,6-dione: To solution of 3-(5-bromo-1-oxoisoindolin-2-yl) piperidine-2,6-dione (30.0 g, 92.8 mmol, 1.00 eq) and ethynyltrimethylsilane (45.5 g, 464 mmol, 64.3 mL, 5.00 eq) in THF (600 mL) was added CuI (3.54 g, 18.5 mmol, 0.20 eq), Pd(dppf)Cl2 (13.5 g, 18.5 mmol, 0.20 eq), TEA (18.7 g, 185 mmol, 25.8 mL, 2.00 eq) under N2. The reaction mixture was stirred at 70 °C for 5 h under N2. It was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 20: 1, TLC: Dichloromethane/Methanol = 15: 1, Rf = 0.41). The crude product was triturated with Dichloromethane (50.0 mL) to give the title compound (20.0 g, 54.9 mmol, 59.1% yield, 93.5% purity in LCMS at 220 nm) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 - 7.69 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.47 - 4.30 (m, 2H), 2.93 - 2.87 (m, 1H), 2.61 - 2.57 (m, 1H), 2.41 - 2.37 (m, 1H), 2.02 - 1.99 (m, 1H), 0.25 (s, 9H). (ESI+) m/z: 341.2 (M+H)+, (C18H20O3N2Si). [1041] B.3-(5-Ethynyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1- oxo-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)piperidine-2,6-dione (20.0 g, 54.9 mmol, 1.00 eq) in THF (396 mL) was added TBAF (1.00 M, 54.9 mL, 1.00 eq) at 20 °C, then the mixture 369 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was stirred at 70 °C for 2 h. The reaction mixture was cooled to 25 °C and filtered. The residue was washed THF (150 mL) and filter and the filter cake was washed with H2O (100 mL) and concentrated to give the title compound (4.00 g, 14.4 mmol, 26.3% yield, 97.0% purity in LCMS at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.73 - 7.71 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.48 - 4.31 (m, 3H), 2.93 - 2.87 (m, 1H), 2.62 - 2.57 (m, 1H), 2.41 - 2.38 (m, 1H), 2.02 - 2.01 (m, 1H). (ESI+) m/z: 269.0 (M+H)+, (C15H12O3N2). [1042] C.3-(1-Oxo-5-(3,3,3-trifluoroprop-1-yn-1-yl)isoindolin-2-yl)piperidine-2,6- dione: To a solution of 3-(5-ethynyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (450 mg, 1.68 mmol, 1.00 eq) in DCM (6.00 mL) was added 3,3-dimethyl-1-(trifluoromethyl)-1,3- dihydro-1l3-benzo[d][1,2]iodaoxole (830 mg, 2.52 mmol, 1.50 eq), CuI (127 mg,670 μmol, 0.40 eq) and 1,10-phenanthroline (120 mg, 670 μmol, 0.40 eq) at 25 °C. The mixture was stirred at 50 °C for 4 h under N2. The mixture was poured into H2O (20.0 mL) and extracted with EtOAc (3 x 20.0 mL) to collect the organic layer combined organic layer was washed with bine (50.0 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 1: 0 to 50: 1, TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.30) to give the title compound (400 mg, 984 μmol, 29.3% yield, 82.8% purity) as a white solid. (ESI+) m/z: 337.2 (M+H)+, (C16H11F3N2O3). [1043] D.3-(1-Oxo-5-(1-phenyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(3,3,3-trifluoroprop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione (200 mg, 492 μmol, 1.00 eq) and azidobenzene (0.50 M, 1.67 mL, 1.70 eq) in DMF (5.00 mL) at 20 °C. The mixture was stirred at 120 °C for 12 h in MW. It was poured into water (50.0 mL) and extracted with EtOAc (3 x 40.0 ml). The organic layers were washed with brine (3 x 40.0 mL) and dried over anhydrous Na2SO4 filtered and the filtrate was concentrated under reduced pressure to get a residue The crude product was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 18 - 48% acetonitrile in water containing 0.05% FA over 20 min at a flow rate of 25 mL/min) give the title compound (4.74 mg, 3.63 μmol, 0.73 % yield, 97.5% purity HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.48 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.73 - 7.70 (m, 5H), 5.17 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.62 - 4.44 (m, 2H), 2.93 - 2.90 (m, 1H), 2.64 - 2.60 (m, 1H), 2.45 - 2.41 (m, 1H), 2.07 - 2.06 (m, 1H). (ESI+) m/z: 456.1(M+H)+, (C22H16F3N5O3). 370 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 327 [1044] Synthesis of 3-(5-{1-Methyl-2-[6-(piperazin-1-yl)pyridin-3-yl]-1H-imidazol-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: [1045] A.1-(5-(4-Bromo-1-methyl-1H-imidazol-2-yl)pyridin-2-yl)piperazine: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (6-(piperazin-1-yl)pyridin-3-yl)boronic acid (41.4 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added Na2CO3 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 323.1 (M+H)+, (C13H16BrN5). [1046] B. tert-Butyl 5-amino-4-(5-(1-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 1-(5-(4-bromo-1-methyl-1H-imidazol-2- yl)pyridin-2-yl)piperazine (48.3 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.3 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 560.3 (M+H)+, (C30H37N7O4). [1047] C.3-(5-{1-Methyl-2-[6-(piperazin-1-yl)pyridin-3-yl]-1H-imidazol-4-yl}-1-oxo- 2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: To a vial containing a solution of tert- butyl 5-amino-4-(5-(1-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The 371 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 6% - 36% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (8.45 mg, 17.4 μmol, 17.4% yield, 92.9% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 486.3 (M+H)+, (C26H27N7O3). EXAMPLE 328 [1048] Synthesis of 3-{5-[1-Methyl-2-(2-methylquinolin-6-yl)-1H-imidazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1049] A.6-(4-Bromo-1-methyl-1H-imidazol-2-yl)-2-methylquinoline: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2-methylquinolin-6-yl)boronic acid (37.4 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 303.0 (M+H)+, (C14H12BrN3). [1050] B. tert-Butyl 5-amino-4-(5-(1-methyl-2-(2-methylquinolin-6-yl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 6-(4-bromo-1-methyl-1H-imidazol-2-yl)-2- methylquinoline (45.5 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 372 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT crude intermediate which was used for next step directly. (ESI+) m/z: 540.3 (M+H)+, (C31H33N5O4). [1051] C.3-{5-[1-Methyl-2-(2-methylquinolin-6-yl)-1H-imidazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(1-methyl-2-(2-methylquinolin-6-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)- 5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 19% - 49% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (10.4 mg, 22.3 μmol, 22.3% yield, 97.7% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 466.3 (M+H)+, (C27H23N5O3). EXAMPLE 329 [1052] Synthesis of 3-{5-[2-(Furan-2-yl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1053] A.4-Bromo-2-(furan-2-yl)-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (furan-2- yl)boronic acid (22.2 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 228.0 (M+H)+, (C8H7BrN2O). [1054] B. tert-Butyl 5-amino-4-(5-(2-(furan-2-yl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 4-bromo-2-(furan-2-yl)-1-methyl-1H-imidazole (34.2 373 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 465.2 (M+H)+, (C25H28N4O5). [1055] C.3-{5-[2-(Furan-2-yl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(2-(furan-2-yl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 12% - 42% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (14.1 mg, 36.1 μmol, 36.1% yield, 97.5% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 391.3 (M+H)+, (C21H18N4O4). EXAMPLE 330 [1056] Synthesis of 3-[5-(2-{[1,1'-Biphenyl]-4-yl}-1-methyl-1H-imidazol-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione: [1057] A.2-([1,1'-Biphenyl]-4-yl)-4-bromo-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and [1,1'- biphenyl]-4-ylboronic acid (39.6 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), Pd(OAc)2 (4.48 mg, 0.02 mmol, 0.10 eq.) and tri(4-fluorophenyl)phosphine(7.32 mg, 0.02 mmol, 0.10 eq) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 314.0 (M+H)+, (C16H13BrN2). 374 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1058] B. tert-Butyl 4-(5-(2-([1,1'-biphenyl]-4-yl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 2-([1,1'-biphenyl]-4-yl)-4-bromo-1-methyl- 1H-imidazole (47.1mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 551.3 (M+H)+, (C33H34N4O4). [1059] C.3-[5-(2-{[1,1'-Biphenyl]-4-yl}-1-methyl-1H-imidazol-4-yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 4-(5-(2- ([1,1'-biphenyl]-4-yl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5- oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. After the reaction was completed, spot checked by LCMS. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 30% - 60% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (4.58 mg, 9.60 μmol, 9.60% yield, 90.8% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 477.3 (M+H)+, (C29H24N4O3). EXAMPLE 331 [1060] Synthesis of 3-(5-{2-[4-(Benzyloxy)phenyl]-1-methyl-1H-imidazol-4-yl}-1-oxo- 2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: [1061] A.2-(4-(Benzyloxy)phenyl)-4-bromo-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and [4-(benzyloxy)phenyl]boronic acid (45.6 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and 375 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 344.0 (M+H)+, (C17H15BrN2O). [1062] B. tert-Butyl 5-amino-4-(5-(2-(4-(benzyloxy)phenyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 2-(4-(benzyloxy)phenyl)-4-bromo-1- methyl-1H-imidazole (51.6 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 581.3 (M+H)+, (C34H36N4O5). [1063] C.3-(5-{2-[4-(Benzyloxy)phenyl]-1-methyl-1H-imidazol-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(4-(benzyloxy)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge C18 (150 * 25mm * 10 um) and gradient of 31% - 61% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (4.25 mg, 8.38 μmol, 8.38% yield, 97.9% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 507.3 (M+H)+, (C30H26N4O4). 376 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 332 [1064] Synthesis of 3-{5-[2-(2,6-Dimethylphenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1065] A.4-Bromo-2-(2,6-dimethylphenyl)-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2,6- dimethylphenyl)boronic acid (30.0 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 266.1 (M+H)+, (C12H13BrN2). [1066] B. tert-Butyl 5-amino-4-(5-(2-(2,6-dimethylphenyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 4-bromo-2-(2,6-dimethylphenyl)-1-methyl- 1H-imidazole (39.9 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 503.3 (M+H)+, (C29H34N4O4). [1067] C.3-{5-[2-(2,6-Dimethylphenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro- 1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5- amino-4-(5-(2-(2,6-dimethylphenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was 377 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 21% - 51% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (5.83 mg, 13.6 μmol, 13.6% yield, 98.5 % purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 429.3 (M+H)+, (C25H24N4O3). EXAMPLE 333 [1068] Synthesis of 3-{5-[2-(2,5-Difluorophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1069] A.4-Bromo-2-(2,5-difluorophenyl)-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2,5- difluorophenyl)boronic acid (32.8 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.0 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 274.0 (M+H)+, (C10H7BrF2N2). [1070] B. tert-Butyl 5-amino-4-(5-(2-(2,5-difluorophenyl)-1-methyl-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 4-bromo-2-(2,5-difluorophenyl)-1-methyl- 1H-imidazole (41.1 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.3 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 378 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT intermediate which was used for next step directly. (ESI+) m/z: 511.2 (M+H)+, (C27H28F2N4O4). [1071] C.3-{5-[2-(2,5-Difluorophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro- 1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5- amino-4-(5-(2-(2,5-difluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 18% - 48% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (7.02 mg, 16.1 μmol, 16.1% yield, 98.7% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 437.3 (M+H)+, (C23H18F2N4O3). EXAMPLE 334 [1072] Synthesis of 3-{5-[2-(3-Aminophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1073] A.3-(4-Bromo-1-methyl-1H-imidazol-2-yl)aniline: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (3- aminophenyl)boronic acid (27.4 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 253.0 (M+H)+, (C10H10BrN3). [1074] B. tert-Butyl 5-amino-4-(5-(2-(3-aminophenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino- 5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 3-(4-bromo-1-methyl-1H-imidazol-2-yl)aniline (38.0 mg, 379 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 490.2 (M+H)+, (C27H31N5O4). [1075] C.3-{5-[2-(3-Aminophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(2-(3-aminophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 9% - 39% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (4.04 mg, 9.71 μmol, 9.71% yield, 96.8% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 416.2 (M+H)+, (C23H21N5O3). EXAMPLE 335 [1076] Synthesis of 3-{5-[2-(2-Amino-5-methylphenyl)-1-methyl-1H-imidazol-4-yl]-1- oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1077] A.2-(4-Bromo-1-methyl-1H-imidazol-2-yl)-4-methylaniline: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2- amino-5-methylphenyl)boronic acid (30.0 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and 380 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 267.0 (M+H)+, (C11H12BrN3). [1078] B. tert-Butyl 5-amino-4-(5-(2-(2-amino-5-methylphenyl)-1-methyl-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 2-(4-bromo-1-methyl-1H-imidazol-2-yl)-4- methylaniline (40.1 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.3 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 504.3 (M+H)+, (C28H33N5O4). [1079] C.3-{5-[2-(2-Amino-5-methylphenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(2-amino-5-methylphenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18 (150 * 25 mm * 5 um) and gradient of 15% - 45% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (10.5 mg, 24.4 μmol, 24.4% yield, 99.0% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 430.3 (M+H)+, (C24H23N5O3). EXAMPLE 336 [1080] Synthesis of 3-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]-1-methyl-1H-imidazol-2-yl}-5-fluorobenzonitrile: [1081] A.3-(4-Bromo-1-methyl-1H-imidazol-2-yl)-5-fluorobenzonitrile: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (3-cyano-5-fluorophenyl)boronic acid (33.0 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 381 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 281.0 (M+H)+, (C11H7BrFN3). [1082] B. tert-Butyl 5-amino-4-(5-(2-(3-cyano-5-fluorophenyl)-1-methyl-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 3-(4-bromo-1-methyl-1H-imidazol-2-yl)-5- fluorobenzonitrile (42.2 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 518.2 (M+H)+, (C28H28FN5O4). [1083] C.3-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-1- methyl-1H-imidazol-2-yl}-5-fluorobenzonitrile: To a vial containing a solution of tert- butyl 5-amino-4-(5-(2-(3-cyano-5-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 18% - 48% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (5.23 mg, 11.8 μmol, 11.8% yield, 98.4% purity in HPLC at 220 nm) as a light yellow solid. (ESI+) m/z: 444.2 (M+H)+, (C24H18FN5O3). 382 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 337 [1084] Synthesis of 3-{5-[2-(1H-Indol-5-yl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1085] A.5-(4-Bromo-1-methyl-1H-imidazol-2-yl)-1H-indole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (1H- indol-5-yl)boronic acid (24.0 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr. The mixture was stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 277.0 (M+H)+, (C12H10BrN3). [1086] B. tert-Butyl 4-(5-(2-(1H-indol-5-yl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 5-(4-bromo-1-methyl-1H-imidazol-2-yl)- 1H-indole (41.6 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 514.2 (M+H)+, (C29H31N5O4). [1087] C.3-{5-[2-(1H-Indol-5-yl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 4-(5-(2-(1H- indol-5-yl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 383 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 15% - 45% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (12.7 mg, 28.9 μmol, 28.9% yield, 93.6% purity in HPLC at 220 nm) as a pink solid. (ESI+) m/z: 440.3 (M+H)+, (C25H21N5O3). EXAMPLE 338 [1088] Synthesis of 2-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]-1-methyl-1H-imidazol-2-yl}-4-fluorobenzonitrile: [1089] A.2-(4-Bromo-1-methyl-1H-imidazol-2-yl)-4-fluorobenzonitrile: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2-cyano-5-fluorophenyl)boronic acid (32.8 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 281.0 (M+H)+, (C11H7BrFN3). [1090] B. tert-Butyl 5-amino-4-(5-(2-(2-cyano-5-fluorophenyl)-1-methyl-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 2-(4-bromo-1-methyl-1H-imidazol-2-yl)-4- fluorobenzonitrile (42.2 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.30 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 384 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT crude intermediate which was used for next step directly. (ESI+) m/z: 518.2 (M+H)+, (C28H28FN5O4). [1091] C.2-{4-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-1- methyl-1H-imidazol-2-yl}-4-fluorobenzonitrile: To a vial containing a solution of tert- butyl 5-amino-4-(5-(2-(2-cyano-5-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 14% - 44% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (4.76 mg, 10.7 μmol, 10.7% yield, 91.4% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 444.3 (M+H)+, (C24H18FN5O3). EXAMPLE 339 [1092] Synthesis of 3-{5-[2-(2,4-Dichlorophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dion: [1093] A.4-Bromo-2-(2,4-dichlorophenyl)-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2,4- dichlorophenyl)boronic acid (38.0 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then was stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 306.0 (M+H)+, (C10H7BrCl2N2). [1094] B. tert-Butyl 5-amino-4-(5-(2-(2,4-dichlorophenyl)-1-methyl-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 4-bromo-2-(2,4-dichlorophenyl)-1-methyl- 385 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H-imidazole (45.9 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.3 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 544.1 (M+H)+, (C27H28Cl2N4O4). [1095] C.3-{5-[2-(2,4-Dichlorophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3-dihydro- 1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5- amino-4-(5-(2-(2,4-dichlorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge C18 (150 * 25 * 10 u) and gradient of 25% - 55% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (6.29 mg, 13.4 μmol, 13.4% yield, 90.1% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 469.1 (M+H)+, (C23H18Cl2N4O3). EXAMPLE 340 [1096] Synthesis of 3-{5-[2-(3-Chloro-2-fluorophenyl)-1-methyl-1H-imidazol-4-yl]-1- oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1097] A.4-Bromo-2-(3-chloro-2-fluorophenyl)-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (3-chloro-2-fluorophenyl)boronic acid (35.2 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then the mixture was stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over 386 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which used for next step directly. (ESI+) m/z: 290.0 (M+H)+, (C10H7BrClFN2). [1098] B. tert-Butyl 5-amino-4-(5-(2-(3-chloro-2-fluorophenyl)-1-methyl-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 4-bromo-2-(3-chloro-2-fluorophenyl)-1- methyl-1H-imidazole (43.2 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.3 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 528.2 (M+H)+, (C27H28ClFN4O4). [1099] C.3-{5-[2-(3-Chloro-2-fluorophenyl)-1-methyl-1H-imidazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(2-(3-chloro-2-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 22% - 52% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (4.70 mg, 10.4 μmol, 10.4% yield, 98.4% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 453.2 (M+H)+, (C23H18ClFN4O3). EXAMPLE 341 [1100] Synthesis of 3-{5-[2-(2,3-Dihydro-1-benzofuran-7-yl)-1-methyl-1H-imidazol-4- yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: 387 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1101] A.4-Bromo-2-(2,3-dihydrobenzofuran-7-yl)-1-methyl-1H-imidazole: To a vial containing a solution of 2,4-dibromo-1-methyl-1H-imidazole (48.0 mg, 0.20 mmol, 1.00 eq.) and (2,3-dihydro-1-benzofuran-7-yl)boronic acid (32.6 mg, 0.20 mmol, 1.00 eq.) in dioxane (1.50 mL) was added K3PO4 (2.00 M in H2O, 0.30 mL, 0.60 mmol, 3.00 eq.), and Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 40 °C for 1 hr, and then the mixture was stirred at 80 °C for 1 hr. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 280.0 (M+H)+, (C12H11BrN2O). [1102] B. tert-Butyl 5-amino-4-(5-(2-(2,3-dihydrobenzofuran-7-yl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)pentanoate (66.6 mg, 0.15 mmol, 1.00 eq.) and 4-bromo-2-(2,3-dihydrobenzofuran-7- yl)-1-methyl-1H-imidazole (42.0 mg, 0.15 mmol, 1.00 eq.) in dioxane (1.00 mL) was added K3PO4 (1.50 M in H2O, 0.3 mL, 0.45 mmol, 3.00 eq.), and Pd-118 (9.77 mg, 0.015 mmol, 0.10 eq.) under protection of N2. The mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under N2 to give a residue. The residue was diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3). The combined organic layers were washed with brine (2.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate which was used for next step directly. (ESI+) m/z: 517.2 (M+H)+, (C29H32N4O5). [1103] C.3-{5-[2-(2,3-Dihydro-1-benzofuran-7-yl)-1-methyl-1H-imidazol-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert- butyl 5-amino-4-(5-(2-(2,3-dihydrobenzofuran-7-yl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10um) and gradient of 19% - 49% acetonitrile in water containing 10 mM NH4HCO3 over 13 mins at a flow rate of 25 mL/min to give final product (22.0 mg, 49.7 μmol, 49.7% yield, 98.0% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 443.2 (M+H)+, (C25H22N4O4). 388 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 342 [1104] Synthesis of 3-[5-(5-Cycloheptyl-1-methyl-1H-pyrazol-4-yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]piperidine-2,6-dione: [1105] A. tert-Butyl 5-amino-4-(5-(5-(cyclohept-1-en-1-yl)-1-methyl-1H-pyrazol-4-yl)- 1-oxoisoindolin-2-yl)-5-oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-4-(5- (5-bromo-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (95.2 mg, 0.20 mmol, 1.00 eq.) in dioxane (2.00 mL) and K3PO4 (2 M in H2O, 200 uL, 0.40 mmol, 2.00 eq.) was added 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66.6 mg, 0.30 mmol, 1.50 eq.), Pd-118 (6.50 mg, 0.01 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL) and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 493.3 (M+H)+, (C28H36N4O4). [1106] B. tert-Butyl 5-amino-4-(5-(5-cycloheptyl-1-methyl-1H-pyrazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5- (cyclohept-1-en-1-yl)-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.20 mmol, 1.00 eq.) and AcOH (3.60 mg, 0.06 mmol, 0.30 eq.) in THF (1.50 mL) and MeOH (1.50 mL) was added Pd/C (10%, 120 mg, 0.60 eq.) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 16 hrs. The mixture was filtered and concentrated to give crude intermediate which was used for next step. (ESI+) m/z: 495.3 (M+H)+, (C28H38N4O4). [1107] C.3-[5-(5-Cycloheptyl-1-methyl-1H-pyrazol-4-yl)-1-oxo-2,3-dihydro-1H- isoindol-2-yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(5-cycloheptyl-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18 (150 * 25 mm * 5 um) and gradient of 29% - 59% acetonitrile in water containing 0.225% FA over 389 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 10 mins at a flow rate of 25 mL/min to give final product (12.4 mg, 29.4 μmol, 29.4% yield, 98.7% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 421.4 (M+H)+, (C24H28N4O3). EXAMPLE 343 [1108] Synthesis of 3-{5-[5-(2,5-Dihydro-1H-pyrrol-3-yl)-1-methyl-1H-pyrazol-4-yl]-1- oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: [1109] A. tert-Butyl 3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1- oxoisoindolin-5-yl)-1-methyl-1H-pyrazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate: Under N2, to a solution of tert-butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (95.2 mg, 0.20 mmol, 1.00 eq.) in dioxane (2.00 mL) and K3PO4 (2 M in H2O, 200 uL, 0.40 mmol, 2.00 eq.) was added tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (88.6 mg, 0.30 mmol, 1.50 eq.), Pd-118 (6.50 mg, 0.01 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL) and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 566.3 (M+H)+, (C30H39N5O6). [1110] B.3-{5-[5-(2,5-Dihydro-1H-pyrrol-3-yl)-1-methyl-1H-pyrazol-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione: To a vial containing a solution of tert-butyl 3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-1-methyl-1H- pyrazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (~0.20 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 800 umol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18 (150 * 25 mm * 5 um) and gradient of 0% - 27% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (9.70 mg, 24.7 μmol, 24.7% yield, 90.4% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 392.2 (M+H)+, (C21H21N5O3). 390 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 344 [1111] Synthesis of 3-[5-(1-Methyl-1H-indazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]piperidine-2,6-dione: [1112] A. tert-Butyl 5-amino-4-(5-(1-methyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (47.6 mg, 100 μmol, 1.00 eq.) and 3-bromo-1-methyl-1H-indazole (31.4 mg, 150 μmol, 1.50 eq.) in dioxane (1.00 mL) was added K3PO4 (2 M in H2O, 100 uL, 200 umol, 2.00 eq.), Pd-118 (3.25 mg, 0.005 umol, 0.05 eq.) under protection of N2. The mixture was stirred at 85 °C for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 449.2 (M+H)+, (C25H28N4O4). [1113] B.3-[5-(1-Methyl-1H-indazol-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(1- methyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 800 umol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Welch Xtimate C18 (150 * 25 mm * 5 um) and gradient of 27% - 57% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (15.7 mg, 41.9 μmol, 41.9% yield, 99.6% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 375.2 (M+H)+, (C21H18N4O3). EXAMPLE 345 [1114] Synthesis of 3-(5-{Imidazo[1,2-a]pyrazin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol- 2-yl)piperidine-2,6-dione: 391 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1115] A. tert-Butyl 5-amino-4-(5-(imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (47.6 mg, 100 μmol, 1.00 eq.) and 3-bromoimidazo[1,2-a]pyrazine (29.4 mg, 150 μmol, 1.50 eq.) in dioxane (1.20 mL) was added K3PO4 (2 M in H2O, 100 uL, 200 umol, 2.00 eq.), Pd-118 (3.25 mg, 0.005 umol, 0.05 eq.) under protection of N2. The mixture was stirred at 85 °C for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (2.00 mL) and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 436.2 (M+H)+, (C23H25N5O4). [1116] B.3-(5-{Imidazo[1,2-a]pyrazin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5- (imidazo[1,2-a]pyrazin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (crude, ~100 μmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 800 umol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under nitrogen gas and the residue was purified by prep-HPLC (using a column: Waters Xbridge (150 * 25 mm * 10 um) and gradient of 0% - 30% acetonitrile in water containing 10 mM NH4HCO3 over 10 mins at a flow rate of 25 mL/min to give final product (4.06 mg, 11.2 μmol, 11.2% yield, 90.1% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 362.2 (M+H)+, (C19H15N5O3). EXAMPLE 346 [1117] Synthesis of 3-(1-Oxo-5-{pyrazolo[1,5-a]pyrimidin-3-yl}-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione: [1118] A. tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(pyrazolo[1,5-a]pyrimidin-3- yl)isoindolin-2-yl)pentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromopyrazolo[1,5-a]pyrimidine (29.7 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 436.2 (M+H)+, (C23H25N5O4). 392 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1119] B.3-(1-Oxo-5-{pyrazolo[1,5-a]pyrimidin-3-yl}-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-5-oxo-4-(1- oxo-5-(pyrazolo[1,5-a]pyrimidin-3-yl)isoindolin-2-yl)pentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18150 * 25mm * 5um and gradient of 14% - 44% acetonitrile in water containing 0.225% FA over 10 mins at a flow rate of 25 mL/min to give final product (7.75 mg, 21.4 μmol, 21.4% yield, 90.19% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 362.3 (M+H)+, (C19H15N5O3). EXAMPLE 347 [1120] Synthesis of 3-(5-{Imidazo[1,2-a]pyridin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol- 2-yl)piperidine-2,6-dione: [1121] A. tert-Butyl 5-amino-4-(5-(imidazo[1,2-a]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromoimidazo[1,2-a]pyridine (29.5 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 435.2 (M+H)+, (C24H26N4O4). [1122] B.3-(5-{Imidazo[1,2-a]pyridin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5- (imidazo[1,2-a]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18150 * 25mm * 5um and gradient of 7% - 37% acetonitrile in water containing 10 mM NH4HCO310 mins at 393 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT a flow rate of 25 mL/min to give final product (11.27 mg, 31.2 umol, 31.2% yield, 93.78% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 361.2 (M+H)+, (C20H16N4O3). EXAMPLE 348 [1123] Synthesis of 3-(1-Oxo-5-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione: [1124] A. tert-Butyl 4-(5-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5- amino-5-oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromo-[1,2,4]triazolo[4,3-a]pyridine (29.7 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 436.2 (M+H)+, (C23H25N5O4). [1125] B.3-(1-Oxo-5-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 4-(5- ([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge 150 * 25mm * 10um and gradient of 0% - 29% acetonitrile in water containing 10 mM NH4HCO3 13 mins at a flow rate of 25 mL/min to give final product (4.69 mg, 12.9 umol, 12.9% yield, 91.96% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 362.2 (M+H)+, (C19H15N5O3). 394 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 349 [1126] Synthesis of 3-(5-{1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: [1127] A. tert-Butyl 5-amino-4-(5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo- 4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (31.8 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 450.2 (M+H)+, (C24H27N5O4). [1128] B.3-(5-{1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-1-oxo-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4- (5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18150 * 25mm * 5um and gradient of 16% - 46% acetonitrile in water containing 0.225% FA 10 mins at a flow rate of 25 mL/min to give final product (12.24 mg, 32.5 umol, 32.5% yield, 98.31% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 376.2 (M+H)+, (C20H17N5O3). EXAMPLE 350 [1129] Synthesis of 3-(5-{Imidazo[1,5-a]pyridin-1-yl}-1-oxo-2,3-dihydro-1H-isoindol- 2-yl)piperidine-2,6-dione: 395 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1130] A. tert-Butyl 5-amino-4-(5-(imidazo[1,5-a]pyridin-1-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 1-bromoimidazo[1,5-a]pyridine (29.5 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 435.2 (M+H)+, (C24H26N4O4). [1131] B.3-(5-{Imidazo[1,5-a]pyridin-1-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5- (imidazo[1,5-a]pyridin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge 150 * 25mm * 10um and gradient of 10% - 40% acetonitrile in water containing 10 mM NH4HCO313 mins at a flow rate of 25 mL/min to give final product (7.06 mg, 19.5 umol, 19.5% yield, 92.55% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 361.2 (M+H)+, (C20H16N4O3). EXAMPLE 351 [1132] Synthesis of 3-(5-{6-Methoxyimidazo[1,2-a]pyridin-3-yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)piperidine-2,6-dione: [1133] A. tert-Butyl 5-amino-4-(5-(6-methoxyimidazo[1,2-a]pyridin-3-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo- 4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromo-6-methoxyimidazo[1,2-a]pyridine (34.1 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated 396 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT to give crude intermediate which was used for next step directly. (ESI+) m/z: 465.2 (M+H)+, (C25H28N4O5). [1134] B.3-(5-{6-Methoxyimidazo[1,2-a]pyridin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol- 2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(6- methoxyimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge C18150 * 25 * 10um and gradient of 10% - 40% acetonitrile in water containing 10 mM NH4HCO310 mins at a flow rate of 25 mL/min to give final product (6.99 mg, 17.8 umol, 17.8% yield, 91.82% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 391.2 (M+H)+, (C21H18N4O4). EXAMPLE 352 [1135] Synthesis of 3-(1-Oxo-5-{1H-pyrrolo[3,2-b]pyridin-3-yl}-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione: [1136] A. tert-Butyl 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1- oxoisoindolin-5-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate: Under N2, to a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added tert-butyl 3-bromo-1H-pyrrolo[3,2-b]pyridine- 1-carboxylate (44.5 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 535.3 (M+H)+, (C29H34N4O6). [1137] B.3-(1-Oxo-5-{1H-pyrrolo[3,2-b]pyridin-3-yl}-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 3-(2-(1-amino-5-(tert- butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-1H-pyrrolo[3,2-b]pyridine-1- carboxylate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was 397 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge C18150 * 25 * 10um and gradient of 8% - 38% acetonitrile in water containing 10 mM NH4HCO310 mins at a flow rate of 25 mL/min to give final product (13.03 mg, 36.1 umol, 36.1% yield, 91.87% purity in HPLC at 220 nm) as a light-yellow solid. (ESI+) m/z: 361.2 (M+H)+, (C20H16N4O3). EXAMPLE 353 [1138] Synthesis of 3-(5-{5-Methoxyimidazo[1,2-a]pyridin-3-yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)piperidine-2,6-dione: [1139] A. tert-Butyl 5-amino-4-(5-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo- 4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromo-5-methoxyimidazo[1,2-a]pyridine (34.1 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL) and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 465.2 (M+H)+, (C25H28N4O5). [1140] B.3-(5-{5-Methoxyimidazo[1,2-a]pyridin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol- 2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(5- methoxyimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge C18150 * 25 * 10um and gradient of 8% - 38% acetonitrile in water containing 10 mM NH4HCO310 mins at a flow rate of 25 mL/min to give final product (8.14 mg, 20.8 umol, 20.8% yield, 96.17% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 391.2 (M+H)+, (C21H18N4O4). 398 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 354 [1141] Synthesis of 3-(5-{Furo[3,2-b]pyridin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: [1142] A. tert-Butyl 5-amino-4-(5-(furo[3,2-b]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq.) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromofuro[3,2-b]pyridine (29.7 mg, 0.15 mmol, 1.50 eq.), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq.). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL), and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 436.2 (M+H)+, (C24H25N3O5). [1143] B.3-(5-{Furo[3,2-b]pyridin-3-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino-4-(5-(furo[3,2- b]pyridin-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (~0.10 mmol, 1.00 eq.) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq.). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Welch Ultimate C18150 * 25mm * 5um and gradient of 16% - 46% acetonitrile in water containing 0.225% FA 10 mins at a flow rate of 25 mL/min to give final product (5.13 mg, 14.2 umol, 14.2% yield, 95.73% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 362.2 (M+H)+, (C20H15N3O4). EXAMPLE 355 [1144] Synthesis of 3-(5-{6-Methoxy-2-methylimidazo[1,2-b]pyridazin-3-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dione: [1145] A. tert-Butyl 5-amino-4-(5-(6-methoxy-2-methylimidazo[1,2-b]pyridazin-3-yl)- 1-oxoisoindolin-2-yl)-5-oxopentanoate: Under N2, to a solution of tert-butyl 5-amino-5- 399 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (44.4 mg, 0.10 mmol, 1.00 eq) in dioxane (1.00 mL) and K3PO4 (2 M in H2O, 100 uL, 0.20 mmol, 2.00 eq.) was added 3-bromo-6-methoxy-2-methylimidazo[1,2-b]pyridazine (36.3 mg, 0.15 mmol, 1.50 eq), Pd-118 (3.25 mg, 0.005 mmol, 0.05 eq). Then the mixture was stirred at 85 ℃ for 16 hrs. The reaction mixture was concentrated under nitrogen flow gas, diluted with H2O (1.00 mL) and extracted with ethyl acetate (2.00 mL * 3), dried over Na2SO4, filtered, and concentrated to give crude intermediate which was used for next step directly. (ESI+) m/z: 480.2 (M+H)+, (C25H29N5O5). [1146] B.3-(5-{6-Methoxy-2-methylimidazo[1,2-b]pyridazin-3-yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)piperidine-2,6-dione: To a vial containing a solution of tert-butyl 5-amino- 4-(5-(6-methoxy-2-methylimidazo[1,2-b]pyridazin-3-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (~0.10 mmol, 1.00 eq) in CH3CN (1.00 mL) was added TsOH.H2O (152 mg, 0.80 mmol, 8.00 eq). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under N2 to give a residue. The residue was purified by prep-HPLC (using a column: Waters Xbridge 150 * 25mm * 10um and gradient of 16% - 36% acetonitrile in water containing 10 mM NH4HCO313 mins at a flow rate of 25 mL/min to give final product (4.32 mg, 10.6 umol, 10.6% yield, 97.85% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 406.2 (M+H)+, (C21H19N5O4). EXAMPLE 356 [1147] Synthesis of 3-(6-Fluoro-5-(1-methyl-4,5-diphenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1148] A. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of 4- bromo-5-fluoro-2-methyl-benzoic acid (25.0 g, 107 mmol, 1.00 eq) in DMF (300 mL) was added K2CO3 (37.0 g, 268 mmol, 2.50 eq) and CH3I (45.6 g, 321 mmol, 20.0 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. Then the mixture was filtered and the filtrate was washed with brine (4 x 150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25.5 g, 98.0 mmol, 91.4% yield, 95.0% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, CDCl3) δ 7.65 400 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (d, J = 9.6 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H). (ESI+) m/z: 246.9 (M+H)+, (C9H8BrFO2). [1149] B. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2-methyl-benzoate (7.00 g, 28.3 mmol, 1.00 eq) in DCE (70.0 mL) was added NBS (6.05 g, 34.0 mmol, 1.20 eq) and AIBN (465 mg, 2.83 mmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 85 °C for 8 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 1: 0 to 100: 2, Rf = 0.50) to give the title compound (5.80 g, 17.7 mmol, 62.8% yield) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 4.89 (s, 2H), 3.96 (s, 3H). (ESI+) m/z: 324.8 (M+H)+, (C9H7Br2FO2). [1150] C.3-(5-Bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-aminopiperidine-2,6-dione (2.93 g, 17.7 mmol, 1.00 eq, HCl) in ACN (140 mL) was added DIEA (5.75 g, 44.4 mmol, 7.75 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h under N2. Then methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.80 g, 17.7 mmol, 1.00 eq) was added and the reaction mixture was stirred at 85 °C for 12 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, DCM: Methanol =100: 1 to 100: 3, Rf = 0.40) to give the title compound (3.20 g, 9.31 mmol, 52.3% yield, 99.2% purity in LCMS at 220 nm) as a blue solid. (ESI+) m/z: 340.9 (M+H)+, (C13H10BrFN2O3). [1151] D.3-(6-Fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.00 g, 5.86 mmol, 1.00 eq) in DMF (30.0 mL)was added BPD (4.44 g, 17.4 mmol, 3.00 eq), KOAc (1.71 g, 17.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (851 mg, 1.17 mmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was added dropped into 50.0 mL of ice water and a brown solid was separated out. The mixture was filtered. The filter cake was washed with H2O (3 x 50.0 mL), then washed with EtOAc until the filtrate was colorless. The filter cake was collected and dried in vacuum to give the title compound (1.00 g, crude) as a gray solid. (ESI+) m/z: 306.9 (M+H)+, (C13H12BFN2O5). [1152] E.3-(6-Fluoro-5-(1-methyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of 3-[6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (322 mg, 830 μmol, 2.00 eq), 2- bromo-1-methyl-4,5-diphenyl-imidazole (130 mg, 415 μmol, 1.00 eq), RuPhos Pd G3 (69.4 401 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mg, 83.0 μmol, 0.20 eq), K3PO4 (264 mg, 1.25 mmol, 3.00 eq) in dioxane (4.00 mL) and H2O (0.02 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 5 μm) and gradiente of 20 - 50% acetonitrile in water containing 0.05% TFA over 18 min at a flow rate of 25 mL/min) to give the title compound (162 mg, 325 μmol, 78.3% yield, 99.1% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.61 - 7.49 (m, 5H), 7.46 - 7.40 (m, 2H), 7.34 - 7.21 (m, 3H), 5.21 - 5.16 (M, 1H), 4.62 - 4.55 (m, 1H), 4.49 - 4.43 (m, 1H), 3.43 (s, 3H), 3.00 - 2.88 (m, 1H), 2.68 - 2.58 (m, 1H), 2.48 - 2.31 (m, 1H), 2.11 - 2.02 (m, 1H). (ESI+) m/z: 495.2 (M+H)+, (C29H23FN4O3). EXAMPLE 357 [1153] Synthesis of 3-(4-Fluoro-5-(1-methyl-4,5-diphenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1154] A.3-(4-Fluoro-5-(1-methyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-4,5-diphenyl-1H-imidazole (200 mg, 624 μmol, 1.00 eq) and 3-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (727 mg, 1.87 mmol, 3.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (52.2 mg, 62.4 μmol, 0.10 eq) and K3PO4 (265 mg, 1.25 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane : Methanol = 20: 1, Rf = 0.20) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 15 - 45% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (69.2 mg, 139 μmol, 22.3% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.87 (t, J = 6.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.58 - 7.47 (m, 5H), 7.45 - 7.42 (m, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.18 - 7.13(m, 402 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 5.18 (dd, J = 13.2, 5.2 Hz, 1H), 4.61 (dd, J = 67.2, 17.6 Hz, 2H), 3.38 (d, J = 2.0 Hz, 3H), 2.99 - 2.91 (m, 1H), 2.60 - 2.59 (m, 1H), 2.48 - 2.46 (m, 1H), 2.06 - 2.03 (m, 1H). (ESI+) m/z: 477.1 (M+H)+, (C29H23FN4O3). EXAMPLE 358 [1155] Synthesis of 3-(5-(1-Cyclobutyl-4,5-diphenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1156] A.1-Cyclobutylurea: To a solution of cyclobutanamine (5.00 g, 70.30 mmol, 6.02 mL, 1.00 eq) in HCl (5 M, 18.0 mL, 1.28 eq) at 0 °C was added KOCN (5.70 g, 70.30 mmol, 2.77 mL, 1.00 eq). The mixture was stirred at 75 °C for 16 h. The mixture was concentrated under vacuo to give a residue. The residue was purified by triturated with MTBE (50.0 mL) at 25 ℃ for 30 min to give the title compound (5.21 g, 45.64 mmol, 64.9% yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ 6.23 (d, J = 8.0 Hz, 1H), 4.01 – 3.95 (m, 1H), 2.13 – 2.09 (m, 1H), 1.74 – 1.72 (m, 1H), 1.54 – 1.46 (m, 1H). (C5H10N2O). [1157] B.1-Cyclobutyl-4,5-diphenyl-1H-imidazol-2(3H)-one: A solution of 2-hydroxy- 1,2-diphenyl-ethanone (2.00 g, 9.42 mmol, 1.00 eq) in AcOH (20.0 mL) was added 1- cyclobutylurea (1.18 g, 10.37 mmol, 1.10 eq). The mixture was stirred at 140 °C for 12 h. The reaction mixture was poured into water (10.0 mL) and extracted with DCM (3 x 20 mL). The organic layers were washed with NaHCO3, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give the title compound (2.70 g, 9.30 mmol, crude) as a white solid. (ESI+) m/z: 291.1 (M+H)+ (C19H18N2O). [1158] C.1-Cyclobutyl-4,5-diphenyl-1H-imidazol-2(3H)-one: A solution of 3- cyclobutyl-4,5-diphenyl-1H-imidazol-2-one (2.20 g, 7.58 mmol, 1 eq) in POBr3 (6.52 g, 22.73 mmol, 2.31 mL, 3.00 eq) mixture was stirred at 130 °C for 8 h. The reaction mixture was poured into ice-H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 49 - 74% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (160 mg, 431 μmol, 403 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 5.70% yield, 95.3% purity in LCMS at 220 nm) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ7.53 - 7.51 (m, 3H), 7.43 - 7.41 (m, 2H), 7.25 - 7.23 (m, 2H), 7.17 - 7.13 (m, 3H), 4.66 – 4.58 (m, 1H), 2.50 – 2.46 (m, 2H), 2.15 – 2.11 (m, 2H), 1.62 – 1.57 (m, 2H). (ESI+) m/z: 354.9 (M+H)+, (C19H17BrN2). [1159] D.3-(5-(1-Cyclobutyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione: To a solution of 1-cyclobutyl-4,5-diphenyl-1H-imidazol-2(3H) (140 mg, 396.31 μmol, 1.00 eq) in 1,4-dioxane (1.40 mL) and H2O (0.14 mL) was added 3-(1-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindolin-2-yl) piperidine-2,6-dione (293 mg, 792.6 μmol, 2.00 eq) and K3PO4 (168 mg, 792 μmol, 2.00 eq) ,RuPhos Pd G3 (33.1 mg, 39.6 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 16 - 46% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL/min) to give the title compound (67.5 mg, 126 μmol, 31.9% yield, 96.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.93 (s, 1H), 7.84 (s, 2H), 7.54 – 7.46 (m, 5H), 7.40 - 7.38 (m, 2H), 7.25 - 7.19 (m, 3H), 5.19 - 5.14 (m, 1H), 5.08 - 5.04 (m, 1H) 4.60 - 4.42 (m, 2H), 2.94 - 2.90 (m, 1H), 2.64 – 2.60 (m, 1H), 2.42 - 2.39 (m, 1H), 2.07 - 1.98 (m, 1H), 1.76 - 1.71 (m, 4H), 1.42 - 1.33 (m, 2H). (ESI+) m/z: 517.2 (M+H)+, (C32H28N4O3). EXAMPLE 359 [1160] Synthesis of 3-(5-(1-Methyl-5-phenyl-4-(o-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1161] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-phenyl-4-(o-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-[5-(4-bromo-1- methyl-5-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (500 mg, 903 μmol, 1.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added o-tolylboronic acid (245 mg, 1.81 mmol, 2.00 eq), Ru-Phos-Pd-G3 (75.5 mg, 90.3 μmol, 0.10 eq) and K3PO4 (575 mg, 2.71 mmol, 3.00 eq) under N2, then the reaction mixture was stirred at 80 °C for 2 h under N2. The 404 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture was filtered and concentrated to give residue. The crude product was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 19: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.60) to give the title compound (350 mg, 619 μmol, 68.6% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.38 - 7.24 (m, 6H), 7.19 - 7.10 (m, 3H), 6.41 (s, 1H), 5.45 (s, 1H), 4.96 - 4.93 (m, 1H), 4.65 - 4.50 (m, 2H), 3.72 (s, 3H), 2.45 - 2.19 (m, 4H), 2.17 (s, 3H), 1.42 (s, 9H). (ESI+) m/z: 565.5 (M+H)+, (C34H36N4O4). [1162] B.3-(5-(1-Methyl-5-phenyl-4-(o-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione : To a solution of tert-butyl 5-amino-4-[5-[1-methyl-4-(o-tolyl)-5- phenyl-imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (150 mg, 265 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (137 mg, 796 μmol, 3.00 eq) and stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give residue. The crude compound was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.50) and preparative-HPLC (using a CD01- Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 15 - 45% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 30.0 mL/min) to give the title compound (81.5 mg, 165 μmol, 62.4% yield, 99.8% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.04 (s, 1H),7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.42 - 7.29 (m, 5H), 7.17 - 7.06 (m, 4H), 5.18 - 5.14 (m, 1H), 4.59 - 4.42 (m, 2H), 3.68 (s, 3H), 2.96 - 2.89 (m, 1H), 2.64 - 2.59 (m, 1H), 2.45 - 2.43 (m, 1H), 2.14 (s, 3H), 2.07 - 2.02 (m, 1H). (ESI+) m/z: 491.1 (M+H)+, (C30H26N4O3). EXAMPLE 360 [1163] Synthesis of 3-(5-(1-Methyl-4-phenyl-5-(p-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1164] A.1-Methyl-4-phenyl-1H-imidazole: To a solution of 4-phenyl-1H-imidazole (30 g, 208 mmol, 1.00 eq) in DMF (450 mL) was added Cs2CO3 (88.1 g, 270 mmol, 1.30 eq) at 20 °C under N2. Then was added MeI (32.4 g, 228 mmol, 14.2 mL, 1.10 eq) under N2. The 405 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture was stirred at 20 °C for 12 h under N2. The reaction mixture was poured into H2O (1000 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine (3 x 500 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 200: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.30) to give the title compound (20.5 g, 129 mmol, 62.2% yield, 100% purity in LCMS at 220 nm) as yellow solid.1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.60 Hz, 2H), 7.48 (s, 1H), 7.39 - 7.35 (m, 2H), 7.22 - 7.27 (m, 1H), 7.18 (s, 1H), 3.72 (s, 3H). (ESI+) m/z: 158.9 (M+H)+, (C10H10N2). [1165] B.2-Iodo-1-methyl-4-phenyl-1H-imidazole: To a solution of 1-methyl-4-phenyl- 1H-imidazole (5.00 g, 31.6 mmol, 1.00 eq) in THF (50.0 mL) was cooled to -70 °C, then n- BuLi (2.5 M, 18.9 mL, 1.50 eq) was dropwise to the mixture at -70 °C under N2. Then the reaction mixture was stirred at -70 °C for 1 h, after that a solution of I2 (8.82 g, 34.7 mmol, 7.00 mL, 1.10 eq) in THF (10.0 mL) was added to the reaction mixture at -70 °C under N2. The mixture was stirred at 0 °C for 2 h under N2. The reaction mixture was quenched with H2O (200 mL) and extracted with ethyl acetate (3 x 200 mL) to get the organic layers, the organic layers was washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under vacuum to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.30) to give the title compound (5.00 g, 17.0 mmol, 53.9% yield, 96.8% purity in LCMS at 220 nm) as yellow solid.1H NMR (400 MHz, CDCl3) δ 7.73 – 7.71 (m, 2H), 7.38 – 7.34 (m, 2H), 7.31 (s, 1H), 7.22 - 7.27 (m, 1H), 3.65 (s, 3H). (ESI+) m/z: 284.1 (M+H)+, (C10H9IN2). [1166] C. tert-Butyl 5-amino-4-(5-(1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 2-iodo-1-methyl-4-phenyl-1H- imidazole (4.40 g, 15.4 mmol, 1.00 eq), tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (7.23 g, 16.2 mmol, 1.05 eq) and K3PO4 (9.86 g, 46.4 mmol, 3.00 eq) in dioxane (50.0 mL) and H2O (2.50 mL) was added Ru-Phos-Pd-G3 (1.30 g, 1.55 mmol, 0.10 eq) under N2.The mixture was stirred at 90 °C for 6 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol =200: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1,Rf=0.40) to give the title compound (3.20 g, 5.46 mol, 35.3% yield, 81% purity in LCMS at 220 nm) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.90 (m, 1H), 7.89 - 7.88 (m, 1H), 7.82 - 7.79 (m, 4H), 7.63 - 7.61 (m, 1H), 7.39 - 7.35 (m, 2H), 7.24 - 7.22 (m, 2H), 4.78 - 4.75 (m, 1H), 406 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 4.67 - 4.53 (m, 2H), 3.83 (s, 3H), 2.21 - 2.15 (m, 3H), 2.14 - 1.99 (m, 1H), 1.06 (s, 9H). (ESI+) m/z: 475.2 (M+H)+, (C27H30N4O4). [1167] D. tert-Butyl 5-amino-4-(5-(5-bromo-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1-methyl-4- phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.80 g, 5.90 mmol, 1.00 eq) in ACN (100 mL) was added NBS (1.16 g, 6.49 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (3 x 200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol =200: 1 to 30: 1, TLC: Dichloromethane: Methanol = 30: 1,Rf=0.40) to give the title compound (1.70 g, 2.88 mmol, 48.8% yield, 93.8% purity in LCMS at 220 nm) as light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.95 (m, 3H), 7.87 - 7.84 (m, 2H), 7.63 - 7.61 (m, 1H), 7.47 - 7.42 (m, 2H), 7.35 - 7.33 (m, 1H), 7.31 - 7.24 (m, 1H), 4.78 - 4.75 (m, 1H), 4.72 - 4.54 (m, 2H), 3.81 (s, 3H), 2.21 - 2.16 (m, 3H), 2.02 - 1.98 (m, 1H), 1.40 - 1.31 (m, 9H),. (ESI+) m/z: 555.0 (M+H)+, (C27H29BrN4O4). [1168] E. tert-Butyl 5-amino-4-(5-(1-methyl-4-phenyl-5-(p-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5-bromo-1- methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 361 μmol, 1.00 eq), p-tolylboronic acid (98.2 mg, 722 μmol, 2.00 eq) and K3PO4 (230 mg, 1.08 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (30.2 mg, 36.1 μmol, 0.10 eq) under N2.The mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC (Dichloromethane: Methanol = 20: 1,Rf=0.40) to give the title compound (160 mg, 276 μmol, 76.4% yield, 97.5% purity in LCMS at 220 nm) as light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.05 - 8.03 (m, 1H), 7.93 - 7.90 (m, 1H), 7.84 - 7.82 (m, 1H), 7.63 - 7.61 (m, 1H), 7.47 - 7.45 (m, 2H), 7.36 - 7.34 (m, 4H), 7.25 - 7.22 (m, 3H), 7.21 - 7.14 (m, 1H), 4.79 - 4.75 (m, 1H), 4.73 - 4.55 (m, 2H), 3.51 (s, 3H), 2.40 (s, 3H), 2.22 - 2.17 (m, 3H), 2.03 - 1.98 (m, 1H), 1.33 (s, 9H). (ESI+) m/z: 565.3 (M+H)+, (C34H36N4O4). [1169] F.3-(5-(1-Methyl-4-phenyl-5-(p-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(1-methyl-4-phenyl-5-(p- tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 mg, 283. μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (97.5 mg, 566 μmol, 2.00 eq) at 80 °C. The mixture 407 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 16.0% - 46.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (105 mg, 213 μmol, 75.3% yield, 99.1% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.12 (s, 1H), 8.03 - 8.00 (m, 2H), 7.51 - 7.49 (m, 2H), 7.46 - 7.40 (m, 4H), 7.37 - 7.32 (m, 3H), 5.21 - 5.16 (m, 1H), 4.63 - 4.46 (m, 2H), 3.63 - 3.55 (m, 3H), 3.00 - 2.90 (m, 1H), 2.65 - 2.61 (m, 1H), 2.47 - 2.40 (m, 4H), 2.07 - 2.04 (m, 1H). (ESI+) m/z: 491.0 (M+H)+, (C30H26N4O3). EXAMPLE 361 [1170] Synthesis of 3-(5-(1-Methyl-4-phenyl-5-(m-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1171] A. tert-Butyl 5-amino-4-(5-(1-methyl-4-phenyl-5-(m-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a mixture of tert-butyl 5-amino-4-(5-(5-bromo-1- methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 361 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.20 mL) was added m-tolylboronic acid (98.2 mg, 722 μmol, 2.00 eq), K3PO4 (230 mg, 1.08 mmol, 3.00 eq) and Ru-phos-Pd-G3 (30.2 mg, 36.1 μmol, 0.10 eq) under N2. The mixtture was stirred at 100°C fot 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 500: 1 to 0: 1, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.32) to give the title compound (180 mg, 342 μmol, 70.4% yield, 96.7% purity) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.92 - 7.90 (m, 1H), 7.84 - 7.60 (m, 1H), 7.40 (s, 1H), 7.44 - 7.43 (m, 3H), 7.33 - 7.30 (m, 2H), 7.30 - 7.22 (m, 4H), 7.20 -7.14 (m, 1H), 4.78 - 4.75 (m, 1H), 4.73 - 4.54 (m, 2H), 3.51 (s, 3H), 2.36 (s, 3H), 2.20 - 2.19 (m, 3H), 2.06 - 2.00 (m, 1H), 1.39 (s, 9H). (ESI+) m/z: 565.3 (M+H)+, (C34H36N4O4). [1172] B.3-(5-(1-Methyl-4-phenyl-5-(m-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a mixture of tert-butyl tert-butyl 5-amino-4-(5-(1-methyl-4- 408 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT phenyl-5-(m-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (180 mg, 318 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (109 mg, 637 μmol, 2.00 eq) under N2. The mixture was stirred at 80 °C for 4 h under N2. The reaction mixture was filtered and the filter cake was washed with 5.00 mL of ACN, dried in vacuum to give product. The residue was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm 10 μm) and gradient of 25 - 55% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25.0 mL/min) to give the title compound (125.13 mg, 249 μmol, 78.1% yield, 97.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.11 (s, 1H), 8.01 - 7.99 (m, 2H), 7.47 - 7.44 (m, 3H), 7.36 - 7.30 (m, 6H), 5.21 - 5.16 (m, 1H), 4.63 - 4.46 (m, 2H), 3.36 (s, 3H), 2.95 - 2.91 (m, 1H), 2.65 - 2.60 (m, 1H), 2.47 - 2.44 (m, 1H), 2.37 (s, 3H), 2.07 - 2.05 (m, 1H). (ESI+) m/z: 491.2 (M+H)+, (C30H26N4O3). EXAMPLE 362 [1173] Synthesis of 3-(5-(1-Methyl-4-phenyl-5-(o-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1174] A. tert-Butyl 5-amino-4-(5-(1-methyl-4-phenyl-5-(o-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: A mixture of tert-butyl 5-amino-4-[5-(5-bromo-1- methyl-4-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (200 mg, 361 μmol, 1.00 eq), o-tolylboronic acid (98.2 mg, 722 μmol, 2.00 eq) , RuPhos Pd G3 (30.2 mg, 36.1 μmol, 0.10 eq), K3PO4 (153 mg, 722 μmol, 2.00 eq) in dioxane (4.00 mL) and H2O (0.40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, DCM: MeOH = 20: 1, Rf = 0.32) to give the title compound (130 mg, 220 μmol, 61.0% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.49 - 7.44 (m, 2H), 7.43 - 7.36 (m, 4H), 7.25 - 7.18 (m, 3H), 7.16 - 7.09 (m, 1H), 4.81 - 4.75 (m, 1H), 4.74 - 4.54 (m, 2H), 3.42 (s, 3H), 2.24 - 2.15 (m, 3H), 2.08 (d, J = 2.0 Hz, 3H), 2.06 - 1.97 (m, 1H), 1.34 (s, 9H). (ESI+) m/z: 565.2 (M+H)+, (C34H36N4O4). 409 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1175] B.3-(5-(1-Methyl-4-phenyl-5-(o-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A mixture of tert-butyl 5-amino-4-(5-(1-methyl-4-phenyl-5-(o- tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (110 mg, 194 μmol, 1.00 eq) and TsOH (134 mg, 779 μmol, 4.00 eq) in ACN (3.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 4 h under N2 atmosphere. The reaction mixture was filtered. The filter cake was concentrated directly in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18 150 x 25 mm x 5 μm) and gradiente of 22 - 52% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (23.52 mg, 47.8 μmol, 24.5% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 11.05 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.55 - 7.47 (m, 2H), 7.47 - 7.39 (m, 4H), 7.37 - 7.22 (m, 3H), 5.21 - 5.16 (m, 1H), 4.64 - 4.46 (m, 2H), 3.48 (s, 3H), 2.99 - 2.90 (m, 1H), 2.65 - 2.60 (m, 1H), 2.49 - 2.40 (m, 1H), 2.10 (s, 3H), 2.09 - 2.01 (m, 1H). (ESI+) m/z: 491.2 (M+H)+, (C30H26N4O3). EXAMPLE 363 [1176] Synthesis of 3-(5-(4-(4-Methoxyphenyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1177] A. tert-Butyl 5-amino-4-(5-(4-(4-methoxyphenyl)-1-methyl-5-phenyl-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-[5-(4-bromo-1-methyl-5-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (500 mg, 903 μmol, 1.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added (4- methoxyphenyl)boronic acid (274 mg, 1.81 mmol, 2.00 eq), Ru-Phos-Pd-G3 (75.5 mg, 90.3 μmol, 0.10 eq) and K3PO4 (575 mg, 2.71 mmol, 3.00 eq) under N2, then the reaction mixture was stirred at 80 °C for 2 h under N2. The mixture was filtered and concentrated to give residue. The crude product was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.60) to give the title compound (400 mg, 688 μmol, 76.2% yield) as a gray solid.1H NMR: (400 MHz, CDCl3) δ 7.95 - 7.86 (m, 3H), 7.49 - 7.46 (m, 5H), 7.41 - 7.39 (m, 2H), 6.79 - 6.77 (m, 2H), 6.40 (s, 410 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 5.41 (s, 1H), 4.96 - 4.93 (m, 1H), 4.65 - 4.50 (m, 2H), 3.78 (s, 3H), 3.55 (s, 3H), 2.45 - 2.19 (m, 4H), 1.43 (s, 9H). (ESI+) m/z: 581.3 (M+H)+, (C34H36N4O5). [1178] B.3-(5-(4-(4-Methoxyphenyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-[4-(4- methoxyphenyl)-1-methyl-5-phenyl-imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (200 mg, 344 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (118 mg, 688 μmol, 2.00 eq) and stirred at 80 °C for 16 h. The reaction mixture was filtered and the filter cake was rinsed with 20.0 mL of ACN. The solid was collected and dried in vacuum to give a gray solid. The crude compound was purified by preparative-HPLC (using a CD06-Waters Xbidge C18 (150 x 40 x 10 μm) and gradient of 22 - 52% acetonitrile in water containing 0.05% TFA over 14 min at a flow rate of 25.0 mL/min) to give the title compound (64.0 mg, 125 μmol, 36.3% yield, 98.8% purity in HPLC at 220 nm) as light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.11 (s, 1H), 8.02 - 7.97 (m, 2H), 7.58 - 7.49 (m, 5H), 7.37 - 7.35 (m, 2H), 6.92 - 6.90 (m, 2H), 5.20 - 5.16 (m, 1H), 4.63 - 4.46 (m, 2H), 3.74 (s, 3H), 3.58 (s, 3H), 2.99 - 2.90 (m, 1H), 2.66 - 2.65 (m, 1H), 2.44 - 2.43 (m, 1H), 2.07 - 2.03 (m, 1H). (ESI+) m/z: 507.1 (M+H)+, (C30H26N4O4). EXAMPLE 364 [1179] Synthesis of 3-(5-(5-(3-Methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1180] A. tert-Butyl 5-amino-4-(5-(5-(3-methoxyphenyl)-1-methyl-4-phenyl-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-[5-(1-methyl-4-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (240 mg, 410 μmol, 1.00 eq) in DMF (3.00 mL) was added 1-bromo-3-methoxy-benzene (230 mg, 1.23 mmol, 156 μL, 3.00 eq) and K2CO3 (113 mg, 819 μmol, 2.00 eq) degassed and purged with N2 for 3 times, and then was added diacetoxypalladium (9.20 mg, 41.0 μmol, 0.100 eq) and tricyclohexylphosphane (23.0 mg, 81.9 μmol, 26.6 μL, 0.200 eq) . The mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was colled to 20 °C and then added into H2O (20.0 mL), extracted with ethyl acetate (10.0 mL x 3). The organic phase 411 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography(SiO2, Dichloromethane/Methanol = 1/0 to 10/1, TLC: Dichloromethane/Methanol = 10/1, Rf = 0.30) to give the title compound (135 mg, 194 μmol, 47.4% yield, 87.3% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.97 - 7.89 (m, 1H), 7.88 - 7.78 (m, 1H), 7.63 (br s, 1H), 7.53 - 7.41 (m, 3H), 7.24 (br t, J = 7.6 Hz, 3H), 7.19 - 7.13 (m, 1H), 7.12 - 6.98 (m, 3H), 4.82 - 4.75 (m, 1H), 4.74 - 4.53 (m, 2H), 3.78 (s, 3H), 3.54 (s, 3H), 2.29 - 2.13 (m, 3H), 2.07 - 1.97 (m, 1H), 1.33 (s, 9H). (ESI+) m/z: 581.3 (M+1)+, (C34H36N4O5). [1181] B.3-(5-(5-(3-Methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-[5-(3- methoxyphenyl)-1-methyl-4-phenyl-imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (135 mg, 194 μmol, 1.00 eq) in MeCN (1.50 mL) was added TsOH (134 mg, 777 μmol, 4.00 eq). The mixture was stirred at 80 °C for 4h under N2 atmosphere. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by Pre- TLC (SiO2, Dichloromethane/Methanol = 10/1, TLC: Dichloromethane/Methanol = 10/1, Rf = 0.55) and then purified by Prep-HPLC (column: CD01-Phenomenex luna C18150 x 25 x 10um;mobile phase: [water(TFA)-ACN]; gradient: 20%-50% B over 10 min) to give the title compound (55.39 mg, 109 μmol, 56.0% yield, 99.1% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.11 (s, 1H), 8.06 - 7.94 (m, 2H), 7.52 - 7.45 (m, 3H), 7.39 - 7.27 (m, 3H), 7.16 - 7.03 (m, 3H), 5.22 - 5.15 (m, 1H), 4.65 - 4.58 (m, 1H), 4.52 - 4.45 (m, 1H), 3.79 (s, 3H), 3.60 (s, 3H), 3.00 - 2.89 (m, 1H), 2.63 (br d, J = 16.4 Hz, 1H), 2.45 (br s, 1H), 2.11 - 2.00 (m, 1H). (ESI+) m/z: 507.0 (M+1)+, (C30H26N4O4). EXAMPLE 365 [1182] Synthesis of 3-(5-(5-(2-Methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1183] A. tert-Butyl 5-amino-4-(5-(5-(2-methoxyphenyl)-1-methyl-4-phenyl-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: A mixture of tert-butyl 5-amino-4- 412 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [5-(5-bromo-1-methyl-4-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (200 mg, 361 μmol, 1.00 eq) , (2-methoxyphenyl)boronic acid (110 mg, 723 μmol, 2.00 eq) , K3PO4 (153 mg, 723 μmol, 2.00 eq) , and Ru-phos-Pd-G3 (30.2 mg, 36.1 μmol, 0.100 eq) in dioxane (2.00 mL) and H2O (0.20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.26) to give the title compound (120 mg, 184 μmol, 50.9% yield, 89.0% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 581.4 (M+H)+, (C34H36N4O5) [1184] B.3-(5-(5-(2-Methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-[5-(2- methoxyphenyl)-1-methyl-4-phenyl-imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (150 mg, 258 μmol, 1.00 eq) in MeCN (5.00 mL) was added TsOH (89.0 mg, 517 μmol, 2.00 eq). The mixture was stirred at 80 °C for 4 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 13- 43% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min), after lyophilization to give the title compound (59.7 mg, 116 μmol, 45.0% yield, 98.6% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.05 (s, 1H), 8.00 - 7.92 (m, 1H), 7.90 - 7.83 (m, 1H), 7.59 - 7.51 (m, 1H), 7.48 - 7.42 (m, 2H), 7.30 - 7.24 (m, 2H), 7.24 - 7.18 (m, 2H), 7.15 - 7.06 (m, 2H), 5.27 - 5.08 (m, 1H), 4.63 - 4.53 (m, 1H), 4.52 - 4.35 (m, 1H), 3.80 (s, 3H), 3.47 (s, 3H), 3.01 - 2.86 (m, 1H), 2.66 - 2.58 (m, 1H), 2.47 - 2.36 (m, 1H), 2.11 - 2.00 (m, 1H). (ESI+) m/z: 507.1 (M+H)+, (C30H26N4O4) EXAMPLE 366 [1185] Synthesis of 3-(5-(1-Methyl-5-phenyl-4-(p-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: 413 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1186] A.2-Bromo-1-methyl-5-phenyl-1H-imidazole: To a solution of 2,5-dibromo-1- methyl-1H-imidazole (15.0 g, 62.4 mmol, 1.00 eq) and phenylboronic acid (11.4 g, 93.6 mmol, 1.50 eq) in THF (300 mL) was added Pd(OAc)2 (1.40 g, 6.24 mmol, 0.10 eq) and K3PO4 (39.6 g, 187 mmol, 3.00 eq) under N2. The reaction mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 8: 1; TLC, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.30) to give the title compound (4.50 g, 18.7 mmol, 30.3% yield) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.47 - 7.45 (m, 3H), 7.44 - 7.42 (m, 2H), 7.08 (s, 1H), 3.61 (s, 3H). (ESI+) m/z: 338.8 (M+H)+, (C10H9BrN2). [1187] B. tert-Butyl 5-amino-4-(5-(1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 2-bromo-1-methyl-5-phenyl- imidazole (4.50 g, 16.4 mmol, 1.00 eq) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (14.6 g, 32.7 mmol, 2.00 eq) in dioxane (100 mL) and H2O (10.0 mL) was added Ru-Phos-Pd-G3 (1.37 g, 1.64 mmol, 0.10 eq) and K3PO4 (10.4 g, 49.2 mmol, 3.00 eq) under N2, then the reaction mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered through a pad of celite, the pad or filter cake was washed with dichloromethane (3 x 100 mL), the filtrate was concentrated to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol=100: 0 to 30: 1, TLC: Dichloromethane: Methanol = 15: 1, Rf = 0.40) to give the title compound (6.00 g, 12.4 mmol, 61.2% yield) as a white solid. (ESI+) m/z: 475.1 (M+H)+, (C27H30N4O4). [1188] C. tert-Butyl 5-amino-4-(5-(4-bromo-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-[5-(1-methyl-5- phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (6.00 g, 12.4 mmol, 1.00 eq) in MeOH (60.0 mL) was added NBS (2.36 g, 13.2 mmol, 1.05 eq) and stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (100 mL), extracted with EtOAc (3 x 100 mL), the combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The crude product was triturated with EtOAc (10.0 mL) at 0 °C for 30 min. Then the solid was collected and dried in vacuum to give the title compound (4.00 g, 7.03 mmol, 81.7% yield) as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.54 - 7.44 (m, 5H), 414 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 6.44 (s, 1H), 5.50 (s, 1H), 4.96 - 4.93 (m, 1H), 4.65 - 4.50 (m, 2H), 3.64 (s, 3H), 2.41 - 2.16 (m, 4H), 1.42 (s, 9H). (ESI+) m/z: 554.8 (M+H)+, (C27H29BrN4O4). [1189] D. tert-Butyl 5-amino-4-(5-(1-methyl-5-phenyl-4-(p-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-[5-(4-bromo-1- methyl-5-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (500 mg, 903 μmol, 1.00 eq) and p-tolylboronic acid (245 mg, 1.81 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added Ru-Phos-Pd-G3 (75.5 mg, 90.3 μmol, 0.10 eq) and K3PO4 (575 mg, 2.71 mmol, 3.00 eq) under N2, then the reaction mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was filtered and concentrated in vacuum to give residue. The crude product was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 20: 1, Rf = 0.45) and triturated with EtOAc (5.00 mL) at 0 °C for 30 min to give the title compound (285 mg, 469 μmol, 51.9% yield, 93% purity in LCMS at 220 nm) as a gray solid.1H NMR: (400 MHz, DMSO-d3) δ 8.02 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.56 - 7.49 (m, 3H), 7.47 - 7.42 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (s, 1H), 7.03 (d, J = 8.0 Hz, 2H), 4.80 - 4.75 (m, 1H), 4.73 - 4.55 (m, 2H), 3.52 (s, 3H), 2.23 (m, 3H), 2.20 - 2.15 (m, 3H), 2.00 - 1.97 (m, 1H), 1.33 (s, 9H). (ESI+) m/z: 565.5 (M+H)+, (C34H36N4O4). [1190] E.3-(5-(1-Methyl-5-phenyl-4-(p-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(1-methyl-5-phenyl-4-(p- tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (250 mg, 442 μmol, 1.00 eq) and TsOH (152 mg, 885 μmol, 2.00 eq) in ACN (5.00 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give residue. The crude compound was purified by prep-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.50) and preparative- HPLC (using a CD06-Waters Xbidge C18 (150 x 40 x 10 μm) and gradient of 23 - 53% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 30.0 mL/min) to give the title compound (180.24 mg, 353 μmol, 79.9% yield, 96.3% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.11 (s, 1H), 8.05 - 8.00 (m, 2H), 7.60 - 7.55 (m, 3H), 7.50 - 7.45 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 5.20 - 5.16 (m, 1H), 4.63 - 4.46 (m, 2H), 3.58 (s, 3H), 2.99 - 2.89 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.40 (m, 1H), 2.27 (s, 3H), 2.05 - 2.02 (m, 1H). (ESI+) m/z: 491.1 (M+H)+, (C30H26N4O3). 415 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 367 [1191] Synthesis of 3-(5-(1-Methyl-5-phenyl-4-(m-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1192] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-phenyl-4-(m-tolyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate：To a solution of tert-butyl 5-amino-4-(5-(4-bromo-1- methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 903 μmol, 1.00 eq) and m-tolylboronic acid (245 mg, 1.81 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added K3PO4 (575 mg, 2.71 mmol, 3.00 eq) and Ru-Phos-Pd-G3 (75.5 mg, 90.3 μmol, 0.10 eq) under N2. The reaction was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was triturated with ethyl acetate (5.00 mL) at 0 °C for 10 min, filtered and dried in vacuum to give the title compound (320 mg, 566 μmol, 62.7% yield) as a gray solid.1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.96 - 7.91 (m, 1H), 7.87 - 7.81 (m, 1H), 7.61 (s, 1H), 7.59 - 7.50 (m, 3H), 7.49 - 7.44 (m, 2H), 7.39 (s, 1H), 7.23 (s, 1H), 7.14 - 7.03 (m, 2H), 7.00 - 6.94 (m, 1H), 4.82 - 4.75 (m, 1H), 4.74 - 4.52 (m, 2H), 3.57 (s, 3H), 3.53 (s, 3H), 2.21 (m, 4H), 1.34 (s, 9H). (ESI+) m/z: 565.4 (M+H)+, (C34H36N4O4). [1193] B.3-(5-(1-Methyl-5-phenyl-4-(m-tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of tert-butyl 5-amino-4-(5-(1-methyl-5-phenyl-4-(m- tolyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 354 μmol, 1.00 eq) in ACN (4.00 mL) was added TsOH (243 mg, 1.42 mmol, 4.00 eq). The reaction was stirred at 80 °C for 16 h. The reaction mixture was filtered, the filter cake was washed with ACN (10.0 mL) and concentrated in vacuum to give residue. The residue was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 26 - 56% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (70.3 mg, 143 μmol, 40.4% yield, 99.9% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.11 (s, 1H), 8.05 - 7.92 (m, 2H), 7.65 - 7.55 (m, 3H), 7.54 - 7.45 (m, 2H), 7.37 (s, 1H), 7.23 - 7.04 (m, 3H), 5.24 - 5.14(m, 1H), 4.67 - 4.41 (m, 2H), 3.58 (s, 3H), 3.03 - 2.86 (m, 1H), 2.6 - 2.61 (m, 1H), 416 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2.47 - 2.40 (m, 1H), 2.24 (s, 3H), 2.13 - 2.00 (m, 1H). (ESI+) m/z: 491.2 (M+H)+, (C30H26N4O3). EXAMPLE 368 [1194] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1195] A. tert-Butyl 5-amino-4-(5-(5-(4-methoxyphenyl)-1-methyl-4-phenyl-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: A mixture of tert-butyl 5-amino-4- (5-(5-bromo-1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (250 mg, 451 μmol, 1.00 eq), (4-methoxyphenyl)boronic acid (137 mg, 903 μmol, 2.00 eq), RuPhos Pd G3 (37.7 mg, 45.1 μmol, 0.10 eq), K3PO4 (191 mg, 903 μmol, 2.00 eq) in dioxane (4.00 mL) and H2O (0.40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue.The residue was purified by preparative-TLC (SiO2, DCM: MeOH = 20: 1, Rf = 0.35) to give the title compound (240 mg, 395 μmol, 87.4% yield) as a yellow solid 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.61 (s, 1H), 7.49 - 7.45 (m, 2H), 7.42 - 7.37 (m, 2H), 7.27 - 7.20 (m, 3H), 7.16 (d, J = 7.2 Hz, 1H), 7.14 - 7.08 (m, 2H), 4.79 - 4.75 (m, 1H), 4.74 - 4.54 (m, 2H), 3.84 (s, 3H), 3.51 (s, 3H), 2.25 - 2.14 (m, 3H), 2.09 - 1.97 (m, 1H), 1.34 (s, 9H). (ESI+) m/z: 581.4 (M+H)+, (C34H36N4O5) [1196] B.3-(5-(5-(4-Methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of tert-butyl 5-amino-4-(5-(5-(4- methoxyphenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (200 mg, 344 μmol, 1.00 eq), TsOH (177 mg, 1.03 mmol, 3.00 eq) in ACN (5.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was filtered. The filter cake was concentrated directly in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 5 μm) and gradiente of 22 - 417 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 52% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (56.81 mg, 109 μmol, 31.7% yield, 97.6% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.11 (s, 1H), 8.04 - 7.95 (m, 2H), 7.49 - 7.40 (m, 4H), 7.40 - 7.24 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 5.20 - 5.16 (m, 1H), 4.64 - 4.46 (m, 2H), 3.85 (s, 3H), 3.58 (s, 3H), 3.01 - 2.87 (m, 1H), 2.63 (d, J = 18.8 Hz, 1H), 2.46 - 2.40 (m, 1H), 2.11 - 2.00 (m, 1H). (ESI+) m/z: 507.1 (M+H)+, (C30H26N4O4). EXAMPLE 369 [1197] Synthesis of 3-(5-(4-(4-Chlorophenyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1198] A. tert-Butyl 5-amino-4-(5-(4-(4-chlorophenyl)-1-methyl-5-phenyl-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-[5-(4-bromo-1-methyl-5-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (500 mg, 903 μmol, 1.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added o- tolylboronic acid (245 mg, 1.81 mmol, 2.00 eq), Ru-Phos-Pd-G3 (75.5 mg, 90.3 μmol, 0.10 eq) and K3PO4 (575 mg, 2.71 mmol, 3.00 eq) under N2, then the reaction mixture was stirred at 80 °C for 2 h under N2. The mixture was filtered and concentrated in vacuum to give residue. The crude product was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 40: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.60) to give the title compound (400 mg, 449 μmol, 49.7% yield) as a yellow solid. (ESI+) m/z: 585.4 (M+H)+, (C33H33ClN4O4). [1199] B.3-(5-(4-(4-Chlorophenyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-[4-(4- chlorophenyl)-1-methyl-5-phenyl-imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (350 mg, 393 μmol, 1.00 eq) in ACN (10.0 mL) was added TsOH (203 mg, 1.18 mmol, 3.00 eq) and stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give residue. The crude compound was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.45) and preparative- HPLC (using a CD01-Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 24 - 54% 418 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 30.0 mL/min) to give the title compound (137 mg, 263 μmol, 66.8% yield, 98.1% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.07 (s, 1H), 8.00 - 7.96 (m, 1H), 7.95 - 7.90 (m, 1H), 7.62 - 7.54 (m, 3H), 7.52 - 7.47 (m, 2H), 7.46 - 7.41 (m, 2H), 7.39 - 7.31 (m, 2H), 5.20 - 5.15 (m, 1H), 4.62 - 4.44 (m, 2H), 3.56 (s, 3H), 3.01 - 2.87 (m, 1H), 2.66 - 2.59 (m, 1H), 2.49 - 2.38 (m, 1H), 2.08 - 2.00 (m, 1H). (ESI+) m/z: 511.0 (M+H)+, (C29H23ClN4O3). EXAMPLE 370 [1200] Synthesis of 3-(5-(5-(2-Fluorophenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1201] A. tert-Butyl 5-amino-4-(5-(5-(2-fluorophenyl)-1-methyl-4-phenyl-1H-imidazol- 2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5- bromo-1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 361 μmol, 1.00 eq) and (2-fluorophenyl)boronic acid (101 mg, 722 μmol, 2.00 eq) in dioxane (3.00 mL) and H2O (0.15 mL) was added K3PO4 (153 mg, 722 μmol, 2.00 eq) and RuPhos-Pd-G3 (30.2 mg, 36.1 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered, the filtrate was concentrated under vacuum to give a residue at 50 °C. The residue was purified by preparative-TLC (SiO2, PE/EtOAc = 0/1, Rf = 0.40) to give the title compound (160 mg, 260 μmol, 72.1% yield, 92.7% purity in LCMS at 220 nm) as a light yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.95 - 7.93 (m, 1H), 7.85 - 7.83 (m, 1H), 7.62 (s, 2H), 7.45 - 7.39 (m, 5H), 7.27 - 7.17 (m, 4H), 4.79 (d, J = 4.4 Hz, 1H), 4.77 - 4.55 (q, 2H), 3.52 (s, 3H), 2.22 - 2.17 (m, 3H), 2.08 - 2.00 (m, 1H), 1.33 (s, 9H). (ESI+) m/z: 569.3 (M+H)+, (C33H33N4O4F). [1202] B.3-(5-(5-(2-Fluorophenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(2- fluorophenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (140 mg, 228 μmol, 1.00 eq) in ACN (2.80 mL) was added TsOH (90.3 mg, 524 μmol, 2.30 eq) at 25 °C. Then the mixture was stirred at 80 °C for 16 h. The reaction mixture was 419 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT filtered, the filter cake was collected. The filter cake was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 15-45% acetonitrile in water containing 0.05% NH4HCO3 over 13 min at a flow rate of 30 mL/min) to give the title compound (56.2 mg, 113 μmol, 49.8% yield, 99.9% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.06 (s, 1H), 7.98 - 7.96 (m, 1H), 7.89 - 7.87 (m, 1H), 7.53 (s, 1H), 7.45 - 7.40 (m, 5H), 7.27 - 7.17 (m, 3H), 5.17 (dd, J = 5.2 Hz, J = 13.6 Hz, 1H), 4.60 - 4.43 (q, 2H), 3.54 (s, 3H), 2.98 - 2.90 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.43 (m, 1H), 2.06 - 2.04 (m, 1H). (ESI+) m/z: 495.2 (M+H)+, (C29H23N4O3F). EXAMPLE 371 [1203] Synthesis of 3-(5-(5-(4-Chlorophenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1204] A. tert-Butyl 5-amino-4-(5-(5-(4-chlorophenyl)-1-methyl-4-phenyl-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-(5-(5-bromo-1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 271 μmol, 1.00 eq) and (4-chlorophenyl) boronic acid (84.7 mg, 542 μmol, 2.00 eq) in dioxane (2.25 mL) and H2O (0.125 mL) was added K3PO4 (115 mg, 542 μmol, 2.00 eq) and RuPhos Pd G3 (22.6 mg, 27.1 μmol, 0.10 eq) at 25 °C under N2. Then the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, the filtrate was concentrated under vacuum to give a residue. The crude product was purified by preparative-HPLC (using a CD01-Phenomenex luna C18150 x 25 x 10 um) and gradiente of 30 - 60% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 25 mL/min) to give the title compound (70.0 mg, 117.96 μmol, 43.5% yield, 98.6% purity) as a white solid. (ESI+) m/z: 585.0 (M+H)+, (C33H33ClN4O4). [1205] B.3-(5-(5-(4-Chlorophenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4- chlorophenyl)-1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (70.0 mg, 117 μmol, 1.00 eq) in ACN (1.50 mL) was added TsOH (81.2 mg, 471 μmol, 4.00 420 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT eq). Then the mixture was stirred at 80 °C for 24 h. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 5 μm) and gradiente of 21 - 51% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (19.12 mg, 37.3 μmol, 27.2% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.08 (s, 1H), 8.01 - 7.93 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.35 - 7.31 (m, 2H), 7.30 - 7.24 (m, 1H), 5.20 - 5.15 (m, 1H), 4.64 - 4.57 (m, 1H), 4.52 - 4.44 (m, 1H), 3.58 (s, 3H), 3.02 - 2.87 (m, 1H), 2.68 - 2.63 (m, 1H), 2.48 - 2.31 (m, 1H), 2.11 - 2.01 (m, 1H). (ESI+) m/z: 511.0 (M+H)+, (C29H23ClN4O3). EXAMPLE 372 [1206] Synthesis of 3-(5-(2-(Difluoromethyl)-5-phenyloxazol-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1207] A.2,2-Difluoro-N-(2-oxo-2-phenylethyl)acetamide: To a solution of 2-amino-1- phenylethan-1-one (5.00 g, 29.1 mmol, 1.00 eq, HCl) and 2,2-difluoroacetic anhydride (5.07 g, 29.1 mmol, 1.00 eq) in THF (100 mL) was added TEA (5.90 g, 58.2 mmol, 8.11 mL, 2.00 eq). The reaction was stirred at 25 °C for 2 h. The reaction was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 50: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (4.50 g, 21.1 mmol, 72.4% yield) as a yellow solid. (ESI+) m/z: 214.0 (M+H)+, (C10H9F2NO2). [1208] B.2-(Difluoromethyl)-5-phenyloxazole: A solution of 2,2-difluoro-N-(2-oxo-2- phenylethyl)acetamide (4.00 g, 18.7 mmol, 1.00 eq) in H2SO4 (40.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was poured into ice cold water (100 mL), extracted with EtOAc (3 x 50.0 mL). The combined organic layer was washed NaHCO3 (2 x 50.0 mL) and brine (2 x 50.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 5: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.40) to give a residue. The residue 421 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was triturated with ethyl acetate at 0 °C for 10 min, filtered and the filter liquor was concentrated in vacuum to give the title compound (1.50 g, 7.69 mmol, 40.9% yield) as a colorless oil. (ESI+) m/z: 196.1 (M+H)+, (C10H7F2NO). [1209] C.4-Bromo-2-(difluoromethyl)-5-phenyloxazole： To a solution of 2- (difluoromethyl)-5-phenyloxazole (900 mg, 4.61 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (861 mg, 4.84 mmol, 1.05 eq) at 0 °C, the reaction was stirred at 25 °C for 3 h. The reaction mixture was cocentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 10: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.60) to give the title compound (610 mg, 2.23 mmol, 48.2% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 8.04 - 7.94 (m, 2H), 7.63 - 7.40 (m, 3H), 6.85 - 6.48 (m, 1H). (ESI+) m/z: 273.9 (M+H)+, (C10H6BrF2NO). [1210] D.3-(5-(2-(Difluoromethyl)-5-phenyloxazol-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(difluoromethyl)-5-phenyloxazole (200 mg, 729 μmol, 1.00 eq) and 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (339 mg, 875 μmol, 1.20 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added Ru-Phos-Pd-G3 (61.0 mg, 72.9 μmol, 0.10 eq) and K3PO4 (309 mg, 1.46 mmol, 2.00 eq) under N2. The reaction was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 28 - 58% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (132 mg, 290 μmol, 39.8% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.97 - 7.91 (m, 1H), 7.72 - 7.66 (m, 1H), 7.54 - 7.24 (m, 6H), 5.20 - 5.12 (m, 1H), 4.58 - 4.36 (m, 2H), 2.98 - 2.87 (m, 1H), 2.64 - 2.58 (m, 1H), 2.47 - 2.36 (m, 1H), 2.12 - 1.99 (m, 1H). (ESI+) m/z: 456.1 (M+H)+, (C23H16F3N3O4). EXAMPLE 373 [1211] Synthesis of 3-(4-Fluoro-5-(1-methyl-5-phenyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxo-1,3,3a,7a-tetrahydro-2H-isoindol-2-yl)piperidine-2,6-dione: 422 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1212] A.1-Methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole：To a solution of 1- methyl-2-(trifluoromethyl)-1H-imidazole (400 mg, 2.66 mmol, 1.00 eq), bromobenzene (1.26 g, 7.99 mmol, 841μL, 3.00 eq), K2CO3 (736 mg, 5.33 mmol, 2.00 eq) and PCy3 (123 mg, 532 μmol, 0.20 eq) in DMF (10.0 mL) was added Pd(OAc)2 (59.8 mg, 266 μmol, 0.10 eq) under N2.The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, TLC : Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (300 mg, 1.33 mmol, 49.7% yield, 95.0% purity in LCMS at 220 nm) as a yellow solid.1HNMR: (400 MHz, DMSO-d6) δ 7.56 - 7.48 (m, 5H), 7.23 (s, 1H), 3.73 (s, 3H). (ESI+) m/z: 227.0 (M+H)+, (C11H9F3N2). [1213] B.4-Bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (300 mg, 1.33 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (259 mg, 1.46 mmol, 1.10 eq) at 0°C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (100 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Petroleum ether: Ethyl acetate =5: 1,Rf = 0.60) to give the title compound (330 mg, 1.08 mmol, 81.5% yield, 100% purity in LCMS at 220 nm) as yellow solid.1HNMR: (400 MHz, DMSO-d6) δ 7.56 - 7.52 (m, 5H), 3.64 (s, 3H). (ESI+) m/z: 304.7 (M+H)+, (C11H8BrF3N2). [1214] C.3-(4-Fluoro-5-(1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxo-1,3,3a,7a-tetrahydro-2H-isoindol-2-yl)piperidine-2,6-dione: To a solution of 4- bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (100 mg, 327 μmol, 1.00 eq), 3- (4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine- 2,6-dione (254 mg, 655 μmol, 2.00 eq) and K3PO4 (208 mg, 981 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (27.4 mg, 32.7 μmol, 0.10 eq) under N2. The mixture was stirred at 80 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 31.0% - 61.0% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (102 mg, 209 μmol, 63.9% yield, 100% purity in HPLC at 220 nm) as white solid.1HNMR: (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.56 - 7.55 (s, 2H), 7.48 - 7.47 (m, 3H), 7.40 - 7.38 (m, 2H), 5.10 - 5.06 (m, 1H), 4.47 - 4.25 (m, 2H), 3.68 (s, 423 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 3H), 2.92 - 2.88 (m, 1H), 2.60 - 2.55 (m, 1H), 2.41 - 2.37 (m, 1H), 2.02 - 1.98 (m, 1H). (ESI+) m/z: 487.3 (M+H)+, (C24H18F4N4O3). EXAMPLE 374 [1215] 3-[5-[5-(2,6-Dimethylphenyl)-1-methyl-4-phenyl-imidazol-2-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: [1216] A. tert-Butyl 5-amino-4-[5-[5-(2,6-dimethylphenyl)-1-methyl-4-phenyl- imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate: To a solution of tert-butyl 5- amino-4-[5-(5-bromo-1-methyl-4-phenyl-imidazol-2-yl)-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (300 mg, 542 μmol, 1.00 eq) in dioxane (3.00 mL) was added H2O (0.10 mL), (2,6-dimethylphenyl)boronic acid (162 mg, 1.08 mmol, 2.00 eq), K3PO4 (230 mg, 1.08 mmol, 2.00 eq) and Ru-phos-Pd-G3 (45.3 mg, 54.2 μmol, 0.10 eq). The mixture was stirred at 100 °C for 24 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol= 15: 1, Rf = 0.43) to give the title compound (120 mg, 163 μmol, 30.2% yield) as yellow oil. (ESI+) m/z: 578 (M+H)+, (C35H38N4O4). [1217] B.3-[5-[5-(2,6-Dimethylphenyl)-1-methyl-4-phenyl-imidazol-2-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-[5-(2,6- dimethylphenyl)-1-methyl-4-phenyl-imidazol-2-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (100 mg, 172 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (119 mg, 691 μmol, 4.00 eq). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 21 - 51% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25.0 mL/min) to give the title compound (25.7 mg, 50.0 μmol, 28.9% yield, 98.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.32 - 7.26 (m, 2H), 7.21 (t, J = 7.6 Hz, 2H), 7.15 - 7.09 (m, 1H), 5.17 (dd, J = 13.2, 4.8 Hz, 1H), 4.61 - 4.41 424 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (dd, J = 25, 8.6 Hz,, 2H), 3.40 (s, 3H), 3.01 - 2.88 (m, 1H), 2.65 - 2.60 (m, 1H), 2.43 (m, 1H), 2.06 (m, 1H), 2.03 (s, 6H). (ESI+) m/z: 504 (M+H)+, (C31H28N4O3). EXAMPLE 375 [1218] Synthesis of 3-(5-(2-(Difluoromethyl)-5-phenyloxazol-4-yl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1219] A.2,2-Difluoro-N-(2-oxo-2-phenylethyl)acetamide: To a solution of 2-amino-1- phenylethan-1-one (5.00 g, 29.1 mmol, 1.00 eq, HCl) and 2,2-difluoroacetic anhydride (5.07 g, 29.1 mmol, 1.00 eq) in THF (100 mL) was added TEA (5.90 g, 58.2 mmol, 8.11 mL, 2.00 eq). The reaction was stirred at 25 °C for 2 h. The reaction was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 50: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (4.50 g, 21.1 mmol, 72.4% yield) as a yellow solid. (ESI+) m/z: 214.0 (M+H)+, (C10H9F2NO2). [1220] B.2-(Difluoromethyl)-5-phenyloxazole: A solution of 2,2-difluoro-N-(2-oxo-2- phenylethyl)acetamide (4.00 g, 18.7 mmol, 1.00 eq) in H2SO4 (40.0 mL), the reaction was stirred at 80 °C for 2 h. The reaction was poured into ice cold H2O (100 mL), extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (2 x 50.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 5: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.40) to give the title compound (1.50 g, 7.69 mmol, 40.9% yield) as a colorless oil. (ESI+) m/z: 196.1 (M+H)+, (C10H7F2NO). [1221] C.4-Bromo-2-(difluoromethyl)-5-phenyloxazole：To a solution of 2- (difluoromethyl)-5-phenyloxazole (900 mg, 4.61 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (861 mg, 4.84 mmol, 1.05 eq) at 0 °C, the reaction was stirred at 25 °C for 3 h. The reaction mixture was poured into H2O (20.0 mL), extracted with ethyl acetate (3 x 10.0 mL). The combined organic layer was washed with brine (2 x 20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 10: 1; TLC: Petroleum 425 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT ether: Ethyl acetate = 3: 1, Rf = 0.60) to give the title compound (610 mg, 2.23 mmol, 48.2% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 8.04 - 7.94 (m, 2H), 7.63 - 7.40 (m, 3H), 6.85 - 6.48 (m, 1H). (ESI+) m/z: 273.9 (M+H)+, (C10H6BrF2NO). [1222] D.3-(5-(2-(Difluoromethyl)-5-phenyloxazol-4-yl)-4-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(difluoromethyl)-5-phenyloxazole (200 mg, 729 μmol, 1.00 eq) and 3-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (339 mg, 875 μmol, 1.20 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added Ru-Phos-Pd-G3 (61.0 mg, 72.9 μmol, 0.10 eq) and K3PO4 (309 mg, 1.46 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h. The reaction was filtered and concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 29 - 39% acetonitrile in water containing 0.05% FA over 11 min at a flow rate of 25 mL/min) to give the title compound (150 mg, 330 μmol, 45.2% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.84 - 7.76 (m, 1H), 7.76 - 7.70 (m, 1H), 7.56 - 7.24 (m, 6H), 5.20 - 5.11 (m, 1H), 4.69 - 4.38 (m, 2H), 2.99 - 2.84 (m, 1H), 2.64 - 2.58 (m, 1H), 2.47 - 2.37 (m, 1H), 2.08 - 1.97 (m, 1H). (ESI+) m/z: 456.0 (M+H)+, (C23H16F3N3O4). EXAMPLE 376 [1223] Synthesis of 3-(1-Oxo-5-(1-phenyl-1H-benzo[d]imidazol-2-yl)isoindolin-2- yl)piperidine-2,6-dione: [1224] A.2-Bromo-1-phenyl-1H-benzo[d]imidazole: To a solution of 2-bromo-1H- benzo[d]imidazole (200 mg, 1.01 mmol, 1.00 eq), phenylboronic acid (371 mg, 3.04 mmol, 3.00 eq) and Na2CO3 (268 mg, 2.53 mmol, 2.50 eq), 2,2-Bipyridyl (118 mg, 1.22 mmol, 1.20 eq) in dioxane (10.0 mL) was added Cu(OAc)2 (221 mg, 1.22 mmol, 1.20 eq) under O2.The mixture was stirred at 60 °C for 12 h under O2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *40 mm *10 um) and gradient of 36.0% - 66.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (40.0 mg, 142 μmol, 11.2% yield, 97.5% purity in HPLC at 220 nm) was 426 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.63 (m, 4H), 7.58 - 7.56 (m, 2H), 7.30 - 7.28 (m, 2H), 7.27 - 7.15 (m, 1H). (ESI+) m/z: 274.8 (M+H)+, (C13H9BrN2). [1225] B.3-(1-Oxo-5-(1-phenyl-1H-benzo[d]imidazol-2-yl)isoindolin-2-yl)piperidine- 2,6-dione: To a solution of 2-bromo-1-phenyl-1H-benzo[d]imidazole (25.0 mg, 91.5 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (67.7 mg, 183 μmol, 2.00 eq) and K3PO4 (58.2 mg, 274 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (7.66 mg, 9.15 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *40 mm *10 um) and gradient of 17.0% - 47.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (22.9 mg, 52.4 μmol, 57.3% yield, 99.8% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.85 - 7.83 (m, 2H), 7.68 - 7.64 (m, 1H), 7.59 - 7.56 (m, 4H), 7.48 - 7.46 (m, 4H), 7.28 - 7.27 (m, 1H), 5.13 - 5.09 (m, 1H), 4.47 - 4.28 (m, 2H), 2.95 - 2.87 (m, 1H), 2.63 - 2.61 (m, 1H), 2.41 - 2.32 (m, 1H), 2.01 - 1.98 (m, 1H). (ESI+) m/z: 437.0 (M+H)+, (C26H20N4O3). EXAMPLE 377 [1226] Synthesis of 3-(5-(1-(4-Methoxyphenyl)-1H-benzo[d]imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1227] A.2-Bromo-1-(4-methoxyphenyl)-1H-benzo[d]imidazole: To a solution of 2- bromo-1H-benzo[d]imidazole (500 mg, 2.54 mmol, 1.00 eq), (4-methoxyphenyl)boronic acid (1.54 mg, 10.1 mmol, 4.00 eq) and Na2CO3 (672 mg, 6.34 mmol, 2.50 eq), 2,2-Bipyridyl (475 mg, 3.05 mmol, 1.20 eq) in dioxane (20.0 mL) was added Cu(OAc)2 (553 mg, 3.05 mmol, 1.20 eq) under O2.The mixture was stirred at 60 °C for 16 h under O2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1,TLC: Petroleum ether: Ethyl acetate = 5:1,Rf = 0.40) to give the title compound (180 mg, 572 427 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT μmol, 22.5% yield, 96.5% purity in LCMS at 220 nm) was obtained as off-white solid. (ESI+) m/z: 302.8 (M+H)+, (C14H11BrN2O). [1228] B.3-(5-(1-(4-Methoxyphenyl)-1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1-(4-methoxyphenyl)-1H- benzo[d]imidazole (100 mg, 329 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (244 mg, 659 μmol, 2.00 eq) and K3PO4 (210 mg, 989 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru- Phos-Pd-G3 (27.5 mg, 32.9 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *40 mm *10 um) and gradient of 17.0% - 47.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (102 mg, 218 μmol, 66.2% yield, 99.6% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.90 - 7.87 (m, 2H), 7.83 - 7.81 (m, 1H), 7.72 - 7.70 (m, 1H), 7.59 - 7.49 (m, 4H), 7.39 - 7.35 (m, 1H), 7.13 - 7.11 (m, 2H), 5.14 - 5.09 (m, 1H), 4.49 - 4.30 (m, 2H), 3.83 (s, 3H), 2.94 - 2.87 (m, 1H), 2.61 - 2.57 (m, 1H), 2.41 - 2.38 (m, 1H), 2.03 - 1.99 (m, 1H). (ESI+) m/z: 467.0 (M+H)+, (C27H22N4O4). EXAMPLE 378 [1229] Synthesis of 3-(5-(1-Cyclopropyl-4,5-diphenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1230] A.1-Cyclopropyl-4,5-diphenyl-1H-imidazole: To a solution of cyclopropylboronic acid (1.17 g, 13.6 mmol, 1.50 eq) and 4,5-diphenyl-1H-imidazole (2.00 g, 9.08 mmol, 1.00 eq) in dioxane (40.0 mL) was added Cu(OAc)2 (1.65 g, 9.08 mmol, 1.00 eq) and Na2CO3 (2.89 g, 27.2 mmol, 3.00 eq). The mixture was stirred at 100 °C for 16 h. The mixture was poured into H2O (100 mL) and extracted with dichloromethane: methanol (9: 1, 3 x 200 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl Acetate = 10: 1 to 0: 1; TLC, Petroleum ether: Ethyl Acetate = 0: 1, Rf 428 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT = 0.45) to give the title compound (200 mg, 757.49 μmol, 8.40% yield, 98.6% purity in LCMS at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.50 - 7.45 (m, 5H), 7.37 - 7.28 (m, 2H), 7.25 - 7.22 (m, 2H), 7.18 - 7.15 (m, 1H), 3.35 - 3.25 (m, 1H), 0.85 - 0.78 (m, 2H), 0.60 - 0.55 (m, 2H). (ESI+) m/z: 261.2 (M+H)+, (C18H16N2). [1231] B.2-Bromo-1-cyclopropyl-4,5-diphenyl-1H-imidazole: To a solution of 1- cyclopropyl-4,5-diphenyl-1H-imidazole (150 mg, 576 μmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.5 M, 345 μL, 1.50 eq) at -78°C under N2, then reaction mixture was stirred at 25 °C for 1 h under N2.1,2-dibromo-1,1,2,2-tetrafluoroethane (157 mg, 605 μmol, 1.05 eq) was added to the mixture at -78 °C under N2. The reaction mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was poured into NH4Cl (10.0 mL), extracted with EtOAc (3 x 10.0 mL). The combined organic layer was washed with brine (2 x 10.0 mL), dried over Na2SO4 and concentrated in vacuum to give residue. The residue was purified by preparative- TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (40.0 mg, 117 μmol, 20.4% yield) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.42 (m, 5H), 7.35 - 7.29 (m, 2H), 7.25 - 7.20 (m, 2H), 7.18 - 7.15 (m, 1H), 3.31 - 3.25 (m, 1H), 0.82 - 0.78 (m, 2H), 0.60 - 0.55 (m, 2H). (ESI+) m/z: 339.0 (M+H)+, (C18H15BrN2). [1232] C.2-Bromo-1-cyclopropyl-4,5-diphenyl-1H-imidazole: To a solution of 2-bromo- 1-cyclopropyl-4,5-diphenyl-1H-imidazole (40.0 mg, 117 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (87.3 mg, 235 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (9.86 mg, 11.7 μmol, 0.10 eq), K3PO4 (50.0 mg, 235 μmol, 2.00 eq) under N2. The reaction was stirred at 65 °C for 4 h under N2. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 20: 1;TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.40) and preparative- HPLC (using a CD06-Waters Xbidge C18 (150 x 40 x 10 μm) and gradient of 20 - 50% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (26.4 mg, 51.8 μmol, 43.9% yield, 98.4% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.17 (s, 1H), 8.13 - 8.10 (m, 1H), 8.00 - 7.92 (m, 1H), 7.60 - 7.50 (m, 5H), 7.45 - 7.35 (m, 2H), 7.30 - 7.25 (m, 3H), 5.20 - 5.15 (m, 1H), 4.63 - 4.45 (m, 2H), 3.84 - 3.81 (m, 1H), 2.95 - 2.90 (m, 1H), 2.64 - 2.50 (m, 1H), 2.45 - 2.40 (m, 1H), 2.08 - 2.00 (m, 1H), 0.75 - 0.65 (m, 2H), 0.30 - 0.25 (m, 2H). (ESI+) m/z: 503.1 (M+H)+, (C31H26N4O3). 429 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 379 [1233] Synthesis of 3-(5-(1,5-Diphenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1234] A.1,5-Diphenyl-1H-imidazole: A solution of 1-(isocyanomethylsulfonyl)-4- methyl-benzene (11.8 g, 60.7 mmol, 1.10 eq), (E)-N,1-diphenylmethanimine (10.0 g, 55.1 mmol, 1.00 eq) and t-BuONa (11.6 g, 121 mmol, 2.20 eq) in THF (200 mL) was stirred at 25 °C for 72 h. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 50: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.35) and triturated with EtOAc (10.0 mL) at 0 °C for 30 min to give the title compound (1.20 g, 5.45 mmol, 10.7% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.45 - 7.41 (m, 3H), 7.30 - 7.27 (m, 4H), 7.23 - 7.20 (m, 2H), 7.18 - 7.15 (m, 2H). (ESI+) m/z: 221.1 (M+H)+, (C15H12N2). [1235] B.2-Bromo-1,5-diphenyl-1H-imidazole: To a solution of 1,5-diphenylimidazole (1.00 g, 4.54 mmol, 1.00 eq) in THF (20.0 mL) was added n-BuLi (2.5 M, 2.72 mL, 1.50 eq) at -78 °C under N2. Then 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (1.24 g, 4.77 mmol, 1.05 eq) was added to the mixture dropwise at -78 °C under N2. The reaction mixture was stirred at 25 °C for 4 h under N2. To the mixture was added dropwise NH4Cl (20.0 mL) at 0 °C under N2, the mixture was stirred for 30 min at 25 °C. Then the mixture was extracted with EtOAc (3 x 30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give the title compound (1.10 g, 3.68 mmol, 80.9% yield) as a yellow solid.1H NMR: (400 MHz, MeOD) δ 7.53 - 7.46 (m, 3H), 7.30 - 7.26 (m, 2H), 7.25 (s, 1H), 7.24 - 7.20 (m, 3H), 7.15 - 7.11 (m, 2H). (ESI+) m/z: 298.8 (M+H)+, (C15H11BrN2). [1236] C.1,5-Diphenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 2-bromo-1,5- diphenyl-imidazole (500 mg, 1.67 mmol, 1.00 eq) in DMF (5.00 mL) and NMP (5.00 mL) was added CuI (954 mg, 5.01 mmol, 3.00 eq), TMSCF3 (712 mg, 5.01 mmol, 3.00 eq) and KF (291 mg, 5.01 mmol, 3.00 eq), then the mixture was stirred at 80 °C for 16 h under N2. The residue was poured into H2O (30.0 mL) and extracted with EtOAc (3 x 30.0 mL). The combined organic layer was washed with brine (2 x 30.0 mL), dried over Na2SO4, filtered 430 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT and concentrated in vacuum to give residue. The crude compound was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1; TLC, Petroleum ether: Ethyl acetate =3: 1, Rf = 0.70) to give the title compound (35.0 mg, 97.1 μmol, 5.81% yield, 80.0% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 289.1 (M+H)+, (C16H11F3N2). [1237] D.4-Bromo-1,5-diphenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1,5-diphenyl-2-(trifluoromethyl)imidazole (35.0 mg, 121 μmol, 1.00 eq) in ACN (0.50 mL) was added NBS (22.6 mg, 127 μmol, 1.05 eq).The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to give residue. The crude compound was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 10: 1; TLC, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.40) to give the title compound (30.0 mg, 81.7 μmol, 67.3% yield) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.47 (m, 2H), 7.45 - 7.43 (m, 3H), 7.33 - 7.29 (m, 5H). (ESI+) m/z: 368.8 (M+H)+, (C16H10BrF3N2). [1238] E.3-(5-(1,5-Diphenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1,5-diphenyl-2- (trifluoromethyl)imidazole (30.0 mg, 81.7 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl]piperidine-2,6-dione (60.5 mg, 163 μmol, 2.00 eq), K3PO4 (34.6 mg, 163 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (6.83 mg, 8.17 μmol, 0.10 eq) under N2, then the mixture was stirred at 80 °C for 2 h under N2. The mixture was filtered through a pad of celite the pad or filter cake was washed with DCM (3 x 20.0 mL), the filtrate was concentrated to give residue. The crude compound was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 15: 1; TLC, Dichloromethane: Methanol = 15: 1, Rf = 0.70) and preparative-HPLC (using a CD01-Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 40 - 70% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 30.0 mL/min) to give the title compound (13.9 mg, 26.3 μmol, 32.1% yield, 100% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.72 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52 - 7.46 (m, 3H), 7.44 - 7.39 (m, 3H), 7.36 - 7.30 (m, 5H), 5.14 - 5.03 (m, 1H), 4.45 - 4.20 (m, 2H), 2.96 - 2.82 (m, 1H), 2.59 - 2.58 (m, 1H), 2.43 - 2.37 (m, 1H), 2.03 - 1.94 (m, 1H). (ESI+) m/z: 531.0 (M+H)+, (C29H21F3N4O3). 431 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 380 [1239] Synthesis of 3-(6-Fluoro-5-(1-methyl-5-phenyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1240] A.1-Methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole：To a solution of 1- methyl-2-(trifluoromethyl)-1H-imidazole (400 mg, 2.66 mmol, 1.00 eq), bromobenzene (1.26 g, 7.99 mmol, 841μL, 3.00 eq), K2CO3 (736 mg, 5.33 mmol, 2.00 eq) and PCy3 (123 mg, 532 μmol, 0.20 eq) in DMF (10.0 mL) was added Pd(OAc)2 (59.8 mg, 266 μmol, 0.10 eq) under N2.The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, TLC : Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (300 mg, 1.33 mmol, 49.7% yield, 95.0% purity in LCMS at 220 nm) as a yellow solid.1HNMR: (400 MHz, DMSO-d6) δ 7.56 - 7.48 (m, 5H), 7.23 (s, 1H), 3.73 (s, 3H). (ESI+) m/z: 227.0 (M+H)+, (C11H9F3N2). [1241] B.4-Bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (300 mg, 1.33 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (259 mg, 1.46 mmol, 1.10 eq) at 0°C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (100 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Petroleum ether: Ethyl acetate =5: 1,Rf = 0.60) to give the title compound (330 mg, 1.08 mmol, 81.5% yield, 100% purity in LCMS at 220 nm) as yellow solid.1HNMR: (400 MHz, DMSO-d6) δ 7.56 - 7.52 (m, 5H), 3.64 (s, 3H). (ESI+) m/z: 304.7 (M+H)+, (C11H8BrF3N2). [1242] C.3-(6-Fluoro-5-(1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-5-phenyl-2- (trifluoromethyl)-1H-imidazole (100 mg, 327 μmol, 1.00 eq), 3-(6-fluoro-5-(1-methyl-5- phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (190 mg, 491 μmol, 1.50 eq) and K3PO4 (208 mg, 981 μmol, 3.00 eq) in dioxane (5.00 mL) and 432 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT H2O (0.25 mL) was added Ru-Phos-Pd-G3 (27.4 mg, 32.7 μmol, 0.10 eq) under N2. The mixture was stirred at 90 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and gradient of 31.0% - 61.0% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min to give the title compound (101 mg, 207 μmol, 63.2% yield, 99.7% purity in HPLC at 220 nm) as white solid.1HNMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.77 (s, 1H), 7.47 - 7.42 (m, 3H), 7.39 - 7.36 (m, 3H), 5.13 - 5.08 (m, 1H), 4.48 - 4.29 (m, 2H), 3.74 - 3.69 (m, 3H), 2.90 - 2.88 (m, 1H), 2.60 - 2.56 (m, 1H), 2.40 - 2.37 (m, 1H), 2.02 - 2.01 (m, 1H). (ESI+) m/z: 487.0 (M+H)+, (C24H18F4N4O3). EXAMPLE 381 [1243] Synthesis of 3-(5-(2-(Difluoromethyl)-5-(p-tolyl)oxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [1244] A.2,2-Difluoro-N-(2-oxo-2-(p-tolyl)ethyl)acetamide: To a solution of 2-amino-1- (p-tolyl)ethan-1-one (1.00 g, 6.70 mmol, 1.00 eq) in THF (20.0 mL) was added 2,2- difluoroacetic anhydride (1.98 g, 11.3 mmol, 1.70 eq) and TEA (1.36 g, 13.4 mmol, 1.87 mL, 2.00 eq) under N2. The mixture was stirred at 25 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (1.00 g, crude) as a yellow solid. (ESI+) m/z: 228.0 (M+H)+, (C11H11F2NO2). [1245] B.2-(Difluoromethyl)-5-(p-tolyl)oxazole: A solution of 2,2-difluoro-N-(2-oxo-2- (p-tolyl)ethyl)acetamide (1.00 g, 4.40 mmol, 1.00 eq) in H2SO4 (12 M, 1.47 mL, 4.00 eq) was stirred at 80 °C for 2 h under N2. After the reaction was completed, the reaction mixture was cooled to 20 °C and adjusted with aq. solution of Na2CO3 (50.0 ml) to pH=7. The mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (500 mg, 2.27 mmol, 51.5% yield, 94.9% 433 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 52.0 Hz, 1H), 2.35 (s, 3H). (ESI+) m/z: 210.0 (M+H)+, (C11H9F2NO). [1246] C.4-Bromo-2-(difluoromethyl)-5-(p-tolyl)oxazole: To a solution of 2- (difluoromethyl)-5-(p-tolyl)oxazole (200 mg, 907 μmol, 1.00 eq) in DMF (2.00 mL) was added NBS (177 mg, 998 μmol, 1.10 eq). The mixture was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was poured to H2O (10.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with saturated NaCl (3 x 10.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (170 mg, 590 μmol, 65.0% yield, 100% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.79 (dd, J = 8.0, Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 52.4 Hz, 1H), 2.36 (s, 3H). (ESI+) m/z: 287.9 (M+H)+, (C11H8BrF2NO). [1247] D.3-(5-(2-(Difluoromethyl)-5-(p-tolyl)oxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(difluoromethyl)-5-(p-tolyl)oxazole (150 mg, 520 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (578 mg, 1.56 mmol, 3.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (43.5 mg, 52.0 μmol, 0.10 eq) and K3PO4 (221 mg, 1.04 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was poured to H2O ( 10.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with saturated NaCl (3 x 10.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5:1, Rf = 0.40) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 32 - 62% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (113 mg, 251 μmol, 48.3% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 52.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 13.2, 5.2 Hz, 1H), 5.42 (dd, J = 52.8, 17.6Hz, 2H), 2.97 - 2.87 (m, 1H), 2.63 - 2.58 (m, 1H), 2.45 - 2.40 (m, 1H), 2.36 (s, 3H), 2.04 - 2.00 (m, 1H). (ESI+) m/z: 452.1 (M+H)+, (C24H19F2N3O4). 434 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 382 [1248] Synthesis of 3-(5-(5-(4-Chlorophenyl)-2-(difluoromethyl)oxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1249] A. N-(2-(4-Chlorophenyl)-2-oxoethyl)-2,2-difluoroacetamide: To a solution of 2- amino-1-(4-chlorophenyl) ethanone hydrochloride (1.00 g, 4.85 mmol, 1.00 eq) , 2,2- difluoroacetic anhydride (844 mg, 4.85 mmol, 1.00 eq)and TEA (982 mg, 9.71 mmol, 1.35 mL, 2 eq) in THF (10.0 mL) was degassed and purged with N2 for 3 times and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title compound (1.85 g, crude) was obtained as orange solid. (C10H8ClF2NO2). [1250] B.5-(4-Chlorophenyl)-2-(difluoromethyl)oxazole: To a solution of N-(2-(4- chlorophenyl)-2-oxoethyl)-2,2-difluoroacetamide (1.85 g, 7.47 mmol, 1.00 eq) in H2SO4 (3.66 g, 37.3 mmol, 1.99 mL, 5.00 eq) at 25 °C. The mixture was stirred at 80 °C for 1 h. The mixture was poured into water (30.0 mL) at 0 °C. Then the solution was neutralized with 28% NH3.H2O and extracted with EA (3 x 50 mL). Combined organic layer was washed with brine (3 x 30.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 0: 1 to 20: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.60) to give the title compound (438 mg, 1.91 mmol, 25.5% yield).1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.8 (d, J = 12 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.42 - 7.16 (m, 1H). (ESI+) m/z: 229.9 (M+H)+, (C10H6ClF2NO). [1251] C.4-Bromo-5-(4-chlorophenyl)-2-(difluoromethyl)oxazole: A mixture of 5-(4- chlorophenyl)-2-(difluoromethyl)oxazole (300 mg, 972 μmol, 1 eq) in ACN (4.00 mL) was added NBS (255 mg, 1.06 mmol, 1.1 eq) at 0 °C and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 24 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.69) to give the title compound (230 mg, 745 μmol, 76.6% yield) as a white solid.1H NMR (400 MHz, DMSO- 435 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT d6) δ 7.96 - 7.87 (m, 2H), 7.70 - 7.63 (m, 2H), 7.42 - 7.16 (m, 1H). (ESI+) m/z: 309.8 (M+H)+, (C10H5BrClF2NO). [1252] D.3-(5-(5-(4-Chlorophenyl)-2-(difluoromethyl)oxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione3-(5-(5-(4-chlorophenyl)-2-(difluoromethyl)oxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 4-bromo-5-(4-chlorophenyl)-2- (difluoromethyl)oxazole (200 mg, 648 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (480 mg, 1.30 mmol, 2.00 eq), RuPhos Pd G3 (54.2 mg, 64.8 μmol, 0.10 eq), K3PO4 (412. mg, 1.94 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 3 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate in vacuum to give residue. The crude product was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 40 - 70% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (8.64 mg, 18.2 μmol, 2.82% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.61 - 7.56 (m, 2H), 7.49 - 7.23 (m, 1H), 5.15 - 5.11 (m, 1H), 4.54 - 4.32 (m, 2H), 2.99 - 2.86 (m, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.42 - 2.39 (m, 1H), 2.08 - 1.98 (m, 1H). (ESI+) m/z: 472.0 (M+H)+, (C23H16ClF2N3O4). EXAMPLE 383 [1253] Synthesis of 3-(5-(5-(2-Chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1254] A.1-Methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 2- (trifluoromethyl)-1H-imidazole (17.0 g, 124 mmol, 1.00 eq) in ACN (500 mL) was added Cs2CO3 (81.4 g, 249 mmol, 2.00 eq) at 25 °C under N2. Then MeI (19.5 g, 137 mmol, 8.56 mL, 1.10 eq) was added under N2. The mixture was stirred at 60 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (14.0 g, 93.2 mmol, 74.6% yield, 100% 436 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT purity in LCMS at 220 nm) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.06 (s, 1H), 3.79 (s, 3H). (ESI+) m/z: 151.0 (M+H)+, (C5H5F3N2). [1255] B.5-(2-Chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1-methyl-2-(trifluoromethyl)-1H-imidazole (200 mg, 1.33 mmol, 1.00 eq) and 1-bromo-2- chlorobenzene (765 mg, 4.00 mmol, 467 μL, 3.00 eq) in DMF (2.00 mL) was added P(oxole)3 (61.8 mg, 266 μmol, 0.20 eq), Pd(OAc)2 (29.9 mg, 133 μmol, 0.10 eq) and K2CO3 (368 mg, 2.66 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was was purified The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (100 mg, 368 μmol, 27.6% yield, 96.1% purity in LCMS at 220 nm) as yellow oil. 1H NMR: (400 MHz, DMSO-d6) δ 7.68 (dd, J = 7.6, 0.8 Hz, 1H), 7.58 - 7.50 (m, 3H), 7.20 (s, 1H), 3.54 (s, 3H). (ESI+) m/z: 261.0 (M+H)+, (C11H8ClF3N2). [1256] C.4-Bromo-5-(2-chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 5-(2-chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole (100 mg, 368 μmol, 1.00 eq) in ACN (1.00 mL) was added NBS (72.1 mg, 405 μmol, 1.10 eq). The mixture was stirred at 60 °C for 12 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.60) to give the title compound (120 mg, 350 μmol, 95.0% yield, 99.2% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.64 (dd, J = 8.0, 1.2 Hz, 1H), 7.58 (td, J = 7.6, 2.0 Hz, 1H), 7.51 (td, J = 7.6, 1.6 Hz, 1H), 7.46 (dd, J = 7.6, 1.6 Hz, 1H), 3.53 (s, 3H). (ESI+) m/z: 338.9 (M+H)+, (C11H7BrClF3N2). [1257] D.3-(5-(5-(2-Chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-5-(2-chlorophenyl)-1- methyl-2-(trifluoromethyl)-1H-imidazole (110 mg, 321 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (356 mg, 964 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (26.8 mg, 32.1 μmol, 0.10 eq) and K3PO4 (136 mg, 642 μmol, 2.00 eq) under N2. The mixture was stirred at 60 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5:1, Rf = 0.40) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 34 - 64% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to 437 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT give the title compound (85.1 mg, 168 μmol, 52.5% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.68 - 7.56 (m, 5H), 7.37 - 7.30 (m, 1H), 5.08 (dd, J = 13.2, 4.8 Hz, 1H), 4.42 - 4.21 (m, 2H), 3.50 (s, 3H), 2.94 - 2.84 (m, 1H), 2.60 - 2.59 (m, 1H), 2.38 - 2.33 (m, 1H), 1.99 - 1.95 (m, 1H). (ESI+) m/z: 503.1 (M+H)+, (C24H18ClF3N4O3). EXAMPLE 384 [1258] Synthesis of 3-(5-(5-(3-Chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1259] A.5-(3-Chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1-methyl-2-(trifluoromethyl)-1H-imidazole (200 mg, 1.33 mmol, 1.00 eq) and 1- bromo-3-chlorobenzene (765 mg, 4.00 mmol, 469 μL, 3.00 eq) in DMF (2.00 mL) was added P(oxole)3 (61.8 mg, 266 μmol, 0.20 eq), Pd(OAc)2 (29.9 mg, 133 μmol, 0.10 eq) and K2CO3 (368 mg, 2.66 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was was purified The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.40) to give the title compound (200 mg, 745 μmol, 55.9% yield, 97.1% purity in LCMS at 220 nm) as a blue solid.1H NMR: (400 MHz, DMSO-d6) δ 7.67 - 7.65 (m, 1H), 7.57 - 7.51 (m, 3H), 7.29 (s, 1H), 3.73 (s, 3H). (ESI+) m/z: 261.0 (M+H)+, (C11H8ClF3N2). [1260] B.4-Bromo-5-(3-chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 5-(3-chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazole (200 mg, 745 μmol, 1.00 eq) in ACN (1.00 mL) was added NBS (145 mg, 819 μmol, 1.10 eq). The mixture was stirred at 60 °C for 12 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.60) to give the title compound ((220 mg, 632 μmol, 84.8% yield, 97.6% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.66 - 7.64 (m, 1H), 7.63 - 7.58 (m, 2H), 7.53 - 7.50 (m, 1H), 3.65 (s, 3H). (ESI+) m/z: 338.9. (M+H)+, (C11H7BrClF3N2). 438 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1261] C.3-(5-(5-(3-Chlorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-5-(3-chlorophenyl)-1- methyl-2-(trifluoromethyl)-1H-imidazole (200 mg, 574 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (638 mg, 1.72 mmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (48.0 mg, 57.4 μmol, 0.10 eq) and K3PO4 (244 mg, 1.15 mmol, 2.00 eq) under N2. The mixture was stirred at 60 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5:1, Rf = 0.40) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 36 - 66% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (73.1 mg, 145 μmol, 25.2% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.70 - 7.65 (m, 3H), 7.62 - 7.57 (m, 2H), 7.48 - 7.44 (m, 1H), 7.37 (dd, J = 8.0, 1.2 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.33 (dd, J = 57.6, 17.6 Hz, 2H), 3.58 (s, 3H), 2.95 - 2.85 (m, 1H), 2.61 - 2.53(m, 1H), 2.39 - 2.34 (m, 1H), 2.00 - 1.96 (m, 1H). (ESI+) m/z: 503.1 (M+H)+, (C24H18ClF3N4O3). EXAMPLE 385 [1262] 3-[5-[5-(4-Chlorophenyl)-1-methyl-2-(trifluoromethyl)imidazol-4-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: [1263] A.5-(4-Chlorophenyl)-1-methyl-2-(trifluoromethyl)imidazole: To a solution of 1-methyl-2-(trifluoromethyl)imidazole (200 mg, 1.33 mmol, 1.00 eq) in DMF (2.00 mL) was added 1-bromo-4-chloro-benzene (765 mg, 4.00 mmol, 765 μL, 3.00 eq), P(oxole)3 (61.8 mg, 266 μmol, 0.20 eq), Pd(OAc)2 (29.9 mg, 133 μmol, 0.10 eq) and K2CO3 (368 mg, 2.66 mmol, 2.00 eq). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.43) to give the title compound (250 mg, 930 μmol, 69.8% yield) as yellow oil.1H NMR: 439 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (400 MHz, DMSO-d6) δ 7.59 (s, 4H), 7.26 (s, 1H), 3.73 (s, 3H). (ESI+) m/z: 260 (M+H)+, (C11H8ClF3N2). [1264] B.4-Bromo-5-(4-chlorophenyl)-1-methyl-2-(trifluoromethyl)imidazole: To a solution of 5-(4-chlorophenyl)-1-methyl-2-(trifluoromethyl)imidazole (200 mg, 767 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (150 mg, 844 μmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.43) to give the title compound(240 mg, 692 μmol, 90.2% yield) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.68 - 7.63 (m, 2H), 7.60 - 7.55 (m, 2H), 3.64 (s, 3H). (ESI+) m/z: 337 (M+H)+, (C11H7BrClF3N2). [1265] C.3-[5-[5-(4-Chlorophenyl)-1-methyl-2-(trifluoromethyl)imidazol-4-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione: To a solution of 4-bromo-5-(4-chlorophenyl)-1- methyl-2-(trifluoromethyl)imidazole (100 mg, 294 μmol, 1.00 eq) in dioxane (1.00 mL) was added H2O (0.05 mL), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl]piperidine-2,6-dione (272 mg, 736 μmol, 2.50 eq), K3PO4 (187 mg, 883 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (49.2 mg, 58.9 μmol, 0.20 eq). The mixture was stirred at 60 °C for 3 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 36 - 66% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25.0 mL/min) to give the title compound (31.0 mg, 61.0 μmol, 20.7% yield, 99% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.68 - 7.58 (m, 4H), 7.54 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 9.2 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.44 - 4.21 (dd, J = 28.6, 8.6 Hz, 2H), 3.57 (s, 3H), 2.96 - 2.84 (m, 1H), 2.60 (m, 1H), 2.43 - 2.35 (m, 1H), 2.03 - 1.93 (m, 1H). (ESI+) m/z: 502.0 (M+H)+, (C24H18ClF3N4O3). 440 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 386 [1266] Synthesis of 3-(5-(5-(4-Aminophenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1267] A.1-Methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 2- (trifluoromethyl)-1H-imidazole (17.0 g, 124 mmol, 1.00 eq) in ACN (500 mL) was added Cs2CO3 (81.4 g, 249 mmol, 2.00 eq) at 25 °C under N2. Then MeI (19.5 g, 137 mmol, 8.56 mL, 1.10 eq) was added under N2. The mixture was stirred at 60 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (14.0 g, 93.2 mmol, 74.6% yield, 100% purity in LCMS at 220 nm) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.06 (s, 1H), 3.79 (s, 3H). (ESI+) m/z: 151.0 (M+H)+, (C5H5F3N2). [1268] B.4,5-Dibromo-1-methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1- methyl-2-(trifluoromethyl)-1H-imidazole (8.00 g, 53.3 mmol, 1.00 eq) in ACN (150 mL) was added NBS (28.4 g, 159 mmol, 3.00 eq). The mixture was stirred at 20 °C for 6 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1; TLC, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (14.0 g, 42.6 mmol, 79.9% yield, 93.7% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 3.76 (s, 3H). (ESI+) m/z: 306.8 (M+H)+, (C5H3Br2F3N2). [1269] C.4-Bromo-1-methyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 4,5- dibromo-1-methyl-2-(trifluoromethyl)-1H-imidazole (12.0 g, 36.5 mmol, 1.00 eq) in THF (120 mL) was added n-BuLi (2.5 M, 17.5 mL, 1.20 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. After the reaction was completed, the reaction mixture was warmed to 20 °C and quenched with aq. solution of NH4Cl (50.0 mL). The mixture was extracted with ethyl acetate (3 x 50.0mL) and the combined organic layers were washed with brine (50.0mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to 441 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1; TLC, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (7.00 g, 30.3 mmol, 83.0% yield, 99.2% purity in LCMS at 220 nm) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 3.79 (s, 3H). (ESI+) m/z: 228.9 (M+H)+, (C5H4BrF3N2). [1270] D.3-(5-(1-Methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-methyl-2-(trifluoromethyl)-1H- imidazole (7.00 g, 30.3 mmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (22.4 g, 60.6 mmol, 2.00 eq) in dioxane (100 mL) and H2O (5.00 mL) was added Ru-Phos-Pd-G3 (2.54 g, 3.03 mmol, 0.10 eq) and K3PO4 (12.8 g, 60.6 mmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 20: 1; TLC, Dichloromethane: Methanol = 20: 1,Rf = 0.40) to give the title compound (2.20 g, 5.29 mmol, 17.4% yield, 94.3% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.91 (dd, J = 32.0, 0.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 5.12 (dd, J = 13.2, 4.8 Hz, 1H), 4.43 (dd, J = 51.6, 17.2 Hz, 2H), 3.86 (s, 3H), 2.96 - 2.88 (m, 1H), 2.63 - 2.58 (m, 1H), 2.44 - 2.38 (m, 1H), 2.04 - 2.01 (m, 1H). (ESI+) m/z: 393.1 (M+H)+, (C18H15F3N4O3). [1271] E.3-(5-(5-Bromo-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2.00 g, 4.80 mmol, 1.00 eq) in DMF (20.0 mL) was added NBS (940 mg, 5.28 mmol, 1.10 eq). The mixture was stirred at 20 °C for 12 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was was triturated with ethyl acetate (20.0 mL) and H2O (20.0 mL) at 20 °C for 30 mins to give the title compound (2.00 g, 4.04 mmol, 84.0% yield, 95.2% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.11 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 5.14 (dd, J = 13.2, 4.8 Hz, 1H), 4.47 (dd, J = 52.817.6 Hz, 2H), 3.81 (s, 3H), 2.96 - 2.88 (m, 1H), 2.64 - 2.59 (m, 1H), 2.44 - 2.38 (m, 1H), 2.04 - 2.01 (m, 1H). (ESI+) m/z: 471.0 (M+H)+, (C18H14BrF3N4O3). [1272] F.3-(5-(5-(4-Aminophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- 442 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (132 mg, 606 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) and K3PO4 (85.7 mg, 404 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5: 1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 24 - 54% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (11.4 mg, 23.2 μmol, 11.5% yield, 98.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 5.55 (s 2H), 5.08 (dd, J = 13.2, 4.8 Hz, 1H), 4.32 (dd, J = 60.0, 17.6 Hz, 2H), 3.53 (s, 3H), 3.92 - 3.86 (m, 1H), 2.61 - 2.59 (m, 1H), 2.41 - 2.34 (m, 1H), 1.99 - 1.97 (m, 1H). (ESI+) m/z: 484.1 (M+H)+, (C24H20F3N5O3). EXAMPLE 387 [1273] Synthesis of 3-(5-(1-Methyl-5-(4-(methylamino)phenyl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1274] A.3-(5-(1-Methyl-5-(4-(methylamino)phenyl)-2-(trifluoromethyl)-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl- 2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) and (4-(methylamino)phenyl)boronic acid (141 mg, 606 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) and K3PO4 (85.7 mg, 404 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5:1, Rf = 0.30) and by preparative-HPLC 443 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 30 - 60% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (48.0 mg, 96.6 μmol, 47.8% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.14 (dd, J = 10.0, 4.8 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.32 (dd, J = 58.8, 17.2 Hz, 2H), 3.53 (s, 3H), 2.95 - 2.85 (m, 1H), 2.74 (d, J = 4.8 Hz, 3H), 2.61 - 2.55 (m, 1H), 2.40 - 2.34 (m, 1H), 2.00 - 1.96 (m, 1H). (ESI+) m/z: 498.1 (M+H)+, (C25H22F3N5O3). EXAMPLE 388 [1275] Synthesis of 3-(5-(1-Methyl-5-(quinolin-6-yl)-2-(trifluoromethyl)-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1276] A.3-(5-(1-Methyl-5-(quinolin-6-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 212 μmol, 1.00 eq), quinolin-6-ylboronic acid (110 mg, 637 μmol, 3.00 eq), Ru-Phos-Pd-G3 (18.0 mg, 21.2 μmol, 0.10 eq) and K3PO4 (90.0 mg, 424 μmol, 2.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 15 - 45% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (55.53 mg, 106 μmol, 50.17% yield, 99.6% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.12 - 8.99 (m, 1H), 8.58 - 8.44 (m, 1H), 8.31 - 8.14 (m, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.76 - 7.62 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 5.6, 13.2 Hz, 1H), 4.39 - 4.18 (m, 444 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2H), 3.63 (s, 3H), 2.93 - 2.83 (m, 1H), 2.60 - 2.57 (m, 1H), 2.39 - 2.28 (m, 1H), 2.02 - 1.89 (m, 1H). (ESI+) m/z: 519.9 (M)+, (C27H20F3N5O3). EXAMPLE 389 [1277] Synthesis of 3-(5-(1-Methyl-5-(quinazolin-6-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1278] A.3-(5-(1-Methyl-5-(quinazolin-6-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazoline (105 mg, 606 μmol, 3.00 eq), K3PO4 (85.7 mg, 404 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a CD01- Phenomenex luna C18 (150 mm x 25 mm 10 μm) and gradient of 15 - 45% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25.0 mL/min) to give the title compound (36.47 mg, 68.7 μmol, 33.1% yield, 98.1% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.66 (s, 1H), 9.41 (s, 1H), 8.40 (s, 1H), 8.20 - 8.18 (m, 1H), 8.09 - 8.06 (m, 1H), 7.66 (s, 1H), 7.56 - 7.54 (m, 1H), 7.41 - 7.39 (m, 1H), 5.08 - 5.03 (m, 1H), 4.37 - 4.19 (m, 2H), 3.64 (s, 3H), 2.89 - 2.84 (m, 1H), 2.57 - 2.54 (m, 1H), 2.35 - 2.31 (m, 1H), 1.97 - 1.94 (m, 1H). (ESI+) m/z: 521.0 (M+H)+, (C26H19N6F3O3). 445 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 390 [1279] Synthesis of 3-(5-(1-Methyl-5-(pyridin-3-yl)-2-(trifluoromethyl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1280] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(pyridin-3-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-(5-(5-bromo-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (200 mg, 366 μmol, 1.00 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added 3-pyridylboronic acid (135 mg, 1.10 mmol, 3.00 eq), K3PO4 (155 mg, 733 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (30.67 mg, 36.67 μmol, 0.1 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.25) to give the title compound (135 mg, 245 μmol, 66.8% yield, 98.7% purity) as a yellow solid. (ESI+) m/z: 544.1 (M+H)+, (C27H28N5O4F3). [1281] B.3-(5-(1-Methyl-5-(pyridin-3-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(1- methyl-5-(pyridin-3-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (80.0 mg, 147 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (101 mg, 588 μmol, 4.00 eq) under N2. The mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 15 - 45% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25.0 mL/min) to give the title compound (13.54 mg, 28.3 μmol, 19.2% yield, 98.4% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.77 - 8.76 (m, 1H), 8.67 - 8.66 (m, 1H), 7.99 - 7.97 (m, 1H), 7.62 - 7.61 (m, 3H), 7.59 - 7.36 (m, 1H), 5.10 - 5.05 (m, 1H), 4.41 - 4.23 (m, 2H), 3.60 (s, 3H), 2.92 - 2.86 (m, 1H), 2.60 - 2.52 (m, 1H), 2.38 - 2.35 (m, 1H), 2.33 - 1.96 (m, 1H). (ESI+) m/z: 470.0 (M+H)+, (C23H18N5F3O3). 446 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 391 [1282] Synthesis of 3-(5-(2-Methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1283] A.1-(Difluoroiodomethyl)-2-methyl-5-phenyl-1H-imidazole: To a solution of 2- methyl-5-phenyl-1H-imidazole (1.00 g, 6.32 mmol, 1.00 eq) in THF (10.0 mL) was added LiHMDS (1 M, 9.48 mL, 1.50 eq) at 0 °C under N2. The reaction was stirred at 25 °C for 1 h under N2. Then CF3I (9.91 g, 12.6 mmol, 25% purity, 2.00 eq) was added at 0 °C under N2. The reaction mixture was stirred at 25 °C for 4 h under N2. The reaction mixture was quenched with sat.aqueous NH4Cl (50.0mL) at 0 °C and extracted with ethyl acetate (3 x 80.0 mL), the organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 150: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.60) to give the title compound (400 mg, 1.20 mmol, 18.9% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.40 (m, 5H), 6.92 (s, 1H), 2.46 - 2.42 (m, 3H). (ESI+) m/z: 334.9 (M+H)+, (C11H9F2IN2). [1284] B.2-Methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole: To a solution of 1- (difluoroiodomethyl)-2-methyl-5-phenyl-1H-imidazole (350 mg, 1.05 mmol, 1.00 eq) in DCM (6.00 mL) was added AgBF4 (407 mg, 2.10 mmol, 2.00 eq). The reaction mixture was stirred at 20 °C for 2 h in the dark. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 15: 1; TLC: Dichloromethane: Methanol = 15: 1, Rf = 0.40) to give the title compound (150 mg, 663 μmol, 63.3% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.51 - 7.43 (m, 3H), 7.43 - 7.38 (m, 2H), 6.97 (s, 1H), 2.55 - 2.53 (m, 3H). (ESI+) m/z: 226.9 (M+H)+, (C11H9F3N2). [1285] C.4-Bromo-2-methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole: To a solution of 2-methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole (150 mg, 663 μmol, 1.00 eq) in ACN (1.50 mL) was added NBS (123 mg, 696 μmol, 1.05 eq). The reaction was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1; TLC: Petroleum 447 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (160 mg, 524 μmol, 79.0% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.52 - 7.42 (m, 3H), 7.40 - 7.34 (m, 2H), 2.66 - 2.59 (m, 3H). (ESI+) m/z: 304.9 (M+H)+, (C11H8BrF3N2). [1286] D.3-(5-(2-Methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-methyl-5-phenyl-1- (trifluoromethyl)-1H-imidazole (150 mg, 491 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (364 mg, 983 μmol, 2.00 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added Ru-Phos-Pd-G3 (41.1 mg, 49.1 μmol, 0.10 eq) and K3PO4 (208 mg, 983 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 60 °C for 16 h under N2. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by preparative-HPLC (using a CD01- Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 31 - 61% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (62.6 mg, 131 μmol, 26.7% yield, 98.4% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.60 - 7.50 (m, 5H), 7.48 - 7.42 (m, 2H), 7.36 - 7.31 (m, 1H), 5.12 - 5.02 (m, 1H), 4.41 - 4.13 (m, 2H), 2.95 - 2.83 (m, 1H), 2.64 - 2.61 (m, 3H), 2.60 - 2.58 (m, 1H), 2.38 - 2.31 (m, 1H), 2.02 - 1.89 (m, 1H). (ESI+) m/z: 469.1 (M+H)+, (C24H19F3N4O3). EXAMPLE 392 [1287] Synthesis of 3-(5-(4-Isopropyl-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1288] A.1-Methyl-5-phenyl-4-(prop-1-en-2-yl)-1H-imidazole: To a solution of 4- bromo-1-methyl-5-phenyl-1H-imidazole (1.00g, 4.22 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl)-1,3,2-dioxaborolane (850 mg, 5.06 mmol, 1.20 eq) and K3PO4 (2.69 g, 12.6 mmol, 3.00 eq) in dioxane (15.0 mL) and H2O (3.75 mL) was added Pd(dtbpf)Cl2 (274 mg, 421 μmol, 0.10 eq) under N2. The mixture was stirred at 70 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.40) to get a residue to give the title 448 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT compound (700 mg, 3.39 mmol, 80.3% yield, 96.0% purity in LCMS at 220 nm) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.48 - 7.41 (m, 3H), 7.36 - 7.34 (m, 2H), 5.01 (s, 1H), 4.72 (s, 1H), 3.35 (s, 3H), 3.17 (s, 3H). (ESI+) m/z: 199.0 (M+H)+, (C13H14N2). [1289] B.4-Isopropyl-1-methyl-5-phenyl-1H-imidazole: To a solution of Pd/C (28.8 mg, 27.0 μmol, 10% purity, 1.86e-2 eq) in MeOH (6.00 mL) was added 1-methyl-5-phenyl- 4-(prop-1-en-2-yl)-1H-imidazole (300 mg, 1.45 mmol, 1.00 eq) at 25 °C under Ar.Degased under vacuum and purged with H2 three times. Then the mixture was stirred at 25 °C for 2 h under H2 (25 Psi). The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The mixture was filtered through celite and the filter cake was washed with MeOH (4 x 10 mL). The filtrate was concentrated under vacuum at 40 °C to get a residue to give the title compound (300 mg, crude) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.49 - 7.40 (m, 2H), 7.39 - 7.33 (m, 3H), 3.46 (s, 3H), 2.81 – 2.72 (m, 1H), 1.12 – 1.10 (m, 6H). (ESI+) m/z: 201.2 (M+H)+, (C13H16N2). [1290] C.2-Bromo-4-isopropyl-1-methyl-5-phenyl-1H-imidazole: To a solution of 4- isopropyl-1-methyl-5-phenyl-1H-imidazole (250 mg, 1.25 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (244 mg, 1.37 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with Ethyl acetate (3 x 150 mL). The combined organic layer was washed with brine (3 x 150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (230 mg, 813 μmol, 65.2% yield, 98.8% purity in LCMS at 220 nm) as light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.50 (m, 2H), 7.48 - 7.42 (m, 1H), 7.41 - 7.35 (m, 2H), 3.37 (s, 3H), 2.79 - 2.68 (m, 1H), 1.11 - 1.09 (m, 6H). (ESI+) m/z: 280.7 (M+H)+, (C13H15BrN2). [1291] D.3-(5-(4-Isopropyl-1-methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-4-isopropyl-1-methyl-5-phenyl-1H- imidazole (100 mg, 358 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (265 mg, 716 μmol, 2.00 eq) and K3PO4 (228 mg, 1.07 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (29.9 mg, 35.8 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 18.0% - 48.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (125 mg, 279 449 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT μmol, 78.1% yield, 99.1% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 - 11.04 (m, 1H), 8.13 - 7.96 (m, 3H), 7.64 - 7.54 (m, 5H), 5.21 - 5.16 (m, 1H), 4.63 - 4.47 (m, 2H), 3.58 (s, 3H), 2.99 - 2.90 (m, 2H), 2.65 - 2.60 (m, 1H), 2.45 - 2.44 (m, 1H), 2.07 - 2.04 (m, 1H), 1.28 - 1.26 (m, 6H). (ESI+) m/z: 442.9 (M+H)+, (C26H26N4O3). EXAMPLE 393 [1292] Synthesis of 3-(5-(1-Methyl-5-phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1293] A.5-Phenyl-4-(trifluoromethyl)-1H-imidazole: To a solution of 5-phenyl-1H- imidazole (2.00 g, 13.8 mmol, 1.00 eq) in DMSO (70.0 mL) was added CF3SO2Na (4.33 g, 27.7 mmol, 4.33 mL, 2.00 eq), Cu(OAc)2 (125 mg, 693 μmol, 0.05 eq) and TBHP (5.36 g, 41.6 mmol, 5.70 mL, 70% purity, 3.00 eq). The mixture was stirred at 25 °C for 12 h. The mixture was added aq. Na2SO3 (20.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layer was dried with the anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1: 4, Rf = 0.43 (Petroleum ether: Ethyl acetate = 1: 4)) to give the title compound (1.40 g, 4.82 mmol, 34.7% yield) as a yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.92 (s, 1H), 7.52 - 7.44 (m, 5H). (ESI+) m/z: 213.0 (M+H)+, (C10H7F3N2). [1294] B.1-Methyl-5-phenyl-4-(trifluoromethyl)imidazole: To a solution of 5-phenyl-4- (trifluoromethyl)-1H-imidazole (1.40 g, 6.60 mmol, 1.00 eq) in ACN (15.0 mL) was added MeI (1.40 g, 9.90 mmol, 616 μL, 1.50 eq) and Cs2CO3(4.30 g, 13.2 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 h under N2 atmosphere. Then the mixture was added TEA (5.00 mL). After stirring for 10 min, the mixture was filtered and extracted with ethyl acetate (3 x 15.0 mL). The combined organic phase was washed with brine (15.0 mL), dried with the anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 21 - 51% acetonitrile in water containing 0.05% FA over 10 min at a 450 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT flow rate of 25.0 mL/min) to give the title compound (200 mg, 866 μmol, 13.1% yield) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.55 - 7.49 (m, 3H), 7.46 - 7.39 (m, 2H), 3.49 (s, 3H). (ESI+) m/z: 227.0 (M+H)+, (C11H9F3N2). [1295] C.2-Bromo-1-methyl-5-phenyl-4-(trifluoromethyl)imidazole: To a solution of 1- methyl-5-phenyl-4-(trifluoromethyl)imidazole (100 mg, 442 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (157 mg, 884 μmol, 2.00 eq). The mixture was stirred at 60 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.43) to give the title compound (120 mg, 393 μmol, 88.9% yield) as yellow oil. (ESI+) m/z: 304.9 (M+H)+, (C11H8BrF3N2). [1296] D.3-(5-(1-Methyl-5-phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-1-methyl-5-phenyl-4- (trifluoromethyl)-1H-imidazole (100 mg, 324 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (360 mg, 974 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (27.1 mg, 32.4 μmol, 0.10 eq) and K3PO4 (137 mg, 649 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5:1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 30 - 60% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (22.0 mg, 46.7 μmol, 14.4% yield, 99.3% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.02 (s, 1H), 7.91 - 7.87 (m, 2H), 7.59 - 7.51 (m, 5H), 5.19 - 5.14 (m, 1H), 4.60 - 4.42 (m, 2H), 3.53 (s, 3H), 2.97 - 2.88 (m, 1H), 2.64 - 2.59 (m, 1H), 2.47 - 2.43 (m, 1H), 2.06 - 2.03 (m, 1H). (ESI+) m/z: 468.9 (M+H)+, (C24H19F3N4O3). EXAMPLE 394 [1297] Synthesis of 3-(5-(4,5-Dimethyl-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: 451 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1298] A.4,5-Dimethyl-1-phenyl-1H-imidazole: To a solution of 4,5-dimethyl-1H- imidazole (1.00 g, 10.4 mmol, 1.00 eq) and phenylboronic acid (1.52 g, 12.4 mmol, 1.20 eq) in MeOH (20.0 mL) was added K2CO3 (1.44 g, 10.4 mmol, 1.00 eq) and Cu(OAc)2 (377 mg, 2.08 mmol, 0.20 eq). The mixture was stirred at 60 °C for 16 h under O2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.25) to give the title compound (640 mg, 3.69 mmol, 35.5% yield, 99.4% purity in LCMS at 220 nm) as light yellow solid. (ESI+) m/z: 173.4 (M+H)+, (C11H12N2). [1299] B.2-Bromo-4,5-dimethyl-1-phenyl-1H-imidazole: To a solution of 4,5-dimethyl- 1-phenyl-1H-imidazole (200 mg, 1.16 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (227 mg, 1.28 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with Ethyl acetate (3 x 150 mL). The combined organic layer was washed with brine (3 x 150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (180 mg, 716 μmol, 61.2% yield, 100% purity in LCMS at 220 nm) as light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.54 (m, 3H), 7.35 - 7.33 (m, 2H), 2.09 (s, 3H), 1.91 (s, 3H). (ESI+) m/z: 252.8 (M+H)+, (C11H11BrN2). [1300] C.3-(5-(4,5-Dimethyl-1-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-4,5-dimethyl-1-phenyl-1H-imidazole (100 mg, 398 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (294 mg, 796 μmol, 2.00 eq) and K3PO4 (253 mg, 1.19 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (33.3 mg, 39.2 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 10.0% - 40.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (93.8 mg, 225 μmol, 56.7% yield, 99.7% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO- d6) δ 11.00 (s, 1H), 7.76 - 7.74 (m, 1H), 7.62 - 7.58 (m, 4H), 7.53 - 7.51 (m, 2H), 7.50 - 7.43 (m, 1H), 5.12 - 5.07 (m, 1H), 4.44 - 4.25 (m, 2H), 2.93 - 2.86 (m, 1H), 2.60 - 2.56 (m, 1H), 2.38 (s, 3H), 2.36 - 2.35 (m, 1H), 2.07 (s, 3H), 2.01 - 1.96 (m, 1H). (ESI+) m/z: 414.9 (M+H)+, (C24H22N4O3). 452 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 395 [1301] Synthesis of 3-(1-Oxo-5-(3-phenylimidazo[1,2-a]pyridin-2-yl)isoindolin-2- yl)piperidine-2,6-dione: [1302] A.2-Bromo-3-phenylimidazo[1,2-a]pyridine: To a solution of pyridin-2-amine (2.00 g, 21.2 mmol, 1.50 eq) and ethynylbenzene (723 mg, 7.08 mmol, 777 μL, 0.50 eq) in ACN (40.0 mL) was added CuBr2 (3.16 g, 14.1 mmol, 663 μL, 1.00 eq). The reaction was stirred at 90 °C for 12 h. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 5: 1; TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.40) to give the title compound (230 mg, 842 μmol, 5.94% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.32 - 8.26 (m, 1H), 7.67 - 7.57 (m, 5H), 7.56 - 7.48 (m, 1H), 7.43 - 7.31 (m, 1H), 7.02 - 6.95 (m, 1H). (ESI+) m/z: 274.9 (M+H)+, (C13H9BrN2). [1303] B.3-(1-Oxo-5-(3-phenylimidazo[1,2-a]pyridin-2-yl)isoindolin-2-yl)piperidine- 2,6-dione: To a solution of 2-bromo-3-phenylimidazo[1,2-a]pyridine (200 mg, 732 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (542 mg, 1.46 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (61.2 mg, 73.2 μmol, 0.10 eq), K3PO4 (310 mg, 1.46 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by preparative-HPLC (using a CD06-Waters Xbidge C18 (150 x 40 x 10 μm) and gradient of 20 - 50% acetonitrile in water containing 0.05% NH4HCO3 over 10 min at a flow rate of 25 mL/min) to give the title compound (126.08 mg, 285 μmol, 38.9% yield, 98.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.06 - 8.04 (m, 1H), 7.86 (s, 1H), 7.68 - 7.62 (m, 1H), 7.60 - 7.55 (m, 5H), 7.52 - 7.45 (m, 2H), 7.37 - 7.33 (m, 1H), 6.94 - 6.91 (m, 1H), 5.12 - 5.07 (m, 1H), 4.44 - 4.25 (m, 2H), 2.93 - 2.86 (m, 1H), 2.60 - 2.50 (m, 1H), 2.40 - 2.35 (m, 1H), 2.08 - 1.99 (m, 1H). (ESI+) m/z: 437.1 (M+H)+, (C26H20N4O3). 453 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 396 [1304] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1305] A.3-(5-(5-(4-Methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) and (4-methoxyphenyl)boronic acid (92.1 mg, 606 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) and K3PO4 (85.7 mg, 404 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5: 1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 32 - 62% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (51.8 mg, 103 μmol, 51.4% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.66 (s 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.44 - 7.40 (m, 3H), 7.13 (d, J = 8.8 Hz, 2H), 5.08 (dd, J = 13.2, 4.8 Hz, 1H), 4.32 (dd, J = 58.0, 17.2 Hz, 2H), 3.84 (s, 3H), 3.54 (s, 3H), 2.91 - 2.89 (m, 1H), 2.60 - 2.59 (m, 1H), 2.39 - 2.32 (m, 1H), 1.99 - 1.96 (m, 1H). (ESI+) m/z: 499.1 (M+H)+, (C25H21F3N4O4). EXAMPLE 397 [1306] Synthesis of 3-(5-(5-(3-Aminophenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 454 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1307] A.3-(5-(5-(3-Aminophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) and (3-aminophenyl)boronic acid (132 mg, 606 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) and K3PO4 (85.7 mg, 404 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5:1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 22 - 52% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (21.0 mg, 42.8 μmol, 21.1% yield, 98.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.73 (dd, J = 8.4, 1.6 Hz, 1H), 6.59 - 6.55 (m, 2H), 5.35 (s 2H), 5.08 (dd, J = 13.6, 5.2 Hz, 1H), 4.32 (dd, J = 60.0, 17.6 Hz, 2H), 3.56 (s, 3H), 2.95 - 2.85 (m, 1H), 2.61 - 2.59 (m, 1H), 2.40 - 2.34 (m, 1H), 2.00 - 1.96 (m, 1H). (ESI+) m/z: 484.1 (M+H)+, (C24H20F3N5O3). EXAMPLE 398 [1308] Synthesis of 3-(5-(5-(2-Chloro-4-methoxyphenyl)-1-methyl-2-(trifluoromethyl)- 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1309] A.3-(5-(5-(2-Chloro-4-methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo- 1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) and (2-chloro-4-methoxyphenyl)boronic acid (112 mg, 606 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) and K3PO4 (85.7 mg, 404 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was 455 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5: 1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 36 - 66% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (19.9 mg, 37.4 μmol, 18.5% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.66 (d, J = 13.6 Hz, 1H), 7.60 (dd, J = 8.0, 2.8 Hz, 1H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.14 (dd, J = 8.4, 2.4 Hz, 1H), 5.08 (dd, J = 13.2, 4.8 Hz, 1H), 4.43 - 4.23 (m, 2H), 3.88 (s, 3H), 3.49 (s, 3H), 2.94 - 2.84 (m, 1H), 2.61 - 2.55 (m, 1H), 2.39 - 2.32 (m, 1H), 2.00 - 1.96 (m, 1H). (ESI+) m/z: 533.1 (M+H)+, (C25H20ClF3N4O4). EXAMPLE 399 [1310] Synthesis of 3-(5-(5-(2-Methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1311] Preparation of 3-(5-(5-(2-Methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo- 1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 202 μmol, 1.00 eq) and (2-methoxyphenyl)boronic acid (92.1 mg, 606 μmol, 3.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (16.9 mg, 20.2 μmol, 0.10 eq) and K3PO4 (85.7 mg, 404 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5: 1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 35 - 65% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (59.5 mg, 119 μmol, 59.1% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.68 - 7.58 (m, 2H), 7.54 (q, J = 4.0 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 5.07 (dd, J = 13.2, 5.2 Hz, 1H), 4.42 - 4.19 (m, 2H), 3.77 (d, J = 2.0 Hz, 3H), 3.48 (s, 3H), 2.94 - 2.84 (m, 456 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 2.60 - 2.55 (m, 1H), 2.38 - 2.32 (m, 1H), 2.00 - 1.95 (m, 1H). (ESI+) m/z: 499.1 (M+H)+, (C25H21F3N4O4). EXAMPLE 400 [1312] Synthesis of 3-(5-(1-Methyl-5-(quinazolin-7-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1313] A.3-(5-(1-Methyl-5-(quinazolin-7-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 212 μmol, 1.00 eq), quinazolin-7-ylboronic acid (111 mg, 637 μmol, 3.00 eq), Ru-Phos-Pd-G3 (17.8 mg, 21.2 μmol, 0.10 eq) and K3PO4 (90.1 mg, 424 μmol, 2.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at100 °C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 13 - 43% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (42.06 mg, 79.03 μmol, 38.5% yield, 97.8% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.06 - 10.79 (m, 1H), 9.74 (s, 1H), 9.42 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.65 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.06 (dd, J = 4.8, 13.2 Hz, 1H), 4.40 - 4.15 (m, 2H), 3.66 (s, 3H), 2.94 - 2.82 (m, 1H), 2.58 - 2.53 (m, 1H), 2.35 - 2.27 (m, 1H), 2.01 - 1.90 (m, 1H). (ESI+) m/z: 520.9 (M+H)+, (C26H19F3N6O3). 457 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 401 [1314] Synthesis of 3-(5-(1-Methyl-5-(pyrimidin-5-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1315] A.3-(5-(1-Methyl-5-(pyrimidin-5-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-[5-bromo-1-methyl-2- (trifluoromethyl)imidazol-4-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (90.0 mg, 190 μmol, 1.00 eq) in 1,4-dioxane (0.90 mL) and H2O (0.05 mL) was added pyrimidin-5- ylboronic acid (70.9 mg, 572 μmol, 3.00 eq), K3PO4 (81.0 mg, 381 μmol, 2.00 eq) and RuPhos Pd G3 (15.9 mg, 19.1 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h. The solvent was evaporated under reduced pressure. The residue was purified by Preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradiente of 14%-44% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (20.0 mg, 41.9 μmol, 21.9% yield, 98.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.37 (s, 1H), 8.98 (s, 2H), 7.63 (d, J = 8Hz, 2H), 7.41 (d, J = 8 Hz, 1H), 5.10 – 5.06 (m, 1H), 4.42 – 4.25 (m, 2H), 3.65 (s, 3H), 2.94 – 2.86 (m, 1H), 2.61 (s, 1H), 2.40 – 2.34 (m, 1H), 2.02 – 1.97 (m, 1H). (ESI+) m/z: 471.1 (M+H)+ (C22H17F3N6O3). EXAMPLE 402 [1316] Synthesis of 3-(5-(2-(Difluoromethyl)-5-(4-methoxyphenyl)oxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1317] A.2,2-Difluoro-N-(2-(4-methoxyphenyl)-2-oxoethyl)acetamide: A mixture of 2- amino-1-(4-methoxyphenyl)ethan-1-one (2.00 g, 9.92 mmol, 1.00 eq, HCl) and TEA (2.01 g, 19.8 mmol, 2.76 mL, 2.00 eq) in THF (20.0 mL)was added 2,2-difluoroacetic anhydride 458 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (3.45 g, 19.8 mmol, 2.00 eq) at 0 °C and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate to give the title compound (6.30 g, crude) as a brown oil. (ESI+) m/z: 243.9 (M+H)+, (C11H11F2NO3). [1318] B.2-(Difluoromethyl)-5-(4-methoxyphenyl)oxazole: A mixture of 2,2-difluoro-N- (2-(4-methoxyphenyl)-2-oxoethyl)acetamide (400 mg, 1.64 mmol, 1.00 eq) and TEA (1.55 g, 15.3 mmol, 2.13 mL, 9.30 eq) in THF (4.00 mL) and ACN (2.00 mL) at -10 °C was purged with N2 for 3 times, then the mixture was dropwise added POCl3 (832 mg, 5.43 mmol, 505 μL, 3.30 eq) , and then the mixture was stirred at -10 °C for 1 h under N2 atmosphere. The reaction was quenched with water (15.0 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 15.0 mL). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue The residue was purified or by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50) to give the title compound (100 mg, 441 μmol, 26.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.74 - 7.69 (m, 2H), 7.39 - 7.13 (m, 1H), 7.11 - 7.05 (m, 2H), 3.81 (s, 3H). (ESI+) m/z: 225.9 (M+H)+, (C11H9F2NO2). [1319] C.4-Bromo-2-(difluoromethyl)-5-(4-methoxyphenyl)oxazole: To a solution of 2- (difluoromethyl)-5-(4-methoxyphenyl)oxazole (80.0 mg, 355 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (69.5 mg, 390 μmol, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was concentrated directly in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 4: 1, Rf = 0.70) to give the title compound (100 mg, 328 μmol, 92.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.80 (m, 2H), 7.41 - 7.25 (m, 1H), 7.17 - 7.12 (m, 2H), 3.83 (s, 3H). (ESI+) m/z: 303.9 (M+H)+, (C11H8BrF2NO2). [1320] D.3-(5-(2-(Difluoromethyl)-5-(4-methoxyphenyl)oxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-2-(difluoromethyl)-5-(4- methoxyphenyl)oxazole (100 mg, 328 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (243 mg, 675 μmol, 2.00 eq) and K3PO4 (209 mg, 986 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (27.5 mg, 32.8 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 30.0% - 60.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (57.1 mg, 459 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 122 μmol, 37.1% yield, 99.8% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.85 (s, 1H), 7.78 - 7.76 (m, 1H), 7.71 - 7.69 (m, 1H), 7.56 - 7.54 (m, 2H), 7.47 - 7.21 (m, 1H), 7.09 - 7.06 (m, 2H), 5.15 - 5.10 (m, 1H), 4.51 - 4.33 (m, 2H), 3.81 (s, 3H), 2.92 - 2.87 (m, 1H), 2.62 - 2.58 (m, 1H), 2.46 - 2.40 (m, 1H) , 2.03 - 2.02 (m, 1H). (ESI+) m/z: 468.0 (M+H)+, (C24H19F2N3O5). EXAMPLE 403 [1321] Synthesis of 3-(6-Fluoro-5-(5-(4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1322] A.2,2,2-Trifluoro-N-(2-(4-methoxyphenyl)-2-oxoethyl)acetamide: A mixture of 2-amino-1-(4-methoxyphenyl)ethan-1-one (2.00 g, 9.92 mmol, 1.00 eq, HCl) and TEA (2.01 g, 19.8 mmol, 2.76 mL, 2.00 eq) and TEA (2.01 g, 19.8 mmol, 2.76 mL, 2.00 eq) in THF (20.0 mL)was added TFAA (4.17 g, 19.8 mmol, 2.76 mL, 2.00 eq) at 0 °C and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction liquid is filtered to collect the filtrate and concentrate to give the title compound (6.30 g, crude) as a brown oil. (ESI+) m/z: 261.9 (M+H)+, (C11H10F3NO3). [1323] B.5-(4-Methoxyphenyl)-2-(trifluoromethyl)oxazole: A mixture of 2,2,2-trifluoro- N-(2-(4-methoxyphenyl)-2-oxoethyl)acetamide (3.00 g, 11.4 mmol, 1.00 eq) and TEA (10.8 g, 106 mmol, 14.8 mL, 9.30 eq) in THF (30.0 mL) and ACN (15.0 mL) at -10 °C was purged with N2 for 3 times, then the mixture was dropwise added POCl3 (5.81 g, 37.9 mmol, 3.53 mL, 3.30 eq) , and then the mixture was stirred at -10 °C for 1 h under N2 atmosphere. The reaction was quenched with water (120 mL). The resulting mixture was extracted with EtOAc (3 x 60 mL).The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 3: 10, TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.70) to give the title compound (800 mg, 3.12 mmol, 27.2% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.80 - 7.72 (m, 2H), 7.14 - 7.06 (m, 2H), 3.82 (s, 3H). (ESI+) m/z: 244.0 (M+H)+, (C11H8F3NO2). 460 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1324] C.4-Bromo-5-(4-methoxyphenyl)-2-(trifluoromethyl)oxazole: A mixture of 5-(4- methoxyphenyl)-2-(trifluoromethyl)oxazole (400 mg, 1.64 mmol, 1.00 eq) in ACN (4.00 mL) was added NBS (322 mg, 1.81 mmol, 1.10 eq) at 0 °C and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated directly in vacuum to give residue.The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 4: 1, Rf = 0.60) to give the title compound (400 mg, 1.21 mmol, 73.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.82 (m, 2H), 7.23 - 7.11 (m, 2H), 3.84 (s, 3H). (ESI+) m/z: 323.7 (M+H)+, (C11H7BrF3NO2). [1325] D.3-(6-Fluoro-5-(5-(4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-5-(4-methoxyphenyl)-2- (trifluoromethyl)oxazole (100 mg, 310 μmol, 1.00 eq) and 3-(6-fluoro-1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (241 mg, 620 μmol, 2.00 eq) and K3PO4 (197 mg, 931 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (25.9 mg, 31.0 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 37.0% - 67.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (84.2 mg, 167 μmol, 53.8% yield, 100% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.94 (d, J=6.00 Hz, 1H), 7.69 (d, J=9.20 Hz, 1H), 7.47 (d, J=8.40 Hz, 2H), 7.05 (d, J=8.80 Hz, 2H), 5.19 - 5.13 (m, 1H), 4.55 - 4.38 (m, 2H), 3.79 (s, 3H), 2.98 - 2.89 (m, 1H), 2.63 - 2.59 (m, 1H), 2.44 - 2.40 (m, 1H) , 2.06 - 2.03 (m, 1H). (ESI+) m/z: 504.0 (M+H)+, (C24H17F4N3O5). EXAMPLE 404 [1326] Synthesis of 3-(5-(1,4-Dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: [1327] A.1-Methyl-5-[4-(trifluoromethyl)phenyl]imidazole: To a solution of 1- methylimidazole (5.00 g, 60.9 mmol, 4.85 mL, 1.00 eq) in DMF (125 mL) was added 1- bromo-4-(trifluoromethyl)benzene (40.7 g, 182 mmol, 3.00 eq), PCy3 (3.42 g, 12.1 mmol, 461 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 3.95 mL, 0.20 eq), Pd(OAc)2 (1.37 g, 6.09 mmol, 0.10 eq) and K2CO3 (16.8 g, 121 mmol, 2.00 eq). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 10: 1, Rf = 0.43 (Dichloromethane: Methanol = 15: 1)) to give the title compound (3.40 g, 14.7 mmol, 24.1% yield, 98.0% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 226.9 (M+H)+, (C11H9F3N2). [1328] B.4-Bromo-1-methyl-5-[4-(trifluoromethyl)phenyl]imidazole: To a solution of 1-methyl-5-[4-(trifluoromethyl)phenyl]imidazole (500 mg, 2.21 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (157 mg, 884 μmol, 0.40 eq). The mixture was stirred at 0 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 15: 1, Rf = 0.43) to give the title compound (400 mg, 1.30 mmol, 58.7% yield, 99.0% purity in LCMS at 220 nm) as yellow oil. (ESI+) m/z: 304.9 (M+H)+, (C11H8BrF3N2). [1329] C.1,4-Dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazole: To a solution of 4- bromo-1-methyl-5-[4-(trifluoromethyl)phenyl]imidazole (330 mg, 1.08 mmol, 1.00 eq) in dioxane (1.50 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (678 mg, 5.41 mmol, 756 μL, 5.00 eq), XPHOS-Pd-G2 (85.1 mg, 108 μmol, 0.10 eq) and K3PO4 (459 mg, 2.16 mmol, 2.00 eq). The mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 2: 1, Rf = 0.50) to give the title compound (100 mg, 381 μmol, 35.2% yield, 91.6% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 241.0 (M+H)+, (C12H11F3N2). [1330] D.2-Bromo-1,4-dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazole: To a solution of 1,4-dimethyl-5-[4-(trifluoromethyl)phenyl]imidazole (100 mg, 381 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (81.4 mg, 457 μmol, 1.20 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 2: 1, Rf = 0.60) to give the title compound (70.0 mg, 211 μmol, 55.5% yield, 96.5% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 3.47 (s, 3H), 2.10 (s, 3H). (ESI+) m/z: 318.9 (M+H)+, (C12H10F3N2Br). [1331] E.3-(5-(1,4-Dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-1,4-dimethyl-5-[4- (trifluoromethyl)phenyl]imidazole (70.0 mg, 211 μmol, 1.00 eq) in dioxane (2.00 mL) and 462 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT H2O (0.10 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl]piperidine-2,6-dione (195 mg, 529 μmol, 2.50 eq), K3PO4 (134 mg, 635 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (35.4 mg, 42.3 μmol, 0.20 eq). The mixture was stirred at 100 °C for 2 h under N2. Then the mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 0: 1, Rf = 0.50) to give the title compound (30.0 mg, 60.3 μmol, 28.4% yield, 97.0% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 483.1 (M+H)+, (C25H21O3N4F3). [1332] F.3-(5-(1,4-Dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: To a solution of 3-[5-[1,4- dimethyl-5-[4-(trifluoromethyl)phenyl]imidazol-2-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (30.0 mg, 60.3 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 301 μL, 10.0 eq). The mixture was stirred at 25 °C for 4 h under N2. Then the mixture was concentrated under reduced pressure to give the title compound (18.46 mg, 35.2 μmol, 58.3% yield, 99.0% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO- d6) δ 11.0 (s, 1H), 8.07 (s, 1H), 8.05 - 7.93 (m, 4H), 7.85 - 7.80 (m, 2H), 5.18 (dd, J = 13.2, 5.2 Hz, 1H), 4.55 (dd, J = 49.6, 17.6 Hz, 2H), 3.69 (s, 3H), 2.99 - 2.89 (m, 1H), 2.65 - 2.60 (m, 1H), 2.43 - 2.39 (m, 1H), 2.33 (s, 3H), 2.09 - 2.03 (m, 1H). (ESI+) m/z: 483.1 (M+H)+, (C25H22O3N4F3Cl). EXAMPLE 405 [1333] Synthesis of 3-(5-(1-Methyl-5-(quinolin-7-yl)-2-(trifluoromethyl)-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; hydrogen chloride: [1334] A.3-(5-(1-Methyl-5-(quinolin-7-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 212 μmol, 1.00 eq), quinolin-7-ylboronic acid (73.4 mg, 424 μmol, 2.00 eq) and K3PO4 (90.0 mg, 424 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (17.7 mg, 21.1 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. 463 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 15.0% - 45.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (70.0 mg, 134 μmol, 63.5% yield, 100% purity in HPLC at 220 nm) was obtained as yellow solid. (ESI+) m/z: 520.0 (M+H)+, (C27H20F3N5O3). [1335] B.3-(5-(1-Methyl-5-(quinolin-7-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(1- methyl-5-(quinolin-7-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (70.0 mg, 134 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 577 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (68.8 mg, 117 μmol, 90.6% yield, 98.7% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.04 - 9.03 (m, 1H), 8.61 - 8.58 (m, 1H), 8.24 – 8.19 (m, 2H), 7.73 – 7.68 (m, 3H), 7.54 (d, J = 8.00 Hz, 1H), 7.40 (d, J = 8.40 Hz, 1H), 5.08 – 5.03 (m, 1H), 4.37 – 4.17 (m, 2H),3.65 (s, 3H), 2.92 - 2.83 (m, 1H), 2.58 - 2.53 (m, 1H), 2.36 - 2.27 (m, 1H), 1.97 - 1.93 (m, 1H). (ESI+) m/z: 520.0 (M+H)+, (C27H20F3N5O3). EXAMPLE 406 [1336] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1-(trifluoromethyl)-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione;hydrochloride: [1337] A.1-(Difluoroiodomethyl)-5-(4-methoxyphenyl)-1H-imidazole: To a solution of 5-(4-methoxyphenyl)-1H-imidazole (600 mg, 3.44 mmol, 1.00 eq) in THF (10.0 mL) was added LiHMDS (1 M, 5.17 mL, 1.50 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. Then CF3I (13.5 g, 17.2 mmol, 25% purity, 5.00 eq) was added and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, the mixture was quenched with 20.0 mL of saturated NH4Cl solution and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.50). to give the title 464 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT compound (500 mg, 1.27 mmol, 23.4% yield, 89% purity in LCMS at 220 nm) as yellow solid. (ESI+) m/z: 350.7 (M+H)+, (C11H9F2IN2O). [1338] B.2-Iodo-5-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-imidazole: To a solution of 1-(difluoroiodomethyl)-5-(4-methoxyphenyl)-1H-imidazole (500 mg, 1.43 mmol, 1.00 eq) in DCM (10.0 mL) was added AgBF4 (556 mg, 2.86 mmol, 2.00 eq). The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (300 mg, crude) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.18 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), (C11H8F3IN2O). [1339] C.4-Bromo-5-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-imidazole: To a solution of 5-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-imidazole (160 mg, 661 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (123 mg, 694 μmol, 1.05 eq). The mixture was stirred at 20 °C for 12 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative -TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.60) to give the title compound (140 mg, 436 μmol, 57.1% yield, 100% purity in LCMS at 220 nm) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.03 - 6.97 (m, 2H), 3.88 (s, 3H). (ESI+) m/z: 322.8 (M+H)+, (C11H8BrF3N2O). [1340] D.3-(5-(5-(4-Methoxyphenyl)-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 4-bromo-5-(4-methoxyphenyl)-1- (trifluoromethyl)-1H-imidazole (70.0 mg, 218 μmol, 1.00 eq) , 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (121 mg, 327 μmol, 1.50 eq) , Ru-Phos-Pd-G3 (18.2 mg, 21.8 μmol, 0.10 eq) and K3PO4 (92.6 mg, 436 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 28 - 58% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (60.0 mg, 123 μmol, 56.58% yield, 99.58% purity in LCMS at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.42 - 4.20 (m, 2H), 3.84 (s, 3H), 465 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2.95 - 2.84 (m, 1H), 2.62 - 2.58 (m, 1H), 2.40 - 2.35 (m, 1H), 2.01 - 1.93 (m, 1H). (ESI+) m/z: 485.1 (M+H)+, (C24H19F3N4O4). [1341] E.3-(5-(5-(4-Methoxyphenyl)-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione;hydrochloride: To a solution of 3-(5-(5-(4- methoxyphenyl)-1-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (60.0 mg, 124 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 619 μL, 10.0 eq). The mixture was stirred at 20 °C for 4 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (57.37 mg, 110 μmol, 99.86% purity in HPLC at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 1.2, 8.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.12 - 7.07 (m, 2H), 5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.42 - 4.21 (m, 2H), 3.84 (s, 3H), 2.96 - 2.85 (m, 1H), 2.62 - 2.57 (m, 1H), 2.37 - 2.31 (m, 1H), 2.01 - 1.93 (m, 1H). (ESI+) m/z: 485.2 (M+H)+, (C24H19F3N4O4). EXAMPLE 407 [1342] Synthesis of 3-(5-(1-(4-Methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1343] A.1-(4-Methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole: To a solution of 4- (trifluoromethyl)-1H-imidazole (500 mg, 3.67 mmol, 1.20 eq) in DMSO (5.00 mL) was added 1-bromo-4-methoxybenzene (572 mg, 3.06 mmol, 383. μL, 1.00 eq) , quinolin-8-ol (66.6 mg, 459 μmol, 79.3μL, 0.15 eq), K2CO3 (846 mg, 6.12 mmol, 2.00 eq) and CuI (87.4 mg, 459 μmol, 0.15 eq), then the mixture was stirred at 100 °C under N2 for 16 h. The mixture was poured into water (50.0 mL) and filtered and the filter cake was concentrated under vacuum The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1, TLC: Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.20) to give the title compound (380 mg, 1.56 mmol, 50.9% yield, 99.5% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.54 (s, 1H), 7.32 - 7.17 (m, 2H), 7.04 - 7.01 (m, 2H), 3.87 (s, 3H). (ESI+) m/z: 242.9 (M+H)+, (C11H9F3N2O). 466 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1344] B.2-Bromo-1-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole: To solution of 1-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole (40.0 mg, 165 μmol, 1.00 eq) in THF (2.00 mL) was cooled to -78 °C, then n-BuLi (2.5 M, 99.0 μL, 1.50 eq) was dropwise to the mixture at -78°C under N2. Then the reaction mixture was stirred at -78°C for 0.5 h, after that a solution of 1,2-dibromo-1,1,2,2-tetrafluoroethane (64.3 mg, 247. μmol, 1.50 eq) in THF (2.00 mL) was added to the reaction mixture at -78 °C under N2. The mixture was stirred at 20 °C for 1.5 h under N2. The mixture was poured into NH4Cl (10.0 mL) and extracted with Ethyl acetate (3 x 30.0 mL). The combined organic layer was washed with saturated NaCl aqeous (3 x 30.0mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *7 um) and gradient of 40.0% - 70.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (180 mg, 560 μmol, 40.2% yield, 100% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.49 - 7.45 (m, 2H), 7.12 - 7.09 (m, 2H), 3.83 (s, 3H). (ESI+) m/z: 320.8 (M+H)+, (C11H8BrF3N2O). [1345] C.3-(5-(1-(4-Methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-1-(4-methoxyphenyl)-4- (trifluoromethyl)-1H-imidazole (120 mg, 373 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (276 mg, 747 μmol, 2.00 eq) and K3PO4 (237 mg, 1.12 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (31.2 mg, 37.7 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD06- Waters Xbidge C18 (150 *40 mm *10 um) and gradient of 25.0% - 55.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (80.0 mg, 164 μmol, 44.1% yield, 99.8% purity in HPLC at 220 nm) was obtained as white solid. (ESI+) m/z: 485.0 (M+H)+, (C24H19F3N4O4). [1346] D.3-(5-(1-(4-Methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(1-(4- methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (80.0 mg, 164 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 825 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (78.7 mg, 150 μmol, 91.3% yield, 99.8% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 467 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.65 - 7.63 (m, 1H), 7.35 (d, J=8.80 Hz, 3H), 7.04 (d, J=8.80 Hz, 2H), 5.12 - 5.07 (m, 1H), 4.47 - 4.27 (m, 2H), 3.79 (s, 3H), 2.94 - 2.85 (m, 1H), 2.61 - 2.55 (m, 1H), 2.45 - 2.40 (m, 1H), 2.01 - 1.99 (m, 1H). (ESI+) m/z: 485.0 (M+H)+, (C24H19F3N4O4). EXAMPLE 408 [1347] Synthesis of 3-(5-(1-(4-Aminophenyl)-1H-benzo[d]imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1348] A. tert-Butyl (4-(2-bromo-1H-benzo[d]imidazol-1-yl)phenyl)carbamate: To a solution of 2-bromo-1H-benzo[d]imidazole (500 mg, 2.54 mmol, 1.00 eq), tert-butyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (810 mg, 2.54 mmol, 1.00 eq) and Na2CO3 (672 mg, 6.34 mmol, 2.50 eq), 2-(2-pyridyl)pyridine (475 mg, 3.05 mmol, 1.20 eq) in dioxane (25.0 mL) and H2O (1.25 mL) was added Cu(OAc)2 (553 mg, 3.05 mmol, 1.20 eq) under O2.The mixture was stirred at 60 °C for 12 h under O2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.30) and by preparative - HPLC (using a Phenomenex luna C18 (150 *40 mm *10 um) and gradient of 43.0% - 73.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (200 mg, 412 μmol, 16.2% yield, 80% purity in HPLC at 220 nm) was obtained as off-white solid. (ESI+) m/z: 389.8 (M+H)+, (C18H18BrN3O2). [1349] B. tert-Butyl (4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- benzo[d]imidazol-1-yl)phenyl)carbamate: To a solution of tert-butyl (4-(2-bromo-1H- benzo[d]imidazol-1-yl)phenyl)carbamate (180 mg, 463 μmol, 1.00 eq) and 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (377 mg, 1.02 mmol, 2.20 eq) and K3PO4 (196 mg, 927 μmol, 2.00 eq) in dioxane (10.0 mL) and H2O (0.50 mL) was added Ru-Phos-Pd-G3 (38.7 mg, 46.3 μmol, 0.10 eq) under N2. The mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated under reduced 468 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT pressure to get a residue at 45 °C. The residue was purified by preparative TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.35) to give the title compound (120 mg, 164 μmol, 35.4% yield, 75.6% purity in LCMS at 220 nm) was obtained as yellow solid. (ESI+) m/z: 552.0 (M+H)+, (C31H29N5O5). [1350] C.3-(5-(1-(4-Aminophenyl)-1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl (4-(2-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-benzo[d]imidazol-1-yl)phenyl)carbamate (100 mg, 182 μmol, 1.00 eq) in DCM (2.00 mL) was added HCl/dioxane (2 M, 725 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *40 mm *10 um) and gradient of 0% - 30.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (60.0 mg, 126 μmol, 69.7% yield, 95.2% purity in HPLC at 220 nm) was obtained as yellow solid. (ESI+) m/z: 452.1 (M+H)+, (C26H21N5O3). [1351] D.3-(5-(1-(4-Aminophenyl)-1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(1-(4-aminophenyl)-1H- benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60.0 mg, 132 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 664 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (38.8 mg, 75.6 μmol, 56.9% yield, 94.9% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.92 - 7.86 (m, 2H), 7.78 - 7.76 (m, 1H), 7.67 - 7.64 (m, 1H), 7.45 - 7.43 (m, 2H), 7.32 - 7.31 (m, 1H), 7.24 - 7.22 (m, 2H), 6.87 – 6.85 (m, 2H), 5.15 - 5.10 (m, 1H), 4.51 - 4.36 (m, 2H), 2.94 - 2.88 (m, 1H), 2.62 - 2.58 (m, 1H), 2.42 - 2.39 (m, 1H), 2.03 - 2.01 (m, 1H). (ESI+) m/z: 452.1 (M+H)+, (C26H21N5O3). EXAMPLE 409 [1352] Synthesis of 3-(5-(4,5-Diphenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: 469 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1353] A.1-(Difluoroiodomethyl)-2-iodo-4,5-diphenyl-1H-imidazole: To a solution of 4,5-diphenyl-1H-imidazole (1.00 g, 4.54 mmol, 1.00 eq) in THF (10.0 mL) was added LiHMDS (1 M, 5.45 mL, 1.20 eq) at 0 °C and the mixture was stirred at 25 °C for 1 h under N2. Then CF3I (10.6 g, 13.6 mmol, 25% purity, 3.00 eq) was added and the reaction mixture was stirred at 25 °C for 1 h. Then LiHMDS (1 M, 5.45 mL, 1.20 eq) was added at 0 °C and the reaction mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was quenched with 20.0 mL of saturated NH4Cl solution and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 5: 1, Rf = 0.60 (Petroleum ether: EtOAc = 5: 1)) to give the title compound (200 mg, 383 μmol, 8.44% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.54 - 7.49 (m, 2H), 7.47 - 7.28 (m, 5H), 7.25 - 7.17 (m, 3H). (ESI+) m/z: 522.8 (M+H)+, (C16H10N2I2F2). [1354] B.2-Iodo-4,5-diphenyl-1-(trifluoromethyl)-1H-imidazole: To a solution of 1- [difluoro(iodo)methyl]-2-iodo-4,5-diphenyl-imidazole (180 mg, 344 μmol, 1.00 eq) in DCM (4.00 mL) was added AgBF4 (134 mg, 689 μmol, 2.00 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 5 : 1, Rf = 0.70) to give the title compound (80.0 mg, 192 μmol, 55.8% yield, 99.6% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 414.9 (M+H)+, (C16H10N2F3I). [1355] C.3-(5-(4,5-Diphenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-iodo-4,5-diphenyl-1-(trifluoromethyl)imidazole (70.0 mg, 168 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 3-[1-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (155 mg, 420 μmol, 2.50 eq), Ru-Phos-Pd-G3 (14.0 mg, 16.8 μmol, 0.10 eq) and K3PO4 (107 mg, 505 μmol, 3.00 eq). The mixture was stirred at 100 °C for 2h under N2. Then the mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 0: 1, Rf = 0.70) and then by preparative-HPLC (using a CD06-Waters Xbidge C18 (150 mm x 40 mm 10 μm) and gradient of 40-70% acetonitrile in water containing 0.5% HCl over 11 min at a flow rate of 25.0 mL/min) to give the title compound (50.0 mg, 92.8 μmol, 55.1% yield, 98.5% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 531.1 (M+H)+, (C29H21O3N4F3). [1356] D.3-(5-(4,5-Diphenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride: To a solution of 3-[5-[4,5-diphenyl-1- 470 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (trifluoromethyl)imidazol-2-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (50.0 mg, 92.8 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 464 μL, 10.0 eq). The mixture was stirred at 25 °C for 4 h. Then the mixture was concentrated under reduced pressure to give the title compound (19.15 mg, 33.7 μmol, 36.3% yield, 100% purity in HPLC at 220 nm, HCl) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.98 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.56 (s, 5H), 7.42 - 7.36 (m, 2H), 7.29 - 7.19 (m, 3H), 5.17 (dd, J = 13.2, 4.8 Hz, 1H), 4.53 (dd, J = 55.6, 17.6 Hz, 2H), 2.99 - 2.88 (m, 1H), 2.66 - 2.60 (m, 1H), 2.46 - 2.38 (m, 1H), 2.10 - 2.02 (m, 1H). (ESI+) m/z: 530.9 (M+H)+, (C29H22O3N4F3Cl). EXAMPLE 410 [1357] Synthesis of 3-(5-(5-(4-Fluorophenyl)-1-methyl-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; hydrogen chloride: [1358] A.3-(5-(5-(4-Fluorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 212 μmol, 1.00 eq), (4-fluorophenyl)boronic acid (59.3 mg, 424 μmol, 2.00 eq) and K3PO4 (90.0 mg, 424 μmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (17.7 mg, 21.1 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 33.0% - 63.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (50.0 mg, 102 μmol, 48.4% yield, 100% purity in HPLC at 220 nm) was obtained as white solid. (ESI+) m/z: 487.0 (M+H)+, (C24H18F4N4O3). [1359] B.3-(5-(5-(4-Fluorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(5-(4- fluorophenyl)-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (50.0 mg, 102 μmol, 1.00 eq) in dioxane (2.00 mL) was added 471 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT HCl/dioxane (2 M, 719 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (18.2 mg, 34.8 μmol, 33.8% yield, 99.7% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.61 (d, J=6.40 Hz, 1H), 7.58 - 7.55 (m, 3H), 7.44 - 7.39 (m, 3H), 5.10 - 5.05 (m, 1H), 4.41 - 4.22 (m, 2H),3.56 (s, 3H), 2.95 - 2.83 (m, 1H), 2.58 - 2.53 (m, 1H), 2.39 - 2.30 (m, 1H), 2.02 - 1.93 (m, 1H). (ESI+) m/z: 487.0 (M+H)+, (C24H18F4N4O3). EXAMPLE 411 [1360] Synthesis of 3-(5-(1-Methyl-5-(pyridin-4-yl)-2-(trifluoromethyl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione: [1361] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(pyridin-4-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：To a solution of tert-butyl 5- amino-4-(5-(5-bromo-1-methyl-2-(trifluoromethyl)imidazol-4-yl)-1-oxo-isoindolin-2-yl)-5- oxo-pentanoate (200 mg, 366 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (225 mg, 1.10 mmol, 3.00 eq), K3PO4 (155 mg, 733 μmol, 2.00 eq) and RuPhos Pd G3 (30.6 mg, 36.6 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h. The solvent was evaporated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 1:1, Rf = 0.35) to give the title compound (150 mg, 261 μmol, 71.4% yield, 94.9% purity in LCMS at 220 nm) as a brown solid. (ESI+) m/z: 544.1 (M+H)+ (C27H28F3N5O4). [1362] B.3-(5-(1-Methyl-5-(pyridin-4-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A solution of tert-butyl 5-amino-4-[5-[1-methyl-5- (4-pyridyl)-2-(trifluoromethyl)imidazol-4-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (80.0 mg, 147 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (101 mg, 588 μmol, 4.00 eq). The mixture was stirred at 80 °C for 4h. Filter and collect filtrate. The residue was purified by Preparative-HPLC (using a CD06-Waters Xbidge C18 (150 mm x 40 mm x 10 μm) and gradiente of 1% - 31% acetonitrile in water containing 0.1% HCl over 40 min at a flow rate of 25 mL/min) to give the title compound (20.0 mg, 42.4 μmol, 28.8% yield, 99.7% purity in 472 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.94 (d, J = 6.4 Hz, 2H), 7.91 (d, J = 6 Hz, 2H), 7.67 – 7.62 (m, 2H), 7.42 (d, J = 8 Hz, 1H), 5.12 – 5.07 (m, 1H), 4.44 – 4.26 (m, 2H), 3.69 (s, 3H), 2.94 – 2.86 (m, 1H), 2.61 (s, 1H), 2.39 – 2.33 (m, 1H), 2.02 – 1.98 (m, 1H). (ESI+) m/z: 470 (M+H)+ (C23H18F3N5O3). EXAMPLE 412 [1363] Synthesis of 3-(5-(1-Methyl-5-(pyrimidin-2-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1364] A.3-(5-(1-Methyl-5-(pyrimidin-2-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-bromo-1-methyl-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (0.13 g, 275 μmol, 1.00 eq) in dioxane (4.00 mL) was added cataCxium A Pd G2 (36.8 mg, 55.1 μmol, 0.20 eq), 2-(tributylstannyl) pyrimidine (122 mg, 331 μmol, 1.20 eq) , Then mixture was stirred 100 °C for 16 h under N2. The reaction mixture was quenched by addition H2O (20.0 mL)), and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The mixture was purified by preparative-TLC (SiO2, petroleum ether: ethyl acetate = 1: 1, Rf = 0.30) to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 12 - 42% acetonitrile in water containing 0.05% HCl over 11 min at a flow rate of 25 mL/min) to give the title compound (20.0 mg, 42.1 μmol, 15.2% yield, 99.1% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 471.0 (M+H)+, (C22H17F3O3N6). [1365] B.3-(5-(1-Methyl-5-(pyrimidin-2-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(1-methyl-5-(pyrimidin-2- yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (10.0 mg, 21.2 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 106 μL, 10.0 eq), Then mixture was stirred 25 °C for 4 h. The mixture was lyophilized to give the title compound (6.01 mg, 11.7 μmol, 55.2% yield, 99.1% purity, in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.98 (d, J = 4.0 Hz, 2H), 7.67 (s, 1H), 473 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.64 - 7.61 (m, 2H), 7.47 (d, J = 4.0 Hz, 1H), 5.10 (dd, J = 8.0 Hz, 1H), 4.36 (dd, J = 10.4 Hz, 2H), 3.88 (s, 3H), 2.93 - 2.87 (m, 1H), 2.61 - 2.57 (m, 1H), 2.38 - 2.35 (m, 1H), 2.01 - 1.99 (m, 1H). (ESI+) m/z: 471.1 (M+H)+, (C22H17O3N6F3). EXAMPLE 413 [1366] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;hydrochloride: [1367] A.5-(4-Methoxyphenyl)-1H-imidazole: To a solution of 4-iodo-1H-imidazole (5.00 g, 25.8 mmol, 1.00 eq) and (4-methoxyphenyl)boronic acid (7.83 g, 51.6 mmol, 2.00 eq) in Tol. (100 mL) and H2O (30.0 mL) was added CsF (7.83 g, 51.6 mmol, 2.00 eq) and Pd(PPh3)4 (2.98 g, 2.58 mmol, 0.10 eq). The mixture was stirred at 100 °C for 12 h. After the reaction was completed, the reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatrography (SiO2, DCM: MeOH = 1: 0 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.50) to give the title compound (750 mg, 4.31 mmol, 16.70% yield in LCMS at 220 nm) as off-white solid.1H NMR: (400 MHz, DMSO- d6) δ 12.07 (s, 1H), 7.77 - 7.61 (m, 3H), 7.42 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.76 (s, 3H). (C10H10N2O). [1368] B.1-(Difluoroiodomethyl)-2-iodo-5-(4-methoxyphenyl)-1H-imidazole: To a solution of 5-(4-methoxyphenyl)-1H-imidazole (500 mg, 2.87 mmol, 1.00 eq) in THF (5.00 mL) was added LiHMDS (1 M, 4.31 mL, 1.50 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. Then CF3I (11.3 g, 14.4 mmol, 25% purity, 5.00 eq) was added and the mixture was stirred at 25 °C for 1 h. And LiHMDS (1 M, 2.87 mL, 1.00 eq) was added again at 0 °C, the last mixture was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was quenched with 50.0 mL of saturated NH4Cl solution and extracted with EtOAc (3 x 50.0 mL). The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 10: 1; TLC, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.35) to give 474 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT the title compound (320 mg, 649 μmol, 22.6% yield, 96.6% purity in LCMS at 220 nm) as yellow solid. (ESI+) m/z: 476.6 (M+H)+, (C11H8F2I2N2O). [1369] C.2-Iodo-5-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-imidazole: To a solution of 1-(difluoroiodomethyl)-2-iodo-5-(4-methoxyphenyl)-1H-imidazole (290 mg, 609 μmol, 1.00 eq) in DCM (3.00 mL) was added AgBF4 (237 mg, 1.22 mmol, 2.00 eq). The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (300 mg, crude) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.33 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 7.2 Hz, 2H), 7.00 (s, 1H), 3.80 (s, 3H). (C11H8F3IN2O). [1370] D.5-(4-Methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazole: A mixture of 2-iodo-5-(4-methoxyphenyl)-1-(trifluoromethyl)-1H-imidazole (300 mg, 815 μmol, 1.00 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (307 mg, 1.22 mmol, 342 μL, 1.50 eq), Pd(dppf)Cl2 (59.6 mg, 81.5 μmol, 0.10 eq) and Cs2CO3 (531 mg, 1.63 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.75) to give the title compound (120 mg, 458 μmol, 57.5% yield, 97.89% purity in LCMS at 220 nm) as brown oil.1H NMR: (400 MHz, DMSO-d6) δ 7.31 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 6.8 Hz, 2H), 6.89 (s, 1H), 3.79 (d, J = 1.2 Hz, 3H), 3.30 (s, 3H). (C12H11F3N2O). [1371] E.4-Bromo-5-(4-methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazole: To a solution of 5-(4-methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazole (70.0 mg, 273 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (53.5 mg, 301 μmol, 1.10 eq). The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was diluted with H2O (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, R = 0.60) to give the title compound (70.0 mg, 204 μmol, 65.9% yield, 97.75% purity in LCMS at 220 nm) as light yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.31 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.32 (s, 3H). (ESI+) m/z: 334.7 (M+H)+, (C12H10BrF3N2O). 475 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1372] F.3-(5-(5-(4-Methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione: A mixture of 4-bromo-5-(4-methoxyphenyl)-2- methyl-1-(trifluoromethyl)-1H-imidazole (60.0 mg, 179 μmol, 1.00 eq) , 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (99.4 mg, 269 μmol, 1.50 eq) , Ru-Phos-Pd-G3 (15.0 mg, 17.9 μmol, 0.10 eq) and K3PO4 (76.0 mg, 358 μmol, 2.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 29 - 59% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (65.0 mg, 128 μmol, 71.5% yield, 98.24% purityin LCMS at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.62 - 7.52 (m, 2H), 7.42 - 7.32 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.40 - 4.17 (m, 2H), 3.83 (s, 3H), 2.95 - 2.82 (m, 1H), 2.62 - 2.59 (m, 3H), 2.57 - 2.53 (m, 1H), 2.39 - 2.32 (m, 1H), 2.03 - 1.91 (m, 1H). (ESI+) m/z: 498.9 (M+H)+, (C25H21F3N4O4). [1373] G.3-(5-(5-(4-Methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazol-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione;hydrochloride: To a solution of 3-(5-(5-(4- methoxyphenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (65.0 mg, 130 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 1.30 mL, 20.0 eq). The mixture was stirred at 25 °C for 4 h. After the reaction was completed, the mixture was without work-up and lyophilized to get the title compound (65.38 mg, 122 μmol, 93.73% yield in HPLC at 220 nm) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.61 - 7.52 (m, 2H), 7.41 - 7.33 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.41 - 4.17 (m, 2H), 3.83 (s, 3H), 2.94 - 2.83 (m, 1H), 2.63 - 2.60 (m, 3H), 2.57 - 2.53 (m, 1H), 2.38 - 2.31 (m, 1H), 2.02 - 1.92 (m, 1H). (ESI+) m/z: 499.0 (M+H)+, (C25H22F3ClN4O4). 476 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 414 [1374] Synthesis of 3-(6-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1375] A.1-(Difluoroiodomethyl)-5-phenyl-1H-imidazole: To a solution of 5-phenyl-1H- imidazole (2.00 g, 13.8 mmol, 1.00 eq) and CF3I (32.6 g, 41.6 mmol, 25% purity, 3.00 eq) in THF (20.0 mL) was added LiHMDS (1 M, 20.8 mL, 1.50 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was poured into H2O (50.0 mL), extracted with EtOAc (3 x 50.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 80: 1; TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.60) to give the title compound (0.90 g, 2.81 mmol, 20.2% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.50 - 7.45 (m, 5H), 7.21 (s, 1H). (ESI+) m/z: 321.0 (M+H)+, (C10H7F2IN2). [1376] B.5-Phenyl-1-(trifluoromethyl)-1H-imidazole: A solution of 1- (difluoroiodomethyl)-5-phenyl-1H-imidazole (0.90 g, 2.81 mmol, 1.00 eq) and AgBF4 (1.09 g, 5.62 mmol, 2.00 eq) in DCM (10.0 mL) was stirred at 25 °C for 24 h in the dark. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 80: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.30) to give the title compound (350 mg, 1.42 mmol, 50.3% yield, 85.9% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 212.9 (M+H)+, (C10H7F3N2). [1377] C.4-Bromo-5-phenyl-1-(trifluoromethyl)-1H-imidazole：To a solution of 5- phenyl-1-(trifluoromethyl)-1H-imidazole (350 mg, 1.65 mmol, 1.00 eq) in ACN (5.00 mL) was added a solution of NBS (308 mg, 1.73 mmol, 1.05 eq) in ACN (3.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into H2O (5.00 mL), extracted with EtOAc (3 x 5.00 mL), combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.30) to give the title 477 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT compound (120 mg, 412 μmol, 24.9% yield) as a colorless oil.1H NMR: (400 MHz, DMSO- d6) δ 8.55 (s, 1H), 7.54 - 7.50 (m, 3H), 7.48 - 7.45 (m, 2H). (ESI+) m/z: 292.8 (M+H)+, (C10H6BrF3N2). [1378] D.3-(6-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione：A mixture of 4-bromo-5-phenyl-1- (trifluoromethyl)-1H-imidazole (50.0 mg, 171 μmol, 1.00 eq), 3-(6-fluoro-1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (133 mg, 343 μmol, 2.00 eq), Ru-Phos-Pd-G3 (14.3 mg, 17.1 μmol, 0.10 eq),and K3PO4 (72.9 mg, 343 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 26 - 56% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (55.0 mg, 116 μmol, 67.7% yield) as a white solid. (ESI+) m/z: 472.9 (M+H)+, (C23H16F4N4O3). [1379] E.3-(6-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione hydrogen chloride：To a solution of 3-(6-fluoro-1- oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione (35.0 mg, 74.0 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 370 μL, 10.0 eq).The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (35.16 mg, 68.7 μmol, 99.4% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.65 (s, 1H), 7.74 - 7.73 (m, 1H), 7.46 - 7.41 (m, 4H), 7.37 - 7.30 (m, 2H), 5.12 - 5.07 (m, 1H), 4.45 - 4.27 (m, 2H), 2.96 - 2.86 (m, 1H), 2.60 - 2.56 (m, 1H), 2.39 - 2.36 (m, 1H), 2.01 - 1.99 (m, 1H). (ESI+) m/z: 473.1 (M+H)+, (C23H16F4N4O3). EXAMPLE 415 [1380] Synthesis of 3-(4-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: 478 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1381] A.1-(Difluoroiodomethyl)-5-phenyl-1H-imidazole: To a solution of 5-phenyl-1H- imidazole (2.00 g, 13.8 mmol, 1.00 eq) and CF3I (32.6 g, 41.6 mmol, 25% purity, 3.00 eq) in THF (20.0 mL) was added LiHMDS (1 M, 20.8 mL, 1.50 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was poured into H2O (50.0 mL), extracted with EtOAc (3 x 50.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 80: 1; TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.60) to give the title compound (0.90 g, 2.81 mmol, 20.2% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.50 - 7.45 (m, 5H), 7.21 (s, 1H). (ESI+) m/z: 321.0 (M+H)+, (C10H7F2IN2). [1382] B.5-Phenyl-1-(trifluoromethyl)-1H-imidazole: A solution of 1- (difluoroiodomethyl)-5-phenyl-1H-imidazole (0.90 g, 2.81 mmol, 1.00 eq) and AgBF4 (1.09 g, 5.62 mmol, 2.00 eq) in DCM (10.0 mL) was stirred at 25 °C for 24 h in the dark. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 80: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.30) to give the title compound (350 mg, 1.42 mmol, 50.3% yield, 85.9% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 212.9 (M+H)+, (C10H7F3N2). [1383] C.4-Bromo-5-phenyl-1-(trifluoromethyl)-1H-imidazole：To a solution of 5- phenyl-1-(trifluoromethyl)-1H-imidazole (350 mg, 1.65 mmol, 1.00 eq) in ACN (5.00 mL) was added a solution of NBS (308 mg, 1.73 mmol, 1.05 eq) in ACN (3.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into H2O (5.00 mL), extracted with EtOAc (3 x 5.00 mL), combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 10: 1, Rf = 0.30) to give the title compound (120 mg, 412 μmol, 24.9% yield) as a colorless oil.1H NMR: (400 MHz, DMSO- d6) δ 8.55 (s, 1H), 7.54 - 7.50 (m, 3H), 7.48 - 7.45 (m, 2H). (ESI+) m/z: 292.8 (M+H)+, (C10H6BrF3N2). [1384] D.3-(4-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione：A mixture of 4-bromo-5-phenyl-1- (trifluoromethyl)-1H-imidazole (60.0 mg, 206 μmol, 1.00 eq), 3-(4-fluoro-1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (160 mg, 412 μmol, 479 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2.00 eq), Ru-Phos-Pd-G3 (17.2 mg, 20.6 μmol, 0.10 eq) and K3PO4 (87.5 mg, 412 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 26 - 56% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (56.0 mg, 118 μmol, 57.5% yield) as a white solid. (ESI+) m/z: 472.9 (M+H)+, (C23H16F4N4O3). [1385] E.3-(4-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione hydrogen chloride：To a solution of 3-(4-fluoro-1- oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione (56.0 mg, 118 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 592 μL, 10.0 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (23.55 mg, 46.0 μmol, 99.5% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.65 (s, 1H), 7.55 - 7.50 (m, 2H), 7.47 - 7.44 (m, 3H), 7.40 - 7.35 (m, 2H), 5.10 - 5.05 (m, 1H), 4.48 - 4.26 (m, 2H), 2.90 - 2.86 (m, 1H), 2.60 - 2.54 (m, 1H), 2.40 - 2.36 (m, 1H), 2.00 - 1.95 (m, 1H). (ESI+) m/z: 473.1 (M+H)+, (C23H16F4N4O3). EXAMPLE 416 [1386] Synthesis of 3-(1-Oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-2- yl)isoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1387] A.1-(Difluoroiodomethyl)-2-iodo-5-phenyl-1H-imidazole: To a solution of 5- phenyl-1H-imidazole (5.00 g, 34.6 mmol, 1.00 eq) and CF3I (81.5 g, 104 mmol, 25% purity, 3.00 eq) in THF (50.0 mL) was added LiHMDS (1 M, 38.1 mL, 1.10 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 16 h under N2, then to the mixture was added LiHMDS (1 M, 34.6 mL, 1.00 eq) and solution of I2 (8.80 g, 34.6 mmol, 6.99 mL, 1.00 eq) in THF (10.0 mL) at 0 °C under N2.The reaction mixture was stirred at 25 °C for 4 h under N2. The reacion mixture was poured into H2O (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to 480 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Dichloromethane = 100: 0 to 1: 1; TLC: Petroleum ether: Dichloromethane = 1: 1, Rf = 0.50) to give the title compound (1.20 g, 2.69 mmol, 7.76% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.47 - 7.44 (m, 3H), 7.42 - 7.40 (m, 2H), 7.04 (s, 1H). (ESI+) m/z: 446.4 (M+H)+, (C10H6F2I2N2). [1388] B.3-(4-Fluoro-1-oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione：A mixture of 2-iodo-5-phenyl-1-(trifluoromethyl)- 1H-imidazole (200 mg, 591 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (438 mg, 1.18 mmol, 2.00 eq), Ru- Phos-Pd-G3 (49.4 mg, 59.1 μmol, 0.10 eq) and K3PO4 (251 mg, 1.18 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (0.50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.40) and preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 28 - 58% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (45.0 mg, 99.0 μmol, 16.7% yield) as a white solid. (ESI+) m/z: 454.9 (M+H)+, (C23H17F3N4O3). [1389] C.3-(1-Oxo-5-(5-phenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)isoindolin-2- yl)piperidine-2,6-dione hydrogen chloride：To a solution of 3-(1-oxo-5-(5-phenyl-1- (trifluoromethyl)-1H-imidazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione (45.0 mg, 99.0 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 495 μL, 10.0 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (28.71 mg, 57.4 μmol, 98.2% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.93 - 7.89 (m, 2H), 7.83 - 7.80 (m, 1H), 7.58 - 7.45 (m, 5H), 7.35 (s, 1H), 5.17 - 5.13 (m, 1H), 4.60 - 4.42 (m, 2H), 2.93 - 2.86 (m, 1H), 2.64 - 2.58 (m, 1H), 2.44 - 2.40 (m, 1H), 2.08 - 2.05 (m, 1H). (ESI+) m/z: 454.9 (M+H)+, (C23H17F3N4O3). 481 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 417 [1390] Synthesis of 3-(5-(4-Methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl) piperidine-2,6-dione hydrogen chloride: [1391] A.4-Methyl-5-phenyl-1H-imidazole: To a solution of 5-bromo-4-methyl-1H- imidazole (5.00 g, 31.0 mmol, 1.00 eq) and phenylboronic acid (7.57 g, 62.1 mmol, 2.00 eq) in dioxane (50.0 mL) and H2O (2.50 mL) was added K3PO4 (13.1 g, 62.1 mmol, 2.00 eq) and Pd(dppf)Cl2 (1.14 g, 1.55 mmol, 0.05 eq) under N2. The reaction mixture was stirred at 100 °C for 24 h under N2. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 60: 1; TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (2.5 g, 13.81 mmol, 44.47% yield, 87.4% purity in LCMS at 220 nm) as a gray solid.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 7.65 - 7.45 (m, 3H), 7.39 - 7.32 (m, 2H), 7.20 - 7.15 (m, 1H), 2.36 (s, 3H). (ESI+) m/z: 159.2 (M+H)+, (C10H10N2). [1392] B.1-(Difluoroiodomethyl)-2-iodo-4-methyl-5-phenyl-1H-imidazole: To a solution of 4-methyl-5-phenyl-1H-imidazole (1.50 g, 9.48 mmol, 1.00 eq) and CF3I (22.2 g, 28.4 mmol, 25% purity, 3.00 eq) in THF (20.0 mL) was added LiHMDS (1 M, 14.2 mL, 1.50 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 16 h under N2.Then to the reaction mixture was added LiHMDS (1 M, 9.48 mL, 1.00 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 4 h under N2. The reaction mixture was poured into H2O (50.0 mL), extracted with EtOAc (3 x 50.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Dichloromethane = 100: 0 to 1: 1; TLC, Petroleum ether: Dichloromethane = 0: 1, Rf = 0.60) to give the title compound (0.80 g, 1.74 mmol, 18.3% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.54 - 7.42 (m, 3H), 7.35 - 7.30 (m, 2H), 1.87 (s, 3H). (ESI+) m/z: 460.7 (M+H)+, (C11H8F2I2N2). [1393] C.2-Iodo-4-methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole：To a solution of 1-(difluoroiodomethyl)-2-iodo-4-methyl-5-phenyl-1H-imidazole (0.80 g, 1.74 mmol, 1.00 eq) in DCM (10.0 mL) was added AgBF4 (677 mg, 3.48 mmol, 2.00 eq). The mixture was stirred at 25 °C for 16 h in the dark. The reaction mixture was concentrated in vacuum to give 482 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Dichloromethane = 100: 1 to 0: 1; TLC, Petroleum ether: Dichloromethane = 0: 1, Rf = 0.65) to give the title compound (150 mg, 426 μmol, 24.5% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.40 (m, 3H), 7.37 - 7.30 (m, 2H), 1.97 (s, 3H). (ESI+) m/z: 352.8 (M+H)+, (C11H8F3IN2). [1394] D.3-(5-(4-Methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione：A mixture of 2-iodo-4-methyl-5-phenyl-1- (trifluoromethyl)-1H-imidazole (150 mg, 426 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (315 mg, 852 μmol, 2.00 eq), Ru-Phos-Pd-G3 (35.6 mg, 42.6 μmol, 0.10 eq), and K3PO4 (180 mg, 852 μmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by preparative- TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.50) and preparative-HPLC (using a CD01-Phenomenex luna C18 (150 x 25 x 10 μm) and gradient of 30 - 60% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (40.0 mg, 85.3 μmol, 20.0% yield) as a white solid. (ESI+) m/z: 469.0 (M+H)+, (C24H19F3N4O3). [1395] E.3-(5-(4-Methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride：To a solution of 3-(5-(4- methyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (40.0 mg, 85.3 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 426 μL, 10.0 eq).The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (27.78 mg, 54.7 μmol, 99.5% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.91 - 7.87 (m, 2H), 7.80 - 7.77 (m, 1H), 7.55 - 7.45 (m, 5H), 5.17 - 5.13 (m, 1H), 4.59 - 4.41 (m, 2H), 2.93 - 2.86 (m, 1H), 2.63 - 2.56 (m, 1H), 2.44 - 2.40 (m, 1H), 2.12 (s, 3H), 2.07 - 2.04 (m, 1H). (ESI+) m/z: 469.0 (M+H)+, (C24H19F3N4O3). 483 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 418 [1396] Synthesis of 3-(5-(4-(1,1-Difluoroethyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1397] A. tert-Butyl 5-amino-4-(5-(5-(3-(2-hydroxyethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 4-bromo-1-methyl- 5-phenyl-1H-imidazole (4.25 g, 17.9 mmol, 1.00 eq) in dioxane (100 mL) was added [2-(2- aminophenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane (2.40 g, 3.59 mmol, 0.20 eq) tributyl(1-ethoxyvinyl)stannane (7.12 g, 19.7 mmol, 6.66 mL, 1.10 eq) , The mixture was stirred at 110 °C for 4 h under N2. The reaction mixture was added HCl (1M) solution (5.00 mL) .The mixture was extracted with EtOAc (3 x 5 mL). The combined organic phase was washed with brine (3 x 5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=30/1 to 1/1, Rf = 0.3) to give the title compound (0.80 g, 3.96 mmol, 22.2% yield, 99.2% purity in LCMS at 220 nm) as a off white solid. (ESI+) m/z: 201.1 (M+H)+, (C12H12N2O). [1398] B.4-(1,1-Difluoroethyl)-1-methyl-5-phenyl-1H-imidazole (nine batches): To a solution of 1-(1-methyl-5-phenyl-imidazol-4-yl)ethanone (50.0 mg, 247 μmol, 1.00 eq) in ACN (0.50 mL) was added DAST (99.8 mg, 619 μmol, 81.8 μL, 2.50 eq) at 0°C, The mixture was stirred at 70 °C for 8 h. The reaction mixture was quenched with NaHCO3 (5.00 mL) and extracted with CH2Cl2 (3 x 5.0 mL).The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-column chromatography (SiO2, Petroleum ether/Ethyl acetate=30/1 to 5/1, Rf = 0.7) to give the title compound (70.0 mg, 296 μmol, 9.0% yield, 94.2% purity in LCMS at 220 nm) as a white solid. (C12H12N2F2). [1399] C.2-Bromo-4-(1,1-difluoroethyl)-1-methyl-5-phenyl-1H-imidazole: To a solution of 4-(1,1-difluoroethyl)-1-methyl-5-phenyl-1H-imidazole (0.03 g, 127 μmol, 1.00 eq) in ACN (0.50 mL) was added NBS (27.1 mg, 152 μmol, 1.20 eq) at 0 °C, The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtrated to give a filtrate. The filtrate 484 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was purified by prep-TLC(SiO2, Petroleum ether/Ethyl acetate =1:1, Rf = 0.6) to give the title compound (35.0 mg, 113 μmol, 89.2% yield, 97.6% purity in LCMS at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1 H), 8.33 (s, 2 H), 7.70 (d, J = 9.20 Hz, 2H), 7.06 (d, J=9.20 Hz, 2H), 4.02 - 3.99 (m, 3H) 3.04 - 3.10 (m, 2H), 2.76 - 2.85 (m, 1H) 1.96 - 1.93 (m, 2H) 1.53 - 1.51 (m, 2H) 1.19 (d, J = 7.20 Hz, 6H) (ESI+) m/z: 303.0 (M+H)+, (C12H11BrF2N2). [1400] D.3-(5-(4-(1,1-Difluoroethyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-4-(1,1-difluoroethyl)-1- methyl-5-phenyl-1H-imidazole (30.0 mg, 97.2 μmol, 1.00 eq) in dioxane (1.00 mL) H2O (0.05 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindolin-2- yl)piperidine-2,6-dione (43.2 mg, 116. μmol, 1.20 eq) K3PO4 (41.2 mg, 194 μmol, 2.00 eq) RuPhos Pd G3 (8.13 mg, 9.72 μmol, 0.10 eq), The mixture was stirred at 100 °C for 2 h under N2. Celite was added the mixture and concentrated to give a solid. The solid was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 1/3, Rf = 0.4) to give the title compound (20.0 mg, 41.5 μmol, 42.6% yield, 96.4% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 464.9 (M+H)+, (C25H22F2O4N2). [1401] E.3-(5-(4-(1,1-Difluoroethyl)-1-methyl-5-phenyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(4-(1,1-difluoroethyl)-1- methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.02 g, 41.5 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (2 M, 207 μL, 10.0 eq) , The mixture was stirred at 25°C for 4h. The mixture was lyophilized to give a residue. The residue was purified by preparative-HPLC ((using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 18 - 48% acetonitrile in water containing 0.05% HCl over 8 min at a flow rate of 25 mL/min) to give the title compound (8.03 mg, 16.8 μmol, 40.6% yield, 97.6% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ11.0 (s, 1 H), 7.99 (s, 1 H), 7.85 - 7.92 (m, 2 H), 7.48 - 7.57 (m, 5 H), 5.18 - 5.13 (m, 1 H), 4.39 - 4.64 (m, 2 H), 3.50 (s, 3 H), 2.86 - 3.02 (m, 1 H), 2.64 - 2.62 (m, 1 H), 2.37 - 2.46 (m, 1 H), 2.01 - 2.09 (m, 1 H), 1.95 (t, J=18.4 Hz, 3 H) (ESI+) m/z: 464.9 (M+H)+, (C25H22F2O4N2). 485 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 419 [1402] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1,4-dimethyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1403] A.4-(1-Methyl-1H-imidazol-5-yl)phenol: To a solution of 5-bromo-1-methyl-1H- imidazole (2.00 g, 12.4 mmol, 1.00 eq) in DMF (50.0 mL) and H2O (50.0 mL) was added K2CO3 (3.43 g, 24.8 mmol, 2.00 eq), Pd(PPh3)2Cl2 (435 mg, 621 μmol, 0.05 eq) and (4- methoxyphenyl)boronic acid (2.27 g, 14.9 mmol, 1.20 eq). The mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into H2O (100 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 30: 1, TLC: Dichloromethane: Methanol = 30: 1, Rf = 0.30) to give the title compound (1.00 g, 5.25 mmol, 42.2% yield, 98.8% purity in LCMS at 220 nm) as brown solid. (ESI+) m/z: 174.2 (M+H)+, (C10H10N2O). [1404] B.4-Bromo-5-(4-methoxyphenyl)-1-methyl-1H-imidazole: To a solution of 4-(1- methyl-1H-imidazol-5-yl)phenol (500 mg, 2.66 mmol, 1.00 eq) in ACN (20.0 mL) was added NBS (472 mg, 2.66 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 50: 1 to 1: 1, TLC: Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.50) to give the title compound (640 mg, 2.40 mmol, 90.1% yield, 100% purity in LCMS at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.37 (d, J=8.80 Hz, 2H), 7.05 (d, J=8.80 Hz, 2H), 3.81 (s, 3H), 3.58 (s, 3H). (ESI+) m/z: 266.9 (M+H)+, (C11H11BrN2O). [1405] C.5-(4-Methoxyphenyl)-1,4-dimethyl-1H-imidazole: To a solution of 4-bromo-5- (4-methoxyphenyl)-1-methyl-1H-imidazole (600 mg, 2.24 mmol, 1.00 eq), 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (2.82 g, 11.2 mmol, 3.14 mL, 5.00 eq) and K3PO4 (1.50 g, 6.74 mmol, 3.00 eq) in dioxane (12.0 mL) was added XPHOS-PD-G2 (176 mg, 224 μmol, 0.10 eq) under N2.The mixture was stirred at 100 °C for 5 h under N2. The reaction mixture was 486 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC (Dichloromethane: Methanol = 20: 1, Rf=0.50) to give the title compound (350 mg, 1.58 mmol, 70.3% yield, 91.3% purity in LCMS at 220 nm) as light yellow oil. (ESI+) m/z: 203.0 (M+H)+, (C12H14N2O). [1406] D.2-Bromo-5-(4-methoxyphenyl)-1,4-dimethyl-1H-imidazole: To a solution of 5-(4-methoxyphenyl)-1,4-dimethyl-1H-imidazole (150 mg, 741 μmol, 1.00 eq) in ACN (5.00 mL) was added NBS (132 mg, 741 μmol, 1.00 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with Ethyl acetate (3 x 50.0 mL). The combined organic layer was washed with brine (3 x 50.0 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by TLC (Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.40) to give the title compound (120 mg, 426 μmol, 57.5% yield, 100% purity in LCMS at 220 nm) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.31 - 7.27 (m, 2H), 7.04 (d, J=8.80 Hz, 2H), 3.80 (s, 3H), 3.39 (s, 3H), 2.03 (s, 3H). (ESI+) m/z: 266.9 (M+H)+, (C12H13BrN2O). [1407] E.3-(5-(5-(4-Methoxyphenyl)-1,4-dimethyl-1H-imidazol-2-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: To a solution of 2-bromo-5-(4-methoxyphenyl)-1,4-dimethyl-1H- imidazole (120 mg, 126 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (316 mg, 853 μmol, 2.00 eq) and K3PO4 (271 mg, 1.28 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (35.7 mg, 42.6 μmol, 0.10 eq) under N2. The mixture was stirred at 80 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *10 um) and gradient of 12.0% - 42.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (50.0 mg, 109 μmol, 25.7% yield, 97.6% purity in HPLC at 220 nm) was obtained as white solid. (ESI+) m/z: 445.0 (M+H)+, (C25H24N4O4). [1408] F.3-(5-(5-(4-Methoxyphenyl)-1,4-dimethyl-1H-imidazol-2-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(5-(4-methoxyphenyl)- 1,4-dimethyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50.0 mg, 109 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 562 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (43.2 mg, 87.4 μmol, 77.7% yield, 97.4% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.10 (s, 1H), 8.08 - 8.03 (m, 1H), 7.96 - 7.94 (m, 1H), 7.50 (d, J=8.80 Hz, 2H), 7.18 (d, J=8.80 Hz, 487 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 2H), 5.21 - 5.16 (m, 1H), 4.64 - 4.47 (m, 2H), 3.85 (s, 3H), 3.65 (s, 3H), 2.97 - 2.90 (m, 1H), 2.65 - 2.61 (m, 1H), 2.45 - 2.32 (m, 1H), 3.30 (s, 3H), 2.07 – 2.04 (m, 1H). (ESI+) m/z: 445.0 (M+H)+, (C25H24N4O4). EXAMPLE 420 [1409] Synthesis of 3-(5-(1-(3-Aminophenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: [1410] A.4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole: A solution of NaH (646 mg, 16.1 mmol, 60% purity, 1.10 eq) in THF (40.0 mL) was stirred at 0°C. Then a solution of 4-(trifluoromethyl)-1H-imidazole (2.00 g, 14.7 mmol, 1.00 eq) in THF (9.00 mL) was added dropwise at 0 °C under N2. After the mixture was stirred at 25 °C for 1 h, SEMCl (3.19 g, 19.1 mmol, 3.38 mL, 1.30 eq) was added and the reaction mixture was stirred as 25 °C for 15 h under N2. The reaction mixture was quenched with 50.0 mL of saturated NH4Cl solution and extracted with EtOAc (3 x 50.0 mL). The combined organic layer was concentrated in vacuum to give the title compound (3.00 g, crude) as yellow oil. (ESI+) m/z: 267.1 (M+H)+, (C10H17F3N2SiO). [1411] B.2-Bromo-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazole: To a solution of trimethyl-[2-[[4-(trifluoromethyl)imidazol-1- yl]methoxy]ethyl]silane (2.80 g, 10.5 mmol, 1.00 eq) in CCl4 (60.0 mL) was added NBS (2.43 g, 13.6 mmol, 1.30 eq) and AIBN (345 mg, 2.10 mmol, 0.20 eq). The mixture was stirred at 60 °C for 4 h. The reaction mixture was quenched with 100 mL of saturated NaHCO3 solution and extracted with DCM (3 x 50.0 mL). The combined organic layer was concentrated in vacuum to give the title compound (2.00 g, crude) as yellow oil. (ESI+) m/z: 345.0 (M+H)+, (C10H16F3N2BrSiO). [1412] C.2-Bromo-4-(trifluoromethyl)-1H-imidazole (Four reactions were carried out in parallel): To a solution of 2-[[2-bromo-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (500 mg, 1.45 mmol, 1.00 eq) in THF (15.0 mL) was added TBAF (1 M, 2.90 mL, 2.00 eq). The mixture was stirred at 60 °C for 4 h. The reaction mixture was concentrated in vacuum to get a residue. The residue was purified by reversed-phase HPLC 488 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (0.05% HCl condition) to give the title compound (800 mg, 3.30 mmol, 56.9% yield, 88.7% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 214.9 (M+H)+, (C4H2N2F3Br). [1413] D. tert-Butyl (3-(2-bromo-4-(trifluoromethyl)-1H-imidazol-1- yl)phenyl)carbamate: To a solution of 2-bromo-4-(trifluoromethyl)-1H-imidazole (400 mg, 1.65 mmol, 1.00 eq) in DCE (16.0 mL) was added (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid (978 mg, 4.13 mmol, 2.50 eq), Cu(OAc)2 (299 mg, 1.65 mmol, 1.00 eq), Na2CO3 (524 mg, 4.95 mmol, 3.00 eq) and 2-(2-pyridyl)pyridine (773 mg, 4.95 mmol, 3.00 eq). The mixture was stirred at 70 °C for 10 h under O2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was diluted in 10.0 mL of EtOAc and then washed with 1M HCl solution (2 x 10.0 mL). The organic layer was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 10: 1, Rf = 0.40 (Petroleum ether: EtOAc = 5: 1)) to give the title compound (300 mg, 675 μmol, 40.9% yield, 91.5% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.35 - 8.31 (m, 1H), 7.71 - 7.65 (m, 1H), 7.57 - 7.52 (m, 1H), 7.49 - 7.43 (m, 1H), 7.19 - 7.11 (m, 1H), 1.47 (s, 9H). (ESI+) m/z: 405.8 (M+H)+, (C15H15BrN3F3O2). [1414] E. tert-Butyl (3-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4- (trifluoromethyl)-1H-imidazol-1-yl)phenyl)carbamate: To a solution of tert-butyl (3-(2- bromo-4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)carbamate (300 mg, 675 μmol, 1.00 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (625 mg, 1.69 mmol, 2.50 eq), Ru- Phos-Pd-G3 (113 mg, 135 μmol, 0.20 eq) and K3PO4 (430 mg, 2.03 mmol, 3.00 eq). The mixture was stirred at 100 °C for 2 h under N2. Then the mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 1: 1, Rf = 0.70 (Petroleum ether: EtOAc = 0: 1)) to give the title compound (200 mg, 305 μmol, 45.1% yield, 86.9% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 569.9 (M+H)+, (C28H26O5N5F3). [1415] F.3-(5-(1-(3-Aminophenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: To a solution of tert-butyl N-[3-[2- [2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4-(trifluoromethyl)imidazol-1- yl]phenyl]carbamate (200 mg, 305 μmol, 1.00 eq) in dioxane (6.00 mL) was added HCl/dioxane (2 M, 3.05 mL, 20.0 eq). The mixture was stirred at 25 °C for 24 h. The reaction mixture was concentrated in vacuum to get a residue. The residue was washed with ACN (3 x 10.0 mL) and dried in vacuum to give the title compound (91.79 mg, 178 μmol, 58.5% yield, 489 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 98.5% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.81 - 6.76 (m, 1H), 6.67 - 6.60 (m, 2H), 5.14 - 5.06 (m, 1H), 4.47 - 4.27 (m, 2H), 2.95 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.45 - 2.35 (m, 1H), 2.04 - 1.97 (m, 1H). (ESI+) m/z: 470.0 (M+H)+, (C23H19F3N5O3Cl). EXAMPLE 421 [1416] Synthesis of 3-(5-(1-(4-Aminophenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: [1417] A. tert-Butyl (4-(2-bromo-4-(trifluoromethyl)-1H-imidazol-1- yl)phenyl)carbamate: To a solution of 2-bromo-4-(trifluoromethyl)-1H-imidazole (400 mg, 1.65 mmol, 1.00 eq) in DCE (16.0 mL) was added (4-((tert- butoxycarbonyl)amino)phenyl)boronic acid (1.96 g, 8.25 mmol, 5.00 eq), Cu(OAc)2 (299 mg, 1.65 mmol, 1.00 eq), Na2CO3 (524 mg, 4.95 mmol, 3.00 eq) and 2-(2-pyridyl)pyridine (773 mg, 4.95 mmol, 3.00 eq). The mixture was stirred at 70 °C for 10 h under O2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was diluted in 10.0 mL of EtOAc and then washed with 1M HCl solution (2 x 10.0 mL). The organic layer was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 10: 1, Rf = 0.40 (Petroleum ether: EtOAc = 5: 1)) to give the title compound (400 mg, 835 μmol, 50.6% yield, 84.8% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.29 - 8.25 (m, 1H), 7.61 (d, J = 9.2 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 1.47 (s, 9H). (ESI+) m/z: 405.8 (M+H)+, (C15H15BrN3F3O2). [1418] B. tert-Butyl (4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4- (trifluoromethyl)-1H-imidazol-1-yl)phenyl)carbamate: To a solution of tert-butyl N-[4-[2- bromo-4-(trifluoromethyl)imidazol-1-yl]phenyl]carbamate (400 mg, 835 μmol, 1.00 eq) in dioxane (8.00 mL) and H2O (0.40 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (772 mg, 2.09 mmol, 2.50 eq), Ru- Phos-Pd-G3 (139 mg, 167 μmol, 0.20 eq) and K3PO4 (531 mg, 2.51 mmol, 3.00 eq). The 490 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture was stirred at 100 °C for 2 h under N2. Then the mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 1: 1, Rf = 0.70 (Petroleum ether: EtOAc = 0: 1)) to give the title compound (300 mg, 464 μmol, 55.5% yield, 88.1% purity in HPLC at 220 nm) as an off-white solid. (ESI+) m/z: 569.9 (M+H)+, (C28H26O5N5F3). [1419] C.3-(5-(1-(4-Aminophenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: To a solution of tert-butyl (4-(2-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-(trifluoromethyl)-1H-imidazol-1- yl)phenyl)carbamate (200 mg, 305 μmol, 1.00 eq) in dioxane (6.00 mL) was added HCl/dioxane (2 M, 3.05 mL, 20.0 eq). The mixture was stirred at 25 °C for 24 h. The reaction mixture was concentrated in vacuum to get a residue. The residue was washed with ACN (3 x 10.0 mL) and dried in vacuum to give the title compound (95.43 mg, 181 μmol, 58.7% yield, 96.3% purity in HPLC at 220 nm, HCl) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.19 (s, 1H), 7.73 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 5.14 - 5.06 (m, 1H), 4.47 - 4.26 (m, 2H), 2.95 - 2.85 (m, 1H), 2.63 - 2.55 (m, 1H), 2.45 - 2.35 (m, 1H), 2.04 - 1.95 (m, 1H). (ESI+) m/z: 470.0 (M+H)+, (C23H19F3N5O3Cl). EXAMPLE 422 [1420] Synthesis of 3-(5-(4-Methyl-1-phenyl-5-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1421] A.4-Methyl-1-phenyl-1H-imidazole: To a solution of 4-methyl-1H-imidazole (5.00 g, 60.9 mmol, 1.00 eq) in MeOH (250 mL) was added phenylboronic acid (8.91 g, 73.0 mmol, 1.20 eq) Cu(OAc)2 (2.21 g, 12.1 mmol, 0.20 eq) K2CO3 (8.42 g, 60.9 mmol, 1.00 eq), The mixture was stirred at 60 °C for 3 h under O2，The mixture was stirred at 100 °C for 2 h under N2. Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 20：1 to 1 ：3, Rf = 0.4) to give the title compound (3.70 g, 23.3 mmol, 47.1% yield, 100% purity in LCMS at 220 nm) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1 H), 7.60 (d, 491 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT J= 1.28 Hz, 2 H), 7.58 - 7.43 (m, 3 H), 7.33 (m, 1.00 H), 2.16 (s, 3 H),. (ESI+) m/z: 159.1 (M+H)+, (C10H10N2). [1422] B.4-Methyl-1-phenyl-5-(trifluoromethyl)-1H-imidazole: A solution of 3,3- dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (3.13 g, 9.48 mmol, 1.00 eq) and 4-methyl-1- phenylimidazole (1.50 g, 9.48 mmol, 1.00 eq) in ACN (15.0 mL) was stirred at 80 °C for 90 h. Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1, Rf = 0.4) to give the title compound (200 mg, 618 μmol, 6.53% yield, 100% purity in LCMS at 220 nm) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.60 (d, J= 1.28 Hz, 2H), 7.58 - 7.43 (m, 3H), 7.33 (m, 1H), 2.16 (s, 3H), (ESI+) m/z: 159.1 (M+H)+, (C11H9N2F3). [1423] B.2-Bromo-4-methyl-1-phenyl-5-(trifluoromethyl)-1H-imidazole: To a solution of 4-methyl-1-phenyl-5-(trifluoromethyl)imidazole (0.10 g, 442 μmol, 1.00 eq) in THF (2 mL) was added 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (114 mg, 442 μmol, 1.00 eq) 1,2- dibromo-1,1,2,2-tetrafluoro-ethane (229 mg, 884 μmol, 2.00 eq) n-BuLi (56.6 mg, 884 μmol, 2.00 eq) at -78°C,The mixture was stirred at 25 °C for 4 h under N2, Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1, Rf = 0.40) to give the title compound (50.0 mg, 1.64 μmol, 37% yield) as a yellow solid. (C11H8N2F3Br). [1424] C.3-(5-(4-Methyl-1-phenyl-5-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-4-methyl-1-phenyl-5- (trifluoromethyl)imidazole (0.05 g, 163 μmol, 1.00 eq) in dioxane (1.00 mL) H2O (0.05 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (72.8 mg, 196 μmol, 1.20 eq) K3PO4 (69.5 mg, 327 μmol, 2.00 eq) RuPhos Pd G3 (13.7 mg, 16.3 μmol, 0.10 eq), The mixture was stirred at 100 °C for 2 h under N2. Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 20：1 to 1：3, Rf = 0.4) to give the title compound (0.04 g, 85.3 μmol, 52.1% yield, 100% purity in HPLC at 220 nm) as a yellow solid.. (ESI+) m/z: 469.0 (M+H)+, (C24H19O3N4O3). [1425] D.3-(5-(4-Methyl-1-phenyl-5-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(4-methyl-1-phenyl-5- (trifluoromethyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (0.04 g, 85.3 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2.00 M, 426 μL, 10.0 eq), The 492 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mixture was stirred at 25 °C for 4 h. The mixture was lyophilized to give a residue to give the title compound (10.0 g, 34.1 mmol, 56.2% yield, 91.6% purity in LCMS at 220 nm) as a off- white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1.00 H) 7.44 - 7.63 (m, 7.00 H) 7.35 (dd, J=8.00, 1.25 Hz, 1.00 H) 5.08 (dd, J=13.2, 4.94 Hz, 1.00 H) 4.18 - 4.42 (m, 2.00 H) 2.81 - 2.96 (m, 1.00 H) 2.60 (s, 1.00 H) 2.41 - 2.45 (m, 3.00 H) 2.31 - 2.39 (m, 1.00 H) 1.93 - 2.02 (m, 1.00 H). (ESI+) m/z: 469.1 (M+H)+, (C24H19F3O3N4). EXAMPLE 423 [1426] Synthesis of 3-(5-(5-(3-Methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1427] A. tert-Butyl 5-amino-4-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)-5-oxopentanoate: A mixture of 4-bromo-1-methyl-1H-1,2,3-triazole (2.50 g, 15.4 mmol, 1.00 eq), tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)pentanoate (6.86 g, 15.4 mmol, 1.00 eq), K3PO4 (6.55 g, 30.8 mmol, 2.00 eq) and cataCXium A Pd G3 (1.12 g, 1.54 mmol, 0.10 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 30: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30). to give the title compound (2.60 g, 6.51 mmol, 42.1% yield, 100% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.07 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.18 (s, 1H), 4.76 - 4.72 (m, 1H), 4.66 - 4.49 (m, 2H), 4.11 (s, 3H), 2.20 - 2.14 (m, 3H), 2.03 - 1.98 (m, 1H), 1.32 (s, 9H). (ESI+) m/z: 400.1 (M+H)+, (C20H25N5O4). [1428] B. tert-Butyl 5-amino-4-(5-(5-(3-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of tert-butyl 5-amino-4-(5-(1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.10 g, 250 μmol, 1.00 eq), 1-bromo-3-methoxybenzene (140 mg, 751 μmol, 95.1 μL, 3.00 eq), Pd(PPh3)2Cl2 (17.5 mg, 25.0 μmol, 0.10 eq) and tetrabutylammounium acetate (301 mg, 1.00 mmol, 304 μL, 4.00 493 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT eq) in NMP (2.50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 4 h under N2 atmosphere. The mixture was poured water (10.0 mL) and extracted with ethyl acetate(3 x 20.0 mL) to collecte the organic layer. The organic layers were washed with brine (2 x 20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum at 45 °C to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.50) to give the title compound (80.0 mg, 113 μmol, 45.5% yield, 72% purity in LCMS at 220 nm) as a yellow oil. (ESI+) m/z: 506.0 (M+H)+, (C27H31N5O5). [1429] C.3-(5-(5-(3-Methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione：To a solution of tert-butyl 5-amino-4-(5-(5-(3-methoxyphenyl)- 1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (80.0 mg, 158 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (54.5 mg, 316 μmol, 2.00 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 18 - 48% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (52.9 mg, 116 μmol, 73.8% yield, 95.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.76 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.11 - 7.09 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 5.12 - 5.07 (m, 1H), 4.47 - 4.26 (m, 2H), 3.91 (s, 3H), 3.78 (s, 3H), 2.93 - 2.88 (m, 1H), 2.61 - 2.55 (m, 1H), 2.39 - 2.34 (m, 1H), 2.00 - 1.99 (m, 1H). (ESI+) m/z: 432.0 (M+H)+, (C23H21N5O4). EXAMPLE 424 [1430] Synthesis of 3-(5-(1-Methyl-5-(m-tolyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [1431] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(m-tolyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of tert-butyl 5-amino-4-(5-(1-methyl-1H- 1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 375 μmol, 1.00 eq), 1- bromo-3-methylbenzene (192 mg, 1.13 mmol, 136 μL, 3.00 eq), Pd(PPh3)2Cl2 (26.3 mg, 37.5 494 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT μmol, 0.10 eq) and tetrabutylammonium acetate (452 mg, 1.50 mmol, 457 μL, 4.00 eq) in NMP (4.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 4 h under N2 atmosphere. The mixture was poured water (10.0 mL) and extracted with ethyl acetate(3 x 20.0 mL) to collecte the organic layer. The organic layers were washed with brine (2 x 20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum at 45 °C to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (100 mg, 173 μmol, 46.2% yield, 85% purity in LCMS at 220 nm) as a white oil. (ESI+) m/z: 490.1 (M+H)+, (C27H31N5O4). [1432] B.3-(5-(1-Methyl-5-(m-tolyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of tert-butyl 5-amino-4-(5-(1-methyl-5-(m-tolyl)- 1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (100 mg, 173 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (59.8 mg, 347 μmol, 2.00 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 21 - 51% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (30.42 mg, 73.1 μmol, 42.1% yield, 99.9% purity in HPLC at 220 nm) as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.75 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.49 - 7.47 (m, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.40 - 7.37 (m, 1H), 7.30 - 7.27 (m, 1H), 5.12 - 5.07 (m, 1H), 4.45 - 4.26 (m, 2H), 3.90 (s, 3H), 2.91 - 2.88 (m, 1H), 2.61 - 2.55 (m, 1H), 2.39 - 2.36 (m, 1H), 2.35 (s, 3H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 416.0 (M+H)+, (C23H21N5O3). EXAMPLE 425 [1433] Synthesis of 3-(5-(1-Methyl-5-(pyrimidin-4-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1434] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(pyrimidin-4-yl)-2-(trifluoromethyl)- 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5- amino-4-(5-(5-bromo-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)- 495 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 5-oxopentanoate (0.15 g, 275 μmol, 1.00 eq) in dioxane (2.00 mL) was added 4- (tributylstannyl) pyrimidine (148 mg, 330 μmol, 1.20 eq, BrH) cataCxium A Pd G2 (36.7 mg, 55.0 μmol, 0.20 eq), The mixture was stirred 100 °C for 16 h. The reaction mixture was quenched by addition H2O (10.0 mL)), and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The mixture was purified by preparative-TLC (SiO2, petroleum ether: ethyl acetate = 1: 1, Rf = 0.3) to give the title compound (70.0 mg, 122 μmol, 22.2% yield, 95.0% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 544.9 (M+H)+, (C26H27F3O4N6). [1435] B.3-(5-(1-Methyl-5-(pyrimidin-4-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(1- methyl-5-(pyrimidin-4-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (70.0 mg, 122 μmol, 1.00 eq) in ACN (1.00 mL) was added TsOH (84.1 mg, 488 μmol, 4.00 eq), The mixture was stirred 80°C for 4h. The mixture was filtrated to give a filtrate. The mixture was purified by preparative-HPLC (using a Welch Xtimate C18150 x 40 mm x 10 μm and gradiente of 14%-44% acetonitrile in water containing 0.05% HCl over 8 min at a flow rate of 25 mL/min) to give the title compound (30.0 mg, 59.9 μmol, 49.0% yield, 94.0% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 471.1 (M+H)+, (C22H17F3O3N6). [1436] C.3-(5-(1-Methyl-5-(pyrimidin-4-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(1-methyl-5-(pyrimidin-4- yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (30.0 mg, 59.9 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (2 M, 299 μL, 10.0 eq) , The mixture was stirred 25 °C for 4 h. The mixture was lyophilized to give the title compound (11.7 mg, 24.8 μmol, 41.4% yield, 99.7% purity in HPLC at 220 nm) as off white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.41 (s, 1H), 8.99 (d, J = 4.0 Hz, 1H), 7.67(d, J = 3.6 Hz, 2H), 7.59 (d, J = 4.0 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H), 5.10 (dd, J = 8.0 Hz, 1H), 4.36 (dd, J = 10.4 Hz, 2H), 3.83 (s, 3H), 2.93 - 2.87 (m, 1H), 2.61 - 2.57 (m, 1H), 2.38 - 2.35 (m, 1H), 2.01 - 1.99 (m, 1H). (ESI+) m/z: 471.1 (M+H)+, (C22H17O3N6F3). 496 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 426 [1437] Synthesis of 3-(5-(2-Ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1438] A.1-(Difluoroiodomethyl)-2-iodo-5-phenyl-1H-imidazole: To a solution of 5- phenyl-1H-imidazole (5.00 g, 34.6 mmol, 1.00 eq) and CF3I (81.5 g, 104 mmol, 25% purity, 3.00 eq) in THF (50.0 mL) was added LiHMDS (1 M, 38.1 mL, 1.10 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 16 h under N2, then to the mixture was added LiHMDS (1 M, 34.6 mL, 1.00 eq) and solution of I2 (8.80 g, 34.6 mmol, 6.99 mL, 1.00 eq) in THF (10.0 mL) at 0 °C under N2.The reaction mixture was stirred at 25 °C for 4 h under N2. The reacion mixture was poured into H2O (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Dichloromethane = 100: 0 to 1: 1; TLC: Petroleum ether: Dichloromethane = 1: 1, Rf = 0.50) to give the title compound (1.20 g, 2.69 mmol, 7.76% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.47 - 7.44 (m, 3H), 7.42 - 7.40 (m, 2H), 7.04 (s, 1H). (ESI+) m/z: 446.4 (M+H)+, (C10H6F2I2N2). [1439] B.2-Iodo-5-phenyl-1-(trifluoromethyl)-1H-imidazole: A mixture of 1- [difluoro(iodo)methyl]-2-iodo-5-phenyl-imidazole (1.20 g, 2.69 mmol, 1.00 eq) and AgBF4 (1.05 g, 5.38 mmol, 2.00 eq) in DCM (10.0 mL) was stirred at 25 °C for 16 h in the dark. The residue was filtered and concentrated in vacuum to give the title compound (0.90 g, crude) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.46 (m, 3H), 7.43 - 7.38 (m, 2H), 7.11 (s, 1H). (ESI+) m/z: 338.8 (M+H)+, (C10H6F3IN2). [1440] C.5-Phenyl-1-(trifluoromethyl)-2-vinyl-1H-imidazole： A mixture of 2-iodo-5- phenyl-1-(trifluoromethyl)-1H-imidazole (0.90 g, 2.66 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (1.23 g, 7.99 mmol, 1.35 mL, 3.00 eq), Ru-Phos-Pd-G3 (222 mg, 266 μmol, 0.10 eq) and K3PO4 (1.13 g, 5.32 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated in 497 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Dichloromethane = 100: 0 to 3: 1; TLC, Petroleum ether: Dichloromethane = 0: 1, Rf = 0.50) to give the title compound (180 mg, 755 μmol, 28.3% yield) as a yellow oil. 1H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.42 (m, 5H), 7.15 (s, 1H), 6.80 - 6.77 (m, 1H), 6.28 (d, J = 16.4 Hz, 1H), 5.66 (d, J = 12.8 Hz, 1H). (ESI+) m/z: 239.1 (M+H)+, (C12H9F3N2). [1441] D.2-Ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole：To a solution of 5- phenyl-1-(trifluoromethyl)-2-vinyl-1H-imidazole (180 mg, 755 μmol, 1.00 eq) in THF (10.0 mL) was added Pd/C (60.0 mg, 56.38 μmol, 10% purity, 0.05 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 4 h. T The reaction mixture was filtered through celite and the cake was washed with dichloromethane (3 x 10.0 mL). The organic layer was concentrated in vacuum to give the title compound (60.0 mg, 249 μmol, 33.0% yield) as a yellow oil. (ESI+) m/z: 241.1 (M+H)+, (C12H11F3N2). [1442] E.4-Bromo-2-ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole：To a solution of 2-ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazole (80.0 mg, 333 μmol, 1.00 eq) in ACN (1.00 mL) was added a solution of NBS (59.2 mg, 333 μmol, 1.00 eq) in ACN (1.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into H2O (10.0 mL), extracted with EtOAc (3 x 10.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Dichloromethane = 1: 1, Rf = 0.40) to give the title compound (40.0 mg, 125 μmol, 37.6% yield) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.51 - 7.48 (m, 3H), 7.41 - 7.39 (m, 2H), 2.91 - 2.85 (m, 2H), 1.28 (t, J = 3.6 Hz, 3H). (ESI+) m/z: 321.0 (M+H)+, (C12H10BrF3N2). [1443] F.3-(5-(2-Ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione：A mixture of 4-bromo-2-ethyl-5-phenyl-1- (trifluoromethyl)-1H-imidazole (40.0 mg, 125 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (92.8 mg, 250 μmol, 2.00 eq), Ru-Phos-Pd-G3 (10.4 mg, 12.5 μmol, 0.10 eq) and K3PO4 (53.2 mg, 250 μmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 h under N2 atmosphere. The reaction was filtered and concentrated in vacuum. The residue was purified by preparative- TLC (SiO2, Dichloromethane: Methanol = 20: 1, Rf = 0.40) and preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 26 - 56% acetonitrile in water containing 498 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (30.0 mg, 62.1 μmol, 49.6% yield) as a white solid. (ESI+) m/z: 483.1 (M+H)+, (C25H21F3N4O3). [1444] G.3-(5-(2-Ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride：To a solution of 3-(5-(2- ethyl-5-phenyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (30.0 mg, 62.1 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 310 μL, 10.0 eq). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (30.5 mg, 58.42 μmol, 99.4% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.56 - 7.51 (m, 5H), 7.49 - 7.45 (m, 2H), 7.37 - 7.34 (m, 1H), 5.08 - 5.04 (m, 1H), 4.37 - 4.17 (m, 2H), 2.96 - 2.94 (m, 2H), 2.92 - 2.90 (m, 1H), 2.59 - 2.50 (m, 1H), 2.37 - 2.36 (m, 1H), 1.97 - 1.94 (m, 1H), 1.38 (t, J = 3.8 Hz, 3H). (ESI+) m/z: 483.1 (M+H)+, (C25H21F3N4O3). EXAMPLE 427 [1445] Synthesis of 3-(5-(5-(3-Aminophenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1446] A. tert-Butyl 5-amino-4-(5-(5-(3-((tert-butoxycarbonyl)amino)phenyl)-1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (Two reactions were carried out in parallel): To a solution of tert-butyl 5-amino-4-(5-(1-methyl-1H-1,2,3- triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 500 μmol, 1.00 eq) in NMP (5.00 mL) was added tert-butyl (3-bromophenyl)carbamate (408 mg, 1.50 mmol, 3.00 eq), Pd(PPh3)2Cl2 (35.1 mg, 50.0 μmol, 0.10 eq) and tetrabutylammonium acetate (603 mg, 2.00 mmol, 609 μL, 4.00 eq) under N2. The mixture was stirred at 120 °C for 4 h. After the reaction was completed, the reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and the filtrated was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.30) to give the title compound (240 mg, 309 μmol, 30.8% yield, 76.1% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 591.2 (M+H)+, (C31H38N6O6). 499 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1447] B.3-(5-(5-(3-Aminophenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(3-((tert- butoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (240 mg, 309 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (212 mg, 1.24 mmol, 4.00 eq). The mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18 150 x 25 mm x 7 μm) and gradiente of 8 - 38% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (65.6 mg, 152 μmol, 49.4% yield, 97.0% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.78 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.74 - 6.71 (m, 1H), 6.59 - 6.54 (m, 2H), 5.35 (s, 2H), 5.13 - 5.07 (m, 1H), 4.46 - 4.26 (m, 2H), 3.89 (s, 3H), 2.96 - 2.86 (m, 1H), 2.61 - 2.56 (m, 1H), 2.41 - 2.35 (m, 1H), 2.02 - 1.96 (m, 1H). (ESI+) m/z: 417.1 (M+H)+, (C22H20N6O3). EXAMPLE 428 [1448] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1449] A. tert-Butyl 5-amino-4-(5-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 500 μmol, 1.00 eq) in NMP (5.00 mL) was added 1-bromo-4-methoxy-benzene (280 mg, 1.50 mmol, 188 μL, 3.00 eq), Pd(PPh3)2Cl2 (35.1 mg, 50.0 μmol, 0.10 eq) and tetrabutylammonium acetate (603 mg, 2.00 mmol, 609 μL, 4.00 eq) under N2. The mixture was stirred at 120 °C for 4 h. After the reaction was completed, the reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and the filtrated was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.30) to give the title compound (170 mg, 292 μmol, 58.3% yield, 500 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 86.9% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 506.2 (M+H)+, (C27H31N5O5). [1450] B.3-(5-(5-(4-Methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-methoxyphenyl)-1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 527 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (177 mg, 1.03 mmol, 4.00 eq). The mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 18 - 48% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (13.4 mg, 30.2 μmol, 11.7% yield, 96.9% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 5.12 - 5.07 (m, 1H), 4.46 - 4.26 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.96 - 2.85 (m, 1H), 2.61 - 2.55 (m, 1H), 2.39 - 2.32 (m, 1H), 2.01 - 1.96 (m, 1H). (ESI+) m/z: 432.1 (M+H)+, (C23H21N5O4). EXAMPLE 429 [1451] Synthesis of 3-(5-(1-Methyl-5-(p-tolyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [1452] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(p-tolyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1-methyl- 1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 500 μmol, 1.00 eq) and 1-bromo-4-methylbenzene (256 mg, 1.50 mmol, 3.00 eq) and tetrabutylammonium acetate (603 mg, 2.00 mmol, 4.00 eq) in NMP (5.00 mL) was added Pd(PPh3)2Cl2 (35.1 mg, 50.7μmol, 0.10 eq) under N2. The mixture was stirred at 120 °C for 4 h under N2. The mixture was poured into aturated H2O aqeous (50.0 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with saturated NaCl aqeous (3 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was 501 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT purified by TLC (Dichloromethane: Methanol = 15: 1, Rf = 0.45) to give the title compound (230 mg, 378 μmol, 75.5% yield, 80.5% purity in LCMS at 220 nm) as brown oil. (ESI+) m/z: 490.0 (M+H)+, (C23H31N5O4). [1453] B.3-(5-(1-Methyl-5-(p-tolyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(1-methyl-5-(p-tolyl)-1H- 1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 306 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (105 mg, 612 μmol, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 19.0% - 49.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (26.2 mg, 63.1 μmol, 20.6% yield, 99.8% purity in HPLC at 220 nm) was obtained as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.74 (s, 1H), 7.66 - 7.64 (m, 1H), 7.51 - 7.49 (m, 1H), 7.40 – 7.35 (m, 4H), 5.11 - 5.07 (m, 1H), 4.44 - 4.25 (m, 2H), 3.89 (s, 3H), 2.93 - 2.87 (m, 1H), 2.57 - 2.55 (m, 1H), 2.40 (s, 3H), 2.38 - 2.32 (m, 1H), 2.00 – 1.98 (m, 1H). (ESI+) m/z: 415.9.(M+H)+, (C23H21N5O3). EXAMPLE 430 [1454] Synthesis of 3-(5-(1-Ethyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: [1455] A.4-Bromo-5-phenyl-1H-1,2,3-triazole: To a solution of 5-phenyl-1H-triazole (4.00 g, 27.5 mmol, 1.00 eq) in DMF (80.0 mL) was added NBS (5.39 g, 30.3 mmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was added to 200 mL of water and a white solid was separated out. The solid was collected and dried in vacuum to give the title compound (4.20 g, 18.7 mmol, 68.0% yield, >99% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 15.6 (br, 1H), 7.87 - 7.81 (m, 2H), 7.55 - 7.43 (m, 3H). (ESI+) m/z: 223.8 (M+H)+, (C8H6BrN3). [1456] B.4-Bromo-1-ethyl-5-phenyl-1H-1,2,3-triazole: To a solution of 4-bromo-5- phenyl-1H-triazole (800 mg, 3.57 mmol, 1.00 eq) in DMF (6.00 mL) was added bromoethane 502 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (778 mg, 7.14 mmol, 532 μL, 2.00 eq) and K2CO3 (986 mg, 7.14 mmol, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into 20.0 mL of H2O and extracted with EtOAc (3 x 10.0 mL). The combined organic layer was washed with brine (3 x 10.0 mL) and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 20: 1, Rf = 0.23 (Petroleum ether: EtOAc = 8: 1)) to give the title compound (50.0 mg, 197 μmol, 5.54% yield, 99.7% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.63 - 7.57 (m, 3H), 7.56 - 7.51 (m, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). (ESI+) m/z: 252.0 (M+H)+, (C10H10N3Br). [1457] C.3-(5-(1-Ethyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-ethyl-5-phenyl-triazole (50.0 mg, 197 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (183 mg, 494 μmol, 2.50 eq), Ru-Phos-Pd-G3 (33.0 mg, 39.5 μmol, 0.20 eq) and K3PO4 (125 mg, 593 μmol, 3.00 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: EtOAc = 1: 1, Rf = 0.50) and then by preparative- HPLC (using a CD24-XPT C18 (150 mm x 25 mm 7 μm) and gradient of 20-50% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25.0 mL/min) to give the title compound (33.05 mg, 79.4 μmol, 40.1% yield, 99.9% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.71 (s, 1H), 7.66 - 7.57 (m, 4H), 7.53 - 7.45 (m, 3H), 5.14 - 5.05 (m, 1H), 4.45 - 4.20 (m, 4H), 2.95 - 2.85 (m, 1H), 2.62 - 2.55 (m, 1H), 2.43 - 2.33 (m, 1H), 2.02 - 1.94 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H). (ESI+) m/z: 416.0 (M+H)+, (C23H21O3N5). EXAMPLE 431 [1458] Synthesis of 3-(5-(1-Isopropyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: 503 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1459] A.4-Bromo-1-isopropyl-5-phenyl-1H-1,2,3-triazole (Two reactions were carried out in parallel): To a solution of 4-bromo-5-phenyl-1H-triazole (600 mg, 2.68 mmol, 1.00 eq) in DMF (6.00 mL) was added 2-bromopropane (658 mg, 5.36 mmol, 502 μL, 2.00 eq) and K2CO3 (740 mg, 5.36 mmol, 2.00 eq) .The mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into 20.0 mL of H2O and extracted with EtOAc (3 x 10.0 mL). The combined organic layer was washed with brine (3 x 10.0 mL) and concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 100: 1 to 20: 1, Rf = 0.30 (Petroleum ether: EtOAc = 8: 1)) to give the title compound (50.0 mg, 186 μmol, 3.62% yield, 99.0% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.64 - 7.55 (m, 3H), 7.53 - 7.45 (m, 2H), 4.61 - 4.49 (m, 1H), 1.45 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 266.0 (M+H)+, (C11H12N3Br). [1460] B.3-(5-(1-Isopropyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 4-bromo-1-isopropyl-5-phenyl-triazole (50.0 mg, 187 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (173 mg, 469 μmol, 2.50 eq), Ru-Phos-Pd-G3 (31.4 mg, 37.5 μmol, 0.20 eq) and K3PO4 (119 mg, 563 μmol, 3.00 eq). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: EtOAc = 1: 1, Rf = 0.55) and then by preparative- HPLC (using a CD24-XPT C18 (150 mm x 25 mm 7 μm) and gradient of 22-52% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25.0 mL/min) to give the title compound (32.55 mg, 75.7 μmol, 40.3% yield, >99% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.69 (s, 1H), 7.65 - 7.58 (m, 4H), 7.51 - 7.45 (m, 3H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.45 - 4.22 (m, 3H), 2.95 - 2.85 (m, 1H), 2.62 - 2.55 (m, 1H), 2.42 - 2.32 (m, 1H), 2.02 - 1.95 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H). (ESI+) m/z: 430.0 (M+H)+, (C24H23O3N5). 504 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 432 [1461] Synthesis of 3-(5-(1-Methyl-5-(pyridin-2-yl)-2-(trifluoromethyl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1462] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(pyridin-2-yl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：To a solution of tert-butyl 5- amino-4-(5-(5-bromo-1-methyl-2-(trifluoromethyl)imidazol-4-yl)-1-oxo-isoindolin-2-yl)-5- oxo-pentanoate (200 mg, 366 μmol, 1.00 eq) in H2O (0.20 mL) and dioxane (2.00 mL) was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (225 mg, 1.10 mmol, 3.00 eq), RuPhos Pd G3 (30.6 mg, 36.6 μmol, 0.10 eq) and K3PO4 (155 mg, 733 μmol, 2.00 eq) under N2. The mixture was stirred at 100 °C for 2 h. The mixture was poured into H2O (20.0 mL) and extracted with EA (3 x 20.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1, Rf = 0.2) to give the title compound (100 mg, 183 μmol, 49.9% yield, 99.5% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 544.1 (M+H)+ (C27H28F3N5O4). [1463] B.5-Cyclohexyl-1-methyl-1H-1,2,3-triazole: A solution of tert-butyl 5-amino-4- [5-[1-methyl-5-(2-pyridyl)-2-(trifluoromethyl)imidazol-4-yl]-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (100 mg, 183 μmol, 1.00 eq) in ACN (1.00 mL) was added TsOH (126 mg, 735 μmol, 4.00 eq). The mixture was stirred at 80 °C for 2 h. The mixture was poured into H2O (10.0mL) and extracted with EA (3 x 20.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by Preparative-HPLC (using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradiente of 6%-36% acetonitrile in water containing 0.1% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (25.1 mg, 50.3 μmol, 27.3% yield, 92.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.41 – 8.39 (m, 1H), 8.12 (s, 1H), 8.08 – 8.06 (m, 1H), 7.84 – 7.82 (m, 1H), 7.79 – 7.75 (m, 1H), 7.67 – 7.65 (m, 1H), 7.47 – 7.44 (m, 1H), 5.18 – 5.09 (m, 1H), 505 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 4.56 – 4.38 (m, 2H), 3.81 (s, 3H), 2.93 – 2.88 (m, 1H), 2.63 – 2.62 (m, 1H), 2.43 – 2.38 (m, 1H), 2.06 – 2.00 (m, 1H), (ESI+) m/z: 470.1 (M+H)+ (C23H18F3N5O3). EXAMPLE 433 [1464] Synthesis of 3-(5-(5-(4-Aminophenyl)-2-methyl-1-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1465] A. tert-Butyl (4-(1H-imidazol-5-yl)phenyl)carbamate：To a solution of 4-iodo- 1H-imidazole (5.00 g, 25.7 mmol, 1.00 eq) in EtOH (200 mL) was added ((4-((tert- butoxycarbonyl)amino)phenyl)boronic acid (7.33 g, 30.9 mmol, 1.20 eq), K2CO3 (10.6 g, 77.3 mmol, 3.00 eq) and Pd(dppf)Cl2 (1.89 g, 2.58 mmol, 0.10 eq) under N2. The mxture was stirred at 100 °C for 16 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 500: 1 to 0: 1, Petroleum ether: Ethyl acetate = 0: 1, Rf = 0.24) to give the title compound (3.60 g, 18.8 mmol, 52.2% yield, 99.6% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.28 (s, 1H), 7.65 - 7.61 (m, 3H), 7.46 - 7.41 (m, 3H), 1.47 (s, 9H). (ESI+) m/z: 260.0 (M+H)+, (C14H17O2N3). [1466] B. tert-Butyl (4-(1-(difluoroiodomethyl)-2-iodo-1H-imidazol-5- yl)phenyl)carbamate：To a solution of tert-butyl (4-(1H-imidazol-5-yl)phenyl)carbamate (1.50 g, 5.78 mmol, 1.00 eq) and CF3I (22.6 g, 28.9 mmol, 25% purity, 5.00 eq) in THF (15.0 mL) was added LiHMDS (1 M, 8.68 mL, 1.50 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. Then the mixture was cooled down to 0 °C and LiHMDS (1 M, 5.78 mL, 1.00 eq) was added. The mixture was stirred at 25 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl solution (100 mL), and then diluted with H2O (50.0 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 500: 1 to 100: 1, 506 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.40) to give the title compound (370 mg, 624 μmol, 10.8% yield, 94.7% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 1.48 (s, 9H). (ESI+) m/z: 561.8 (M+H)+, (C15H15F2I2N3O2). [1467] C.4-(2-Iodo-1-(trifluoromethyl)-1H-imidazol-5-yl)aniline：To a solution of tert- butyl (4-(1-(difluoroiodomethyl)-2-iodo-1H-imidazol-5-yl)phenyl)carbamate (270 mg, 481 μmol, 1.00 eq) in DCM (4.00 mL) was added AgBF4 (187 mg, 962 μmol, 2.00 eq) under N2. The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title compound (150 mg, 406 μmol, 84.4% yield, 95.6% purity) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 7.00 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.58 (d, J = 8.0 Hz, 2H), 5.44 (s, 2H). (ESI+) m/z: 353.8 (M+H)+, (C10H7F3N3I). [1468] D.4-(2-Methyl-1-(trifluoromethyl)-1H-imidazol-5-yl)aniline：To a solution of 4-(2-iodo-1-(trifluoromethyl)-1H-imidazol-5-yl)aniline (240 mg, 679 μmol, 1.00 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (170 mg, 1.36 mmol, 190 μL, 2.00 eq), Cs2CO3 (442 mg, 1.36 mmol, 2.00 eq) and Pd(dppf)Cl2 (49.7 mg, 67.9 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.25) to give the title compound (50.0 mg, 198 μmol, 29.2% yield, 95.9% purity) as yellow oil.1H NMR: (400 MHz, CD3OD) δ 7.08 (d, J = 8.4 Hz, 2H), 6.75 - 6.71 (m, 3H), 2.57 - 2.55 (m, 3H). (ESI+) m/z: 241.9 (M+H)+, (C11H10F3N3). [1469] E. tert-Butyl (4-(2-methyl-1-(trifluoromethyl)-1H-imidazol-5- yl)phenyl)carbamate：To a solution of 4-(2-methyl-1-(trifluoromethyl)-1H-imidazol-5- yl)aniline (30.0 mg, 118 μmol, 1.00 eq) in THF (2.00 mL) was added Boc2O (51.5 mg, 236 μmol, 54.2 μL, 2.00 eq) and DIEA (15.2 mg, 118 μmol, 20.5 μL, 1.00 eq) under N2. The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was poured into H2O (5.00 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layer was washed with brine (3 x 10.0 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative- TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1,Rf = 0.43) to give the title compound (25.0 507 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mg, 73.2 μmol, 58.9% yield, 90.2% purity) as yellow oil. (ESI+) m/z: 342.0 (M+H)+, (C16H18F3N3O2). [1470] F. tert-Butyl (4-(4-bromo-2-methyl-1-(trifluoromethyl)-1H-imidazol-5- yl)phenyl)carbamate：To a solution of tert-butyl (4-(2-methyl-1-(trifluoromethyl)-1H- imidazol-5-yl)phenyl)carbamate (25.0 mg, 73.2 μmol, 1.00 eq) in ACN (0.50 mL) was added a solution of NBS (13.0 mg, 73.2 μmol, 1.00 eq) in ACN (0.50 mL). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was poured into H2O (5.00 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layer was washed with brine (3 x 10.0 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.43) to give the title compound (20.0 mg, 45.83 μmol, 62.5% yield, 96.3% purity) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 9.59 (s,1H), 7.56 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 2.52 (s, 3H), 1.48 (s, 9H). (ESI+) m/z: 421.9 (M+H)+, (C16H17F3N3BrO2). [1471] G. tert-Butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2-methyl- 1-(trifluoromethyl)-1H-imidazol-5-yl)phenyl)carbamate：To a solution of tert-butyl (4- (4-bromo-2-methyl-1-(trifluoromethyl)-1H-imidazol-5-yl)phenyl)carbamate (20.0 mg, 47.5 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.05 mL) was added 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (26.4 mg, 71.3 μmol, 1.50 eq), K3PO4 (20.2 mg, 95.1 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (7.96 mg, 9.52 μmol, 0.20 eq) under N2. The mixture was stirred at 100 °C for 2 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The product was purified by preparative-HPLC (using a CD01- Phenomenex luna C18150 mm x 25 mm x 10 um) and gradient of 35-65% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25.0 mL/min) to give the title compound (20.0 mg, 34.2 μmol, 72.0% yield, 100% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.65 (s, 1H), 7.61 - 7.59 (m, 3H), 7.56 - 7.54 (m, 1H), 7.39- 7.37 (m, 1H), 7.32 - 7.30 (m, 2H), 5.09 - 5.04 (m, 1H), 4.39 - 4.18 (m, 2H), 2.90 - 2.88 (m, 1H), 2.60 (s, 3H), 2.38 - 2.34 (m, 2H), 1.98 - 1.96 (m, 1H), 1.46 (s, 9H). (ESI+) m/z: 584.1 (M+H)+, (C29H28N5O5F3). [1472] H.3-(5-(5-(4-Aminophenyl)-2-methyl-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione：To a solution of tert-butyl (4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2-methyl-1-(trifluoromethyl)-1H-imidazol-5- 508 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT yl)phenyl)carbamate (20.0 mg, 34.2 μmol, 1.00 eq) in HCl/dioxane (5.00 mL) .The mixture was stirred at 25°C for 4 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The product was pre-purified by preparative-HPLC (using a CD06-Waters Xbidge C18 (150 mm x 40 mm 10 μm) and gradient of 10 - 40% acetonitrile in water containing 0.5% HCl over 11 min at a flow rate of 25.0 mL/min) to give the title compound (8.05 mg, 15.4 μmol, 45.1% yield, 100% purity in HPLC at 220 nm, HCl) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.65 (s, 1H), 7.61 – 7.59 (m, 3H), 7.56 – 7.54 (m, 1H), 7.39 – 7.37 (m, 1H), 7.32 – 7.30 (m, 2H), 5.09 – 5.04 (m, 1H), 4.39 – 4.18 (m, 2H), 2.90 – 2.88 (m, 1H), 2.60 (s, 3H), 2.38 – 2.34 (m, 2H), 1.98 – 1.96 (m, 1H). (ESI+) m/z: 484.0 (M+H)+, (C24H21N5O3F3Cl). EXAMPLE 434 [1473] Synthesis of 3-(5-(5-Methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1474] A.5-Methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazole: To a solution of 5- methyl-1-phenyl-imidazole (160 mg, 1.01 mmol, 1.00 eq) in ACN (6.00 mL) was added 3,3- dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (400 mg, 1.21 mmol, 1.20 eq) under N2. The mixture was stirred at 80 °C for 90 h Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10: 1 to 3: 1, Rf = 0.4) to give the title compound (100 mg, 441 μmol, 21.7% yield) as a yellow solid. (ESI+) m/z: 227 (M+H)+, (C11H9F3N2). [1475] B.2-Bromo-5-methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazole: To a solution of 5-methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazole (0.10 g, 442 μmol, 1.00 eq) in THF (2.00 mL) was added 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (114 mg, 442 μmol, 1.00 eq) 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (229 mg, 884 μmol, 2.00 eq) n-BuLi (56.6 mg, 884 μmol, 2.00 eq) at -78°C, The mixture was stirred at 25 °C for 4 h under N2, Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1, Rf = 0.4) to give the title compound (70.0 mg, 228 μmol, 51.5% yield, 99.4% purity) as a yellow solid. (ESI+) m/z: 304.7 (M+H)+, (C11H8N2F3Br). 509 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1476] C.3-(5-(5-Methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-5-methyl-1-phenyl-4- (trifluoromethyl)imidazole (35 mg, 114.72 μmol, 1 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (106 mg, 286 μmol, 2.50 eq) and K3PO4 (73.0 mg, 344 μmol, 3.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) were added Ru-Phos-Pd-G3 (9.59 mg, 11.4 μmol, 0.10 eq) under N2. Then the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduce pressure to get residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 40 mm x 10 μm and gradiente of 25%-58% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 25 mL/min) to give the title compound (30.0 mg, 64.0μmol l, 27.9% yield,) as a yellow solid. (C24H19O3N4F3). [1477] D.3-(5-(5-Methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-methyl-1-phenyl-4- (trifluoromethyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 64.0 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 320 μL, 10.0 eq) . Then the mixture was stirred at 25 °C for 4 h. The reaction mixture was under reduce pressure to give the title compound (21.9 mg, 43.5 μmol, 67.9% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H) 7.59 - 7.47 (m, 5H), 7.45 (d, J = 8.00 Hz, 1.H), 7.31 (d, J = 4.00 Hz, 1.H), 5.10 - 5.07 (m 1H) 4.41 - 4.22 (m, 2H) 2.92 - 2.86 (m, 1H) 2.61 - 2.56 ( m, 1H), 2.17 ( s, 1H) 2.33 - 2.42 (m, 1H) 1.92 - 2.03 (m, 1H) (ESI+) m/z: 468.9 (M+H)+, (C24H19O3N4F3). EXAMPLE 435 [1478] Synthesis of 3-(5-(5-(4-Aminophenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1479] A. tert-Butyl 5-amino-4-(5-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (500 mg, 1.25 mmol, 1.00 eq) and tert-butyl (4-bromophenyl)carbamate (1.02 510 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT g, 3.76 mmol, 3.00 eq) and tetrabutylammonium acetate (1.51 g, 5.01 mmol, 4.00 eq) in NMP (10.0 mL) was added Pd(PPh3)2Cl2 (87.8 mg, 125μmol, 0.10 eq) under N2. The mixture was stirred at 120 °C for 4 h under N2. The mixture was poured into aturated H2O aqeous (50.0 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with saturated NaCl aqeous (3 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative - HPLC (using a CD18-Welch Utimate C18 (150 *40 mm *7 um) and gradient of 32.0% - 62.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (110 mg, 175 μmol, 14.0% yield, 94.5% purity in LCMS at 220 nm) as yellow solid. (ESI+) m/z: 591.0 (M+H)+, (C31H38N6O6). [1480] B.3-(5-(5-(4-Aminophenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-((tert- butoxycarbonyl)amino)phenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (110 mg, 186 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (64.1 mg, 372 μmol, 2.00 eq). The mixture was stirred at 80 °C for 20 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 6.0% - 36.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (16.5 mg, 39.2 μmol, 21.0% yield, 98.8% purity in HPLC at 220 nm) was obtained as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.78 (s, 1H), 7.66 - 7.64 (m, 1H), 7.57 - 7.55 (m, 1H), 7.14 – 7.12 (m, 2H), 6.78 – 6.76 (m, 2H), 5.12 - 5.07 (m, 1H), 4.45 - 4.26 (m, 2H), 3.88 (s, 3H), 2.94 - 2.87 (m, 1H), 2.60 - 2.56 (m, 1H), 2.39 - 2.35 (m, 1H), 2.00 – 1.97 (m, 1H). (ESI+) m/z: 416.8.(M+H)+, (C22H20N6O3). EXAMPLE 436 [1481] Synthesis of 3-(1-Oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: 511 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1482] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(m-tolyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of 4-bromo-5-phenyl-1H-1,2,3-triazole (2.00 g, 8.93 mmol, 1.00 eq), 2-bromo-1,1,1-trifluoroethane (7.50 g, 35.7 mmol, 3.50 mL, 4.00 eq) and K2CO3 (2.47 g, 17.8 mmol, 2.00 eq) in DMF (20.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was poured into H2O (20.0 mL), extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with NaCl (2 x 10.0 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 50: 1; TLC, Petroleum ether: Ethyl acetate = 8: 1, Rf = 0.25) to give the title compound (65.0 mg, 212 μmol, 2.38% yield) as a white oil.1H NMR: (400 MHz, DMSO-d6) δ 7.60 - 7.55 (m, 3H), 7.54 - 7.52 (m, 2H), 5.47 - 5.40 (m, 2H). (ESI+) m/z: 308.6 (M+H)+, (C10H7BrF3N3). [1483] B.3-(1-Oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione：A mixture of 4-bromo-5-phenyl-1-(2,2,2- trifluoroethyl)-1H-1,2,3-triazole (65.0 mg, 212 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (165 mg, 424 μmol, 2.00 eq), Ru-Phos-Pd-G3 (17.7 mg, 21.2 μmol, 0.10 eq) and K3PO4 (90.1 mg, 424 μmol, 2.00 eq) in dioxane (3.00 mL) and H2O (0.15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 15: 1, Rf = 0.50) and preparative-HPLC (using a CD24- XPT C18 (150 x 25 x 7 μm) and gradient of 21 - 51% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (35.2 mg, 74.8 μmol, 35.5% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.50 - 7.45 (m, 3H), 5.34 - 5.28 (m, 2H), 5.11 - 5.07 (m, 1H), 4.45 - 4.26 (m, 2H), 2.91 - 2.88 (m, 1H), 2.61 - 2.55 (m, 1H), 2.39 - 2.34 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 470.1 (M+H)+, (C23H18F3N5O3). 512 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 437 [1484] Synthesis of 3-(5-(5-Cyclohexyl-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: [1485] A.5-(Cyclohex-1-en-1-yl)-1-methyl-1H-1,2,3-triazole：To a solution of 5-bromo- 1-methyl-triazole (500 mg, 3.09 mmol, 1.00 eq) in dioxane (5.00 mL) and H2O (1.00 mL) was added cyclohexen-1-ylboronic acid (583 mg, 4.63 mmol, 1.50 eq) and K3PO4 (1.31 g, 6.17 mmol, 2.00 eq), XPhos Pd G3 (261 mg, 308 μmol, 0.10 eq) under N2. The mixture was stirred at 80°C for 12h under N2. The mixture was poured into H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10: 1 to 2: 1,Rf = 0.25) to give the title compound (450 mg, 2.58 mmol, 83.5% yield, 93.5% purity in LCMS at 220 nm) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 6.11 - 6.09 (m, 1H), 3.98 (s, 3H), 2.27 - 2.24 (m, 2H), 2.20 - 2.17 (m, 2H), 1.71 - 1.68 (m, 2H), 1.64 - 1.59 (m, 2H). (ESI+) m/z: 164.2 (M+H)+ (C9H13N3). [1486] B.5-Cyclohexyl-1-methyl-1H-1,2,3-triazole: To a solution of Pd/C (400 mg, 375 μmol, 10.0% purity, 1.53e-1 eq) in THF (4.00 mL) and EtOH (4.00 mL) was added 5- (cyclohexen-1-yl)-1-methyl-triazole (400 mg, 2.45 mmol, 1.00 eq). The mixture was stirred at 25°C for 3h under H2 (4.94 mg, 2.45 mmol, 1.00 eq) (15 PSI). The mixture was filtered through celite and the filter cake was washed with DCM (100 mL). The combined filtrates were concentrated to obtain crude product at 40°C to give the title compound (380 mg, 2.12 mmol, 86.4% yield, 92.1% purity in LCMS at 220 nm) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 3.98 (s, 3H), 2.60 (s, 1H), 1.94 – 1.86(m, 4H), 1.79 – 1.76 (m, 1H), 1.43 – 1.37 (m, 4H), 1.30 – 1.26 (m, 1H). (ESI+) m/z: 166.1 (M+H)+ (C9H15N3). [1487] C.4-Bromo-5-cyclohexyl-1-methyl-1H-1,2,3-triazole: A solution of 5- cyclohexyl-1-methyl-triazole (380 mg, 2.30 mmol, 1.00 eq) in DMF (4.00 mL) was added NBS (573 mg, 3.22 mmol, 1.40 eq). The mixture was stirred at 25°C for 24h. The mixture was poured into H2O (20.0 mL) and extracted with EA (20.0 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under 513 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT reduced pressure to get a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3:1, Rf = 0.2) to give the title compound (500 mg, 2.00 mmol, 87.1% yield, 97.8% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 4.01 (s, 3H), 2.91 – 2.84 (m, 1H), 1.80 – 1.69 (m, 7H), 1.38 – 1.19 (m, 3H). (ESI+) m/z: 245.9 (M+H)+ (C9H14BrN3). [1488] D.3-(5-(5-Cyclohexyl-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To solution of 4-bromo-5-cyclohexyl-1-methyl-triazole (100 mg, 409 μmol, 1.00 eq) in dioxane (1.00 mL) and H2O (0.10 mL) was added 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (379 mg, 1.02 mmol, 2.5 eq) and K3PO4 (173 mg, 819 μmol, 2.00 eq), RuPhos Pd G3 (34.2 mg, 40.9 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h. The mixture was poured into H2O (20.0 mL) and extracted with EA (3 x 20.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1, Rf = 0.25). The residue was purified by Preparative-HPLC (using a CD01- Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradiente of 20%-50% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (25.2 mg, 61.6 μmol, 15.0% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 – 10.9 (m, 1H), 7.82 – 7.80 (m, 1H), 7.69 (s, 1H), 7.61 – 7.59 (m, 1H), 5.16 – 5.12 (m, 1H), 4.56 – 4.38 (m, 2H), 4.09 (s, 3H), 2.99 – 2.88 (m, 2H), 2.64 – 2.59 (m, 1H), 2.43 – 2.36 (m, 1H), 2.07 – 2.02 (m, 1H), 1.76 – 1.61 (m, 7H), 1.38 – 1.16 (m, 3H). (ESI+) m/z: 408.1 (M+H)+ (C22H25N5O3). EXAMPLE 438 [1489] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen: [1490] A. tert-Butyl 5-amino-4-(5-(5-(4-methoxyphenyl)-1,2-dimethyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5- bromo-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 407 514 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT μmol, 1.00 eq) and (4-methoxyphenyl)boronic acid (185 mg, 1.22 mmol, 3.00 eq) and K3PO4 (259 mg, 1.22 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (1.00 mL) was added Ru-Phos- Pd-G3 (34.0 mg, 40.7μmol, 0.10 eq) under N2. The mixture was stirred at 70 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give the title compound (140 mg, 229 μmol, 56.3% yield, 85.0% purity in LCMS at 220 nm) as yellow oil. (ESI+) m/z: 519.2 (M+H)+, (C29H34N4O5). [1491] B.3-(5-(5-(4-Methoxyphenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-methoxyphenyl)- 1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (140 mg, 269 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (92.7 mg, 539 μmol, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 7.0% - 37.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (70.0 mg, 153 μmol, 56.8% yield, 97.5% purity in HPLC at 220 nm) was obtained as white solid. (ESI+) m/z: 445.1 (M+H)+, (C25H24N4O4). [1492] C.3-(5-(5-(4-Methoxyphenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(5-(4-methoxyphenyl)- 1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70.0 mg, 157 μmol, 1.00 eq) in dioxane (5.00 mL) was added HCl/dioxane (2 M, 784 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (74.7 mg, 153 μmol, 97.2% yield, 98.6% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.73 - 7.69 (m, 1H), 7.62 (s, 1H), 7.45 - 7.37 (m, 3H), 7.14 - 7.12 (m, 2H), 5.12 - 5.07 (m, 1H), 4.44 - 4.26 (m, 2H), 3.83 (s, 3H), 3.49 (s, 3H), 2.90 - 2.87 (m, 1H), 2.72 (s, 3H), 2.61 - 2.56 (m, 1H), 2.40 - 2.37 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 445.2 (M+H)+, (C25H24N4O4). 515 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 439 [1493] Synthesis of 3-(5-(5-(3-Methoxyphenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1494] A. tert-Butyl 5-amino-4-(5-(5-(3-methoxyphenyl)-1,2-dimethyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of tert-butyl 5-amino-4-(5-(5- bromo-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 407 μmol, 1.00 eq), (3-methoxyphenyl)boronic acid (185 mg, 1.22 mmol, 3.00 eq), K3PO4 (172 mg, 814 μmol, 2.00 eq) and Pd(dtbpf)Cl2 (34.0 mg, 40.7 μmol, 0.10 eq) in dioxane (5.00 mL) and H2O (1.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 4 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.40). to give the title compound (140 mg, 267 μmol, 65.7% yield, 99.1% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 519.2 (M+H)+, (C29H34N4O5). [1495] B.3-(5-(5-(3-Methoxyphenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-[5-[5-(3-methoxyphenyl)- 1,2-dimethyl-imidazol-4-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (140 mg, 267 μmol, 1.00 eq) in ACN (3.00 mL) was added TsOH (92.1 mg, 535 μmol, 2.00 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 15: 1; TLC, Dichloromethane: Methanol = 15: 1, Rf = 0.30) and preparative-HPLC (using a CD24- XPT C18 (150 x 25 x 7 μm) and gradient of 6 - 36% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (40.0 mg, 89.9 μmol, 33.6% yield, 100% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 445.2 (M+H)+, (C25H24N4O4). [1496] C.3-(5-(5-(3-Methoxyphenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione hydrogen chloride：A solution of 3-[5-[5-(3-methoxyphenyl)- 1,2-dimethyl-imidazol-4-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (40.0 mg, 89.9 μmol, 516 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1.00 eq) and HCl/dioxane (2 M, 449 μL, 10.0 eq) in dioxane (2.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (27.93 mg, 57.2 μmol, 98.5% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.74 - 7.72 (m, 1H), 7.60 (s, 1H), 7.52 - 7.45 (m, 1H), 7.44 - 7.40 (m, 1H), 7.22 - 7.15 (m, 1H), 7.04 (s, 1H), 6.99 - 6.94 (m, 1H), 5.12 - 5.07 (m, 1H), 4.47 - 4.26 (m, 2H), 3.78 (s, 3H), 3.52 (s, 3H), 3.00 - 2.95 (m, 1H), 2.71 (s, 3H), 2.61 - 2.55 (m, 1H), 2.41 - 2.36 (m, 1H), 2.00 - 1.99 (m, 1H). (ESI+) m/z: 445.2 (M+H)+, (C25H24N4O4). EXAMPLE 440 [1497] Synthesis of 3-(5-(1-Cyclobutyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: [1498] A.4-Bromo-1-cyclobutyl-5-phenyl-1H-1,2,3-triazole: To a solution of 4-bromo- 5-phenyl-1H-1,2,3-triazole (200 mg, 893 μmol, 1.00 eq) in DMF (5.00 mL) was added bromocyclobutane (181 mg, 1.34 mmol, 126 μL, 1.50 eq) and K2CO3 (247 mg, 1.79 mmol, 2.00 eq). The mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.55) to give the tittle compound (40.0 mg, 144 μmol, 5.30% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.55 (m, 3H), 7.49 - 7.43 (m, 2H), 4.93 - 4.82 (m, 1H), 2.60 (dt, J = 2.4, 9.6 Hz, 2H), 2.38 - 2.30 (m, 2H), 1.87 - 1.77 (m, 2H). (C12H12BrN3). [1499] B.3-(5-(1-Cyclobutyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (: A mixture of 4-bromo-1-cyclobutyl-5-phenyl-1H-1,2,3-triazole (20.0 mg, 71.9 μmol, 1.0 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (66.6 mg, 180 μmol, 2.50 eq), RuPhos Pd G3 (6.01 mg, 7.19 μmol, 0.10 eq) and K3PO4 (30.5 mg, 144 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the mixture 517 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 30 - 60% acetonitrile in water containing 0.05% HCl over 10 min at a flow rate of 25 mL/min) to give the title compound (15.93 mg, 35.8 μmol, 23.8% yield, 99.26% purity in HPLC at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.48 (d, J = 8.0 Hz, 1H), 7.46 - 7.37 (m, 2H), 5.13 - 5.04 (m, 1H), 4.74 (t, J = 8.4 Hz, 1H), 4.48 - 4.21 (m, 2H), 2.93 - 2.84 (m, 1H), 2.64 - 2.58 (m, 2H), 2.41 - 2.25 (m, 4H), 2.04 - 1.92 (m, 1H), 1.89 - 1.73 (m, 2H). (ESI+) m/z: 442.1 (M+H)+, (C25H23N5O3). EXAMPLE 441 [1500] Synthesis of 3-(5-(5-(4-(2-Hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: [1501] A. tert-Butyl 5-amino-4-(5-(5-(4-(2-hydroxyethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 418 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.50 mL) was added (4-(2- hydroxyethyl)phenyl)boronic acid (104 mg, 628 μmol, 1.50 eq), Pd(dtbpf)Cl2 (27.3 mg, 41.9 μmol, 0.10 eq) and K3PO4 (266 mg, 1.26 mmol, 3.00 eq) under N2. The mixture was stirred at 65 °C for 16 h. After the reaction was completed, the reaction mixture was filtered and the filtrated was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.20) to give the title compound (150 mg, 277 μmol, 66.2% yield, 95.9% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 519.2 (M+H)+, (C29H34N4O5). [1502] B.3-(5-(5-(4-(2-Hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-(2- hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 518 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (150 mg, 277μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (191 mg, 1.11 mmol, 4.00 eq). The mixture was stirred at 80 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 0 - 30% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) and by preparative-HPLC (using a Xbidge BEH C18150 x 25 mm x 10 μm) and gradiente of 6 - 36% acetonitrile in water containing 0.05% NH4HCO3 over 11 min at a flow rate of 25 mL/min) to give the title compound (30.0 mg, 65.7 μmol, 23.7% yield, 97.4% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.83 (s, 1H), 7.63 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.10 - 5.04 (m, 1H), 4.69 (t, J = 5.2Hz, 1H), 4.38 - 4.18 (m, 2H), 3.71 - 3.65 (m, 2H), 3.46 (s, 3H), 2.95 - 2.85 (m, 1H), 2.81 (t, J = 6.8Hz, 2H), 2.60 - 2.54 (m, 1H), 2.39 - 2.32 (m, 1H), 1.99 - 1.92 (m, 1H). (ESI+) m/z: 445.1 (M+H)+, (C25H24N4O4). [1503] C.3-(5-(5-(4-(2-Hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: To a solution of 3-(5-(5-(4-(2- hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 65.7 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 328 μL, 10.0 eq).The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (12.6 mg, 25.2 μmol, 38.4% yield, 96.3% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.11 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.45 - 7.37 (m, 5H), 5.13 - 5.07 (m, 1H), 4.44 - 4.25 (m, 2H), 3.69 - 3.65 (m, 5H), 2.95 - 2.86 (m, 1H), 2.81 (t, J = 6.8 Hz, 2H), 2.62 - 2.56 (m, 1H), 2.41 - 2.36 (m, 1H), 2.03 - 1.98 (m, 1H). (ESI+) m/z: 445.1 (M+H)+, (C25H25N4O4Cl). EXAMPLE 442 [1504] Synthesis of 3-(1-Oxo-5-(1-phenyl-5-(trifluoromethyl)-1H-imidazol-2- yl)isoindolin-2-yl)piperidine-2,6-dione: 519 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1505] A. 5-Methyl-1-phenyl-4-(trifluoromethyl)-1H-imidazole: To a solution of bis(trifluoromethylsulfonyloxy)copper (273 mg, 757 μmol, 0.05 eq) and 1- methylbenzimidazole (400 mg, 3.03 mmol, 0.20 eq) in HFIP (50.0 mL) was added Cs2CO3 (7.40 g, 22.7 mmol, 1.50 eq) . The mixture was stirred at 25 °C for 0.5 h and then was added (1H-imidazol-5-yl)(phenyl)-l3-iodaneyl acetate (5.00 g,15.1 mmol, 1.00 eq) . The mixture was stirred at 50 °C for 16 h. Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 3: 1, Rf = 0.4) to give the title compound (1.5 g, crude) as a yellow solid. (C9H7IN2). [1506] B. 1-Phenyl-5-(trifluoromethyl)-1H-imidazole: To a solution of 5-iodo-1-phenyl- imidazole (300 mg, 1.11 mmol, 1.00 eq) and [Ph2SCF3]+[OTf]-, (898 mg, 2.22 mmol, 2.00 eq) in DMF (3.00 mL) was added Cu (211 mg, 3.33 mmol, 23.6 μL, 3.00 eq) . The mxiture was stiired at 80 °C for 1 h. Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 20: 1, Rf = 0.4) to give the title compound (0.11 g, 10.9 mmol, 46.8% yield) as a yellow solid. (C11H9N2F3). [1507] C.2-Bromo-1-phenyl-5-(trifluoromethyl)-1H-imidazole: To a solution of 1- phenyl-5-(trifluoromethyl)-1H-imidazole (0.10 g, 442 μmol, 1.00 eq) in THF (2 mL) was added 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (114 mg, 442 μmol, 1.00 eq) 1,2-dibromo- 1,1,2,2-tetrafluoro-ethane (229 mg, 884 μmol, 2.00 eq) n-BuLi (56.6 mg, 884 μmol, 2.00 eq) at -78°C,The mixture was stirred at 25 °C for 4 h under N2, Celite was added the mixture and concentrated to give a solid. The solid was purified by prep column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100: 1 to 20: 1, Rf = 0.4) to give the title compound (30.0 mg, 103 μmol, 21.8% yield, 100% purity) as a yellow solid. (ESI+) m/z: 290.9 (M+H)+, (C10H6N2F3Br). [1508] D.3-(1-Oxo-5-(1-phenyl-5-(trifluoromethyl)-1H-imidazol-2-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1-phenyl-5-(trifluoromethyl)imidazole (30.0 mg, 103 μmol, 1.00 eq) in dioxane (1.00 mL) H2O (0.05 mL) was added 3-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (45.7 mg, 123 μmol, 1.20 eq) K3PO4 (43.7 mg, 206 μmol, 2 eq) RuPhos Pd G3 (8.62 mg, 10.3 μmol, 0.10 eq), The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was quenched with H2O (10.0 mL) and extracted with dichloromethane (3 x 10.0 mL). The residue was purified by preparative -TLC (SiO2, dichloromethane: methanol = 10: 1, Rf = 520 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 0.4). The mixture was purified by preparative -HPLC (using a Welch Xtimate C18150 x 40 mm x 10 μm and gradiente of 26%-56% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (0.02 g, 43.7 μmol, 42.4% yield, 99.5% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 455.0 (M+H)+, (C23H17O3N4F3). [1509] E.3-(1-Oxo-5-(1-phenyl-5-(trifluoromethyl)-1H-imidazol-2-yl)isoindolin-2- yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(1-phenyl-5-(trifluoromethyl)-1H- imidazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione (20.0 mg, 43.7 μmol, 1.00 eq) in was added HCl/dioxane (2 M, 218 μL, 10.0 eq) , The mixture was stirred at 25 °C for 4 h. The mixture was quenched by addition NH4Cl aq and washed with Ethyl acetate (20.0 mL), The mixture was concentrated to give the title compound (12.2 mg, 24.4 μmol, 55.7% yield, 98.2% purity in HPLC at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1 H) 7.89 (d, J=1.00 Hz, 1H) 7.64 (s, 1H), 7.61 (d, J=8.00 Hz, 1H), 7.48 - 7.58 (m, 5H), 7.43 - 7.39 (m, 1H), 5.10 - 5.08 (m, 1H), 4.17 - 4.46 (m, 2H), 2.83 - 2.95 (m, 1H), 2.60 ( s, 1H), 2.33 - 2.42 (m, 1H), 1.92 - 2.03 (m, 1H) (ESI+) m/z: 455.1 (M+H)+, (C23H17O3N4F3). EXAMPLE 443 [1510] Synthesis of 3-(5-(5-(4-Aminophenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1511] A. tert-Butyl 5-amino-4-(5-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1,2- dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert- butyl 5-amino-4-(5-(5-bromo-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (400 mg, 814 μmol, 1.00 eq) , (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (578 mg, 2.44 mmol, 3.00 eq) and K3PO4 (518 mg, 2.44 mmol, 3.00 eq) in dioxane (10.0 mL) and H2O (2.00 mL) was added Pd(dtbpf)Cl2 (53.0 mg, 81.4μmol, 0.10 eq) under N2. The mixture was stirred at 70 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give the title compound (400 mg, 530 521 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT μmol, 65.1% yield, 80.0% purity in LCMS at 220 nm) as yellow oil. (ESI+) m/z: 604.2 (M+H)+, (C33H41N5O6). [1512] B.3-(5-(5-(4-Aminophenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-((tert- butoxycarbonyl)amino)phenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (400 mg, 662 μmol, 1.00 eq) in ACN (10.0 mL) was added TsOH (342 mg, 1.99 mmol, 3.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD06-Waters Xbidge C18 (150 *40 mm *10 um) and gradient of 6.0% - 36.0% acetonitrile in water containing 0.05% NH4HCO3 over 10 min at a flow rate of 25 mL/min to give the title compound (110 mg, 250 μmol, 37.8% yield, 97.9% purity in HPLC at 220 nm) was obtained as white solid. (ESI+) m/z: 430.1 (M+H)+, (C24H23N5O3). [1513] C.3-(5-(5-(4-Aminophenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(5-(4-aminophenyl)-1,2- dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (110 mg, 256 μmol, 1.00 eq) in dioxane (3.00 mL) was added HCl/dioxane (2 M, 1.28 mL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (64.9 mg, 136 μmol, 53.1% yield, 97.7% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.73 - 7.70 (m, 2H), 7.48 - 7.46 (m, 1H), 7.29 - 7.27 (m, 2H), 7.10 - 7.07 (m, 2H), 5.12 - 5.08 (m, 1H), 4.45 - 4.26 (m, 2H), 3.50 (s, 3H), 2.93 - 2.90 (m, 1H), 2.74 (s, 3H), 2.60 - 2.56 (m, 1H), 2.41 - 2.37 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 430.1 (M+H)+, (C24H23N5O3). EXAMPLE 444 [1514] Synthesis of 3-(5-(5-(3-Methoxyphenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1515] A.3-(5-(5-(3-Methoxyphenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(1-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione (0.10 g, 169 μmol, 1.00 eq) in 522 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT NMP (2.00 mL) was added 1-iodo-3-methoxybenzene (118 mg, 507 μmol, 60.4 μL, 3.00 eq) ,tetrabutylammonium;acetate (204 mg, 677 μmol, 206 μL, 4 eq)， Pd(OAc)2 (3.80 mg, 16.9 μmol, 0.10 eq), then the mixture was stirred at 80 °C for 16 h under N2. The mixture was filtrated to give a filtrate. The filtrate was added H2O (20mL).The mixture was extracted with Dichloromethane: methyl alcohol =15:1 (3 x 15 mL).The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: methyl alcohol =20:1, Rf = 0.4). The mixture was purified by prep-HPLC ((using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 29 - 59% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 25 mL/min) to give the title compound (22.26 mg, 45.86 μmol, 27.8% yield, 98.5% purity in LCMS at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ10.94 - 11.07 (m, 1 H), 7.79 (s, 1 H), 7.74 - 7.69 (m, 1 H), 7.48 - 7.56 (m, 2 H), 7.18 - 7.25 (m, 2 H), 7.16 - 7.10 (m, 1 H), 5.05 - 5.16 (m, 1 H), 4.27 - 4.49 (m, 2 H), 3.77 (s, 3 H), 2.86 - 2.95 (m, 1 H), 2.64 - 2.60 (m, 1 H), 2.36 - 2.43 (m, 1 H), 1.94 - 2.05 (m, 1 H). (ESI+) m/z: 379.9 (M+H)+, (C23H18F3N5O4). EXAMPLE 445 [1516] Synthesis of 3-(5-(1-(3-Aminophenyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride: [1517] A. tert-Butyl (3-(2-bromo-1H-imidazol-1-yl)phenyl)carbamate: To a mixture of 2-bromo-1H-imidazole (500 mg, 3.40 mmol, 1.00 eq) in DCE (5.00 mL) was added (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid (2.02 g, 8.50 mmol, 2.50 eq), Cu(OAc)2 (617 mg, 3.40 mmol, 1.00 eq), Na2CO3 (1.08 g, 10.2 mmol, 3.00 eq) and 2-(2-pyridyl)pyridine (1.59 g, 10.2 mmol, 3.00 eq) under O2. The mixture was stirred at 70 °C for 10 h under O2 atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500: 1 to 50: 1, Rf = 0.40 (TLC: Dichloromethane: Methanol = 10: 1)) to give the title compound (600 mg, 1.74 mmol, 51.1% yield, 98% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.39 - 523 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 7.33 (m, 2H), 7.15 - 7.12 (m, 2H), 7.04 - 7.02 (m, 1H) 6.72 (s, 1H),1.53 (s, 9H). (ESI+) m/z: 337.9 (M+H)+, (C14H16BrN3O2). [1518] B. tert-Butyl (3-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- imidazol-1-yl)phenyl)carbamate: To a mixture of tert-butyl (3-(2-bromo-1H-imidazol-1- yl)phenyl)carbamate (300 mg, 887 μmol, 1.00 eq) in dioxane (6.00 mL) and H2O (0.30 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (656 mg, 1.77 mmol, 2.00 eq), K3PO4 (376 mg, 1.77 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (74.1 mg, 88.7 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 500: 1 to 50: 1, Rf = 0.36 (TLC: Dichloromethane: Methanol = 10: 1)) to give the title compound (250 mg, 473 μmol, 53.3% yield, 95% purity) as a brown solid. (ESI+) m/z: 502.2 (M+H)+, (C27H27O5N5). [1519] C.3-(5-(1-(3-Aminophenyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione hydrochloride: To a mixture of tert-butyl (3-(2-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-imidazol-1-yl)phenyl)carbamate (150 mg, 299 μmol, 1.00 eq) in dioxane (5.00 mL) was added HCl/dioxane (2.0 M, 2.99 mL, 20.0 eq) .The mixture was stirred at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue. The product was pre-purified by preparative-HPLC (using a CD02-Waters Xbidge C18 (150 mm x 40 mm 10 μm) and gradient of 0 - 22% acetonitrile in water containing 0.5% HCl over 11 min at a flow rate of 25.0 mL/min) to give the title compound (26.30 mg, 64.2 μmol, 21.4% yield, 98.0% purity) in HPLC at 220 nm, HCl) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.19 - 7.15 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 6.56 (d, J = 7.2 Hz, 1H), 5.15 - 5.10 (m, 1H), 4.50 - 4.32 (m, 2H), 2.96 - 2.90 (m, 1H), 2.61 - 2.57 (m, 1H), 2.42 - 2.38 (m, 1H), 2.04 - 2.02 (m, 1H). (ESI+) m/z: 402.0 (M+H)+, (C22H20O3N5Cl). 524 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 446 [1520] Synthesis of 3-(5-(5-(3-Acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: [1521] A. tert-Butyl 4-(5-(5-(3-acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate：To a mixture of tert-butyl 5-amino-4-(5-(5- bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 418 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.50 mL) was added 1-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one (206 mg, 837 μmol, 2.00 eq), K3PO4 (266 mg, 1.26 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (27.3 mg, 41.9 μmol, 0.10 eq) under N2. The mixture was stirred at 65 °C for 16 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.30) to give the title compound (180 mg, 319 μmol, 75.6% yield, 91.8% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 517.2 (M+H)+, (C29H32O5N4). [1522] B.3-(5-(5-(3-Acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a mixture of tert-butyl 4-(5-(5-(3-acetylphenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (100 mg, 193 μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (133 mg, 774 μmol, 4.00 eq) under N2. The mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, DCM: MeOH = 20: 1, Rf = 0.35) to give the title compound (20.0 mg, 45.2 μmol, 23.3% yield, 90% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 443.1 (M+H)+, (C25H22O4N4). [1523] C.3-(5-(5-(3-Acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride: A mixture of 3-(5-(5-(3-acetylphenyl)-1-methyl- 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20.0 mg, 45.2 μmol, 1.00 eq) in HCl/dioxane (2.00 mL) was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a CD02-Waters Xbidge BEH C18 (150 mm x 25 mm 10 μm) and gradient of 0 - 25% 525 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT acetonitrile in water containing 0.5% HCl over 11 min at a flow rate of 25.0 mL/min) to give the title compound (10.52 mg, 21.8 μmol, 48.3% yield, 99.41% purity in HPLC at 220 nm, HCl) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.99 - 8.85 (m, 1H), 8.18 - 8.10 (m, 1H), 8.07 (s, 1H), 7.76 - 7.69 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.45 - 4.22 (m, 2H), 3.64 (s, 3H), 2.95 - 2.85 (m, 1H), 2.60 (s, 3H), 2.56 (br, 1H), 2.43 - 2.34 (m, 1H), 2.03 - 1.94 (m, 1H) (ESI+) m/z: 443.1 (M+H)+, (C25H23O4N4Cl). EXAMPLE 447 [1524] Synthesis of 3-(5-(5-(4-Aminophenyl)-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1525] A. tert-Butyl (4-(1-(trifluoromethyl)-1H-imidazol-5-yl)phenyl)carbamate：To a mixture of tert-butyl tert-butyl (4-(2-iodo-1-(trifluoromethyl)-1H-imidazol-5- yl)phenyl)carbamate (200 mg, 441 μmol, 1.00 eq) in THF (2.00 mL) was added n-BuLi (2.5 M, 185 μL, 1.05 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. The mixture was poured into H2O (5.00 mL) and extracted with ethyl acetate (3 x 5.00 mL). The combined organic layers were washed with brine (3 x 5.00 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.43) to give the title compound (65.0 mg, 178 μmol, 40.5% yield, 90% purity) as a yellow solid. (ESI+) m/z: 327.9 (M+H)+, (C15H16F3N3O2). [1526] B. tert-Butyl (4-(4-bromo-1-(trifluoromethyl)-1H-imidazol-5- yl)phenyl)carbamate: To a mixture of tert-butyl (4-(1-(trifluoromethyl)-1H-imidazol-5- yl)phenyl)carbamate (65.0 mg, 198 μmol, 1.00 eq) in ACN (2.00 mL) was added NBS (35.3 mg, 198 μmol, 1.00 eq) .The mixture was stirred at 25 °C for 2 h. The mixture was poured into H2O (5.00 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 4: 1,Rf = 0.43) to give the title compound (33.0 mg, 81.2 526 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT μmol, 40.9% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.51 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 1.49 (s, 9H). (ESI+) m/z: 405.9 (M+H)+, (C15H15F3N3BrO2). [1527] C. tert-Butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1- (trifluoromethyl)-1H-imidazol-5-yl)phenyl)carbamate: To a mixture of tert-butyl (4-(4- bromo-1-(trifluoromethyl)-1H-imidazol-5-yl)phenyl)carbamate (30.0 mg, 73.8 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazoline (82.0 mg, 221 μmol, 3.00 eq), K3PO4 (31.3 mg, 147 μmol, 2.00 eq) and Ru-Phos-Pd-G3 (4.81 mg, 7.39 μmol,, 0.10 eq) under N2. The mixture was stirred at 60 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a CD01- Phenomenex luna C18 (150 mm x 25 mm 10 μm) and gradient of 36 - 66% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25.0 mL/min) to give the title compound (27.0 mg, 41.2 μmol, 55.8% yield, 98% purity) as a yellow solid. (ESI+) m/z: 570.2 (M+H)+, (C28H26O5N5F3). [1528] D. 3-(5-(5-(4-Aminophenyl)-1-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a mixture of tert-butyl (4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-(trifluoromethyl)-1H-imidazol-5- yl)phenyl)carbamate (27.0 mg, 47.4 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (2.5 M, 379 μL, 20.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The product was pre-purified by preparative-HPLC (using a CD06-Waters Xbidge C18 (150 mm x 40 mm 10 μm) and gradient of 8 - 38% acetonitrile in water containing 0.5% HCl over 11 min at a flow rate of 25.0 mL/min) to give the title compound (10.90 mg, 23.1 μmol, 48.7% yield, 99.6% purity in HPLC at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.41 (s,1H), 8.56 (s,1H), 7.69 (s,1H), 7.58 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.28 - 7.26 (m, 2H), 7.00 - 6.98 (m, 2H), 5.10 - 5.06 (m, 1H), 4.41 - 4.21 (m, 2H), 2.91 - 2.86 (m, 1H), 2.60 - 2.50 (m, 1H), 2.38 - 2.34 (m, 1H), 1.99 - 1.97 (m, 1H). (ESI+) m/z: 470.0 (M+H)+, (C23H20O3N5F3Cl2). 527 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 448 [1529] Synthesis of 3-(5-(5-(3-Aminophenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1530] A. tert-Butyl 5-amino-4-(5-(5-(3-((tert-butoxycarbonyl)amino)phenyl)-1,2- dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of tert- butyl 5-amino-4-(5-(5-bromo-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (400 mg, 814 μmol, 1.00 eq), (3-((tert-butoxycarbonyl)amino)phenyl)boronic acid (578 mg, 2.44 mmol, 3.00 eq), Pd(dtbpf)Cl2 (53.0 mg, 81.4 μmol, 0.10 eq) and K3PO4 (345 mg, 1.63 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (2.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 4 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.40). to give the title compound (400 mg, 579 μmol, 71.2% yield, 87.5% purity in LCMS at 220 nm) as a yellow oil. (ESI+) m/z: 604.3 (M+H)+, (C33H41N5O6). [1531] B.3-(5-(5-(3-Aminophenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of tert-butyl 5-amino-4-(5-(5-(3-((tert- butoxycarbonyl)amino)phenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (300 mg, 434 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (299 mg, 1.74 mmol, 4.00 eq). The mixture was stirred at 80 °C for 32 h. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by preparative-HPLC (using a CD02-Waters Xbidge BEH C18 (150 x 25 x 10 μm) and gradient of 9 - 39% acetonitrile in water containing 0.05% NH4HCO3 over 15 min at a flow rate of 25.0 mL/min) to give the title compound (80.0 mg, 186 μmol, 42.8% yield) as a white solid. (ESI+) m/z: 430.1 (M+H)+, (C24H23N5O3). [1532] C.3-(5-(5-(3-Aminophenyl)-1,2-dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrogen chloride：A solution of 3-(5-(5-(3-aminophenyl)-1,2- dimethyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80.0 mg, 186 μmol, 528 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1.00 eq) and HCl/dioxane (2 M, 931 μL, 10.0 eq) in dioxane (2.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (46.19 mg, 95.2 μmol, 96.1% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.74 - 7.70 (m, 1H), 7.67 (s, 1H), 7.54 - 7.50 (m, 1H), 7.48 - 7.46 (m, 1H), 7.33 - 7.30 (m, 1H), 7.20 - 7.15 (m, 2H), 5.12 - 5.07 (m, 1H), 4.47 - 4.27 (m, 2H), 3.52 (s, 3H), 2.91 - 2.86 (m, 1H), 2.76 (s, 3H), 2.60 - 2.55 (m, 1H), 2.41 - 2.36 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 430.1 (M+H)+, (C24H23N5O3). EXAMPLE 449 [1533] Synthesis of 3-(1-Oxo-5-(5-(m-tolyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [1534] A.3-(1-Oxo-5-(5-(m-tolyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(1-(trifluoromethyl)-1H-1,2,3-triazol- 4-yl)isoindolin-2-yl)piperidine-2,6-dione (0.10 g, 169 μmol, 1.00 eq) in NMP (2.00 mL) was added 1-iodo-3-methyl-benzene (110 mg, 507 μmol, 65.2 μL, 3.00 eq) ,tetrabutylammonium;acetate (204 mg, 677 μmol, 206 μL, 4.00 eq) Pd(OAc)2 (3.80 mg, 16.9 μmol, 0.10 eq) at 20 °C, then the mixture was stirred at 80 °C for 8 h under N2. The mixture was filtrated to give a filtrate. The filtrate was added H2O (20.0 mL). The mixture was extracted with Dichloromethane: methyl alcohol =15:1 (3 x 15 mL).The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: methyl alcohol = 20: 1, Rf = 0.8). The mixture was purified by prep-HPLC ((using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 32 - 62% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (18.8 mg, 40.0 μmol, 23.6% yield, 99.9% purity in HPLC at 220 nm) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ ppm 10.9 (s, 1H) 7.78 (s, 1H) 7.69 (d, J = 8.00 Hz, 1H) 7.44 - 7.53 (m, 3H) 7.35 - 7.42 (m, 2H) 5.13 - 5.09 (m, 1H) 4.22 - 4.51 (m, 2H) 2.84 - 2.96 (m, 1H) 2.61 (s, 1H) 2.35 - 2.43 (m, 4H) 1.93 - 2.05 (m, 1H). (ESI+) m/z: 470.1 (M+H)+, (C23H18F3N5O3). EXAMPLE 450 529 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1535] Synthesis of 3-(5-(5-(4-Methoxyphenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1536] A.3-(5-(5-(4-Methoxyphenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(1-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl) isoindolin-2-yl)piperidine-2,6-dione (0.10 g, 169 μmol, 1.00 eq) in NMP (2.00 mL) was added 1-iodo-4-methoxy-benzene (118 mg, 507 μmol, 3.00 eq) ,tetrabutylammonium;acetate (204 mg, 677 μmol, 206 μL, 4.00 eq) Pd(OAc)2 (3.80 mg, 16.9 μmol, 0.10 eq) at 20 °C, then the mixture was stirred at 80 °C for 8 h under N2. The mixture was filtrated to give a filtrate. The filtrate was added H2O (20.0mL).The mixture was extracted with Dichloromethane: methyl alcohol = 15: 1 (3 x 15 mL).The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: methyl alcohol = 20:1, Rf = 0.8).The mixture was purified by preparative-HPLC (using a Welch Xtimate C18 150 x 25 mm x 10 μm) and gradiente of 30 - 60% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 25 mL/min) to give the title compound (10.0 mg, 20.3 μmol, 12.0% yield, 98.5% purity in HPLC at 220 nm) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1 H) 7.77 (s, 1 H) 7.71 (d, J = 8.12 Hz, 1 H) 7.46 - 7.55 (m, 3 H) 7.14 (d, J = 8.76 Hz, 2 H) 5.10 (m, 1 H) 4.25 - 4.50 (m, 2 H) 3.84 (s, 3 H) 2.90 (m, 1 H) 2.61 (s, 1 H) 2.37 (m, 1 H) 1.93 - 2.05 (m, 1 H) (ESI+) m/z: 486.0 (M+H)+, (C23H18F3N5O4). EXAMPLE 451 [1537] Synthesis of 3-(5-(1-(3-Aminophenyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrogen chloride: 530 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1538] A. tert-Butyl (3-(4-bromo-1H-imidazol-1-yl)phenyl)carbamate: To a solution of 4-bromo-1H-imidazole (500 mg, 3.40 mmol, 1.00 eq), (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid (1.21 g, 5.10 mmol, 1.50 eq), K2CO3 (940 mg, 6.80 mmol, 2.00 eq) and 2-(2-pyridyl)pyridine (637 mg, 4.08 mmol, 1.20 eq) in dioxane (10.0 mL) was added Cu(OAc)2 (741 mg, 4.08 mmol, 1.20 eq).The mixture was stirred at 65 °C for 20 h under O2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 10: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.30) and by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 33.0% - 63.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (400 mg, 1.18 mmol, 34.5% yield, 99.5% purity in LCMS at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 1.20 Hz, 1H), 7.12 (s, 1H), 7.40 - 7.37 (m, 2H), 7.22 - 7.17 (m, 1H), 1.48 (s, 9H). (ESI+) m/z: 337.7 (M+H)+, (C14H16BrN3O2). [1539] B. tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- imidazol-1-yl)phenyl)carbamate: To a solution of tert-butyl (3-(4-bromo-1H-imidazol-1- yl)phenyl)carbamate (200 mg, 591 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (547 mg, 1.48 mmol, 2.50 eq) and K3PO4 (376 mg, 1.77 mmol, 3.00 eq) in dioxane (10.0 mL) and H2O (0.50 mL) was added Ru-Phos-Pd-G3 (49.4 mg, 59.1 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C.10 mL ACN was added to the reaction mixture and stirred at 25 °C for 15 min. The solid was precipitated, filtered, and dried under vacuum to give the title compound (200 mg, 272 μmol, 46.1% yield, 68.4% purity in LCMS at 220 nm) as yellow solid. (ESI+) m/z: 502.2 (M+H)+, (C27H27N5O5). [1540] C.3-(5-(1-(3-Aminophenyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione: To a solution of tert-butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)-1H-imidazol-1-yl)phenyl)carbamate (200 mg, 398 μmol, 1.00 eq) in dioxane (5.00 mL) was added HCl/dioxane (2 M, 1.21 mL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (14.84 mg, 33.6 μmol, 9.21% yield, 99.2% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.25 (s, 1H), 8.68 (s, 1H), 8.16 - 8.06 (m, 2H), 7.86 - 7.84 (m, 1H), 7.39 - 7.35 (m, 1H), 7.13 - 7.11 (m, 2H), 6.92 - 6.90 (m, 1H), 5.17 - 5.12 531 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (m, 1H), 4.57 - 4.39 (m, 2H), 2.96 - 2.90 (m, 1H), 2.63 - 2.59 (m, 1H), 2.43 - 2.39 (m, 1H), 2.04 - 2.01 (m, 1H). (ESI+) m/z: 402.0 (M+H)+, (C22H19N5O3). EXAMPLE 452 [1541] Synthesis of 3-(5-(1-(4-Aminophenyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride: [1542] A. tert-Butyl (4-(4-bromo-1H-imidazol-1-yl)phenyl)carbamate: To a solution of 4-bromo-1H-imidazole (500 mg, 3.40 mmol, 1.00 eq) and (4-((tert- butoxycarbonyl)amino)phenyl)boronic acid (1.21 g, 5.10 mmol, 1.50 eq) in dioxane (10.0 mL) was added Cu(OAc)2 (741 mg, 4.08 mmol, 1.20 eq), K2CO3 (940 mg, 6.80 mmol, 2.00 eq) and 2-(2-pyridyl)pyridine (637 mg, 4.08 mmol, 1.20 eq). The mixture was stirred at 60 °C for 12 h under O2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 0 to 1: 1; TLC, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.40) to give the title compound (300 mg, 871 μmol, 25.6% yield, 98.2% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.59 - 7.51 (m, 4H), 1.48 (s, 9H). (ESI+) m/z: 338.0 (M+H)+, (C14H16BrN3O2). [1543] B. tert-Butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- imidazol-1-yl)phenyl)carbamate: To a solution of tert-butyl (4-(4-bromo-1H-imidazol-1- yl)phenyl)carbamate (280 mg, 783 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (725 mg, 1.96 mmol, 2.50 eq) in dioxane (4.00 mL) and H2O (0.20 mL) was added Ru-Phos-Pd-G3 (65 mg, 78.3 μmol, 0.10 eq) and K3PO4 (332 mg, 1.56 mmol, 2.00 eq). The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatrography (SiO2, Dichloromethane: Methanol = 100: 0 to 20: 1; TLC, Dichloromethane: Methanol = 20: 1, Rf = 0.30) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 28 - 58% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 10 mL/min) to give the title compound (50.0 mg, 96.4 μmol, 12.2% yield, 95.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 532 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT MHz, DMSO-d6) δ 10.9 (s, 1H), 9.56 (s, 1H), 8.41 (s, 2H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.62 (s, 4H), 5.16 - 5.10 (m, 1H), 4.54 - 4.35 (m, 2H), 2.96 - 2.89 (m, 1H), 2.67 - 2.63 (m, 1H), 2.45 - 2.40 (m, 1H), 2.05 - 2.02 (m, 1H), 1.48 (s, 9H). (ESI+) m/z: 502.2 (M+H)+, (C27H27N5O5). [1544] C. 3-(5-(1-(4-Aminophenyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione hydrochloride: To a solution of tert-butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-imidazol-1-yl)phenyl)carbamate (50.0 mg, 95.4 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (2 M, 477 μL, 10.0 eq). The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (19.0 mg, 43.2 μmol, 45.2% yield, 99.5% purity in HPLC at 220 nm, 2HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.97 (s, 1H), 8.54 (s, 1H), 8.09 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.6 Hz, 2H), 5.17 - 5.12 (m, 1H), 4.57 - 4.38 (m, 2H), 2.97 - 2.92 (m, 1H), 2.65 - 2.63 (m, 1H), 2.43 - 2.38 (m, 1H), 2.05 - 2.02 (m, 1H). (ESI+) m/z: 402.1 (M+H)+, (C22H21N5O3Cl2). EXAMPLE 453 [1545] Synthesis of 3-(5-(5-(3-(2-Hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1546] A. tert-Butyl 5-amino-4-(5-(5-(3-(2-hydroxyethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.20 g, 418 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.5 mL) was added (3-(2- hydroxyethyl)phenyl)boronic acid (76.5 mg, 460 μmol, 1.10 eq) ditert-butyl(cyclopenta-1,4- dien-1-yl)phosphane;dichloropalladium;iron (27.3 mg, 41.9 μmol, 0.10 eq) K3PO4 (266 mg, 1.26 mmol, 3.00 eq) ,The mixture was stirred at 65 °C for 16 h under N2，The reaction mixture was quenched with H2O (10.0 mL) and extracted with CH2Cl2 (3 x 10.0 mL).The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Dichloromethane: 533 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT methyl alcohol = 20:1, Rf = 0.4). to give the title compound (0.15 g, 269 μmol, 64.3% yield, 93.2% purity in LCMS at 220 nm) as a off white solid. (ESI+) m/z: 470.0 (M+H)+, (C29H34N4O5). [1547] B. 3-(5-(1-Methyl-5-(pyrimidin-2-yl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(3-(2- hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.13 g, 233 μmol, 1.00 eq) in ACN (2.00 mL) and TsOH (160 mg, 934 μmol, 4.00 eq) , The mixture was stirred at 80 °C for 4 h. The mixture was filtrated to give a filtrate. The filtrate was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 7 - 37% acetonitrile in water containing 0.05% NH4HCO3 over 8 min at a flow rate of 25 mL/min) to give the title compound (0.05 g, 112 μmol, 48.1% yield, 100% purity in HPLC at 220 nm) as a white solid. (C25H24O4N4). [1548] C.3-(5-(5-(3-(2-Hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-(5-(3-(2- hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 67.4 μmol, 1.00 eq) in dioxane (1.00 mL) and HCl/dioxane (2 M, 337 μL, 10.0 eq) ,The mixture was stirred at 25 °C for 4 h. The mixture was lyophilized to give the title compound (16.8 mg, 34.9 μmol, 51.8% yield, 94.4% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ10.9 (s, 1 H), 9.07 - 9.25 (m, 1 H), 7.70 (d, J=8.00 Hz, 1 H), 7.65 (s, 1 H), 7.42 - 7.50 (m, 3 H), 7.35 (s, 1 H), 7.31 (m, 1 H), 5.10 - 5.07 (m, 1 H), 4.23 - 4.44 (m, 2 H), 3.66 (s, 3 H), 3.58 - 3.62 (m, 2 H), 2.85 - 2.97 (m, 1 H), 2.76 - 2.74 (m, 2 H), 2.56 - 2.61 (m, 1 H), 2.38 - 2.35 (m, 1 H) 1.92 - 2.05 (m, 1 H) (ESI+) m/z: 445.1 (M+H)+, (C25H24O4N4). EXAMPLE 454 [1549] Synthesis of 3-(5-(5-(3-Aminophenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 534 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1550] A. tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1- (trifluoromethyl)-1H-1,2,3-triazol-5-yl)phenyl)carbamate: To a solution of 3-(1-oxo-5-(1- (trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione (0.30 g, 507 μmol, 1.00 eq) in NMP (1.00 mL) was added Pd(OAc)2 (11.4 mg, 50.7 μmol, 0.10 eq) tert- butyl(3-iodophenyl)carbamate (486 mg, 1.52 mmol, 3.00 eq), tetrabutylammonium;acetate (612 mg, 2.03 mmol, 618 μL, 4.00 eq), Pd(OAc)2 (11.4 mg, 50.7 μmol, 0.10 eq) , then the mixture was stirred at 80 °C for 16 h under N2. The mixture was filtrated to give a filtrate. The filtrate was added H2O (5.0mL). The mixture was extracted with Dichloromethane: methyl alcohol =15: 1 (3 x 5 mL). The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: methyl alcohol = 20:1, Rf = 0.8).The mixture was purified by preparative-HPLC ((using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 36 - 66% acetonitrile in water containing 0.05% NH4HCO3 over 8 min at a flow rate of 25 mL/min) to give the title compound (70.0 mg, 121 μmol, 23.8% yield, 98.7% purity in LCMS at 220 nm) as a white solid. (ESI+) m/z: 486.0 (M+H)+, (C23H18F3N5O4). [1551] B.3-(5-(5-(3-Aminophenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: A solution of tert-butyl (3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-(trifluoromethyl)-1H-1,2,3-triazol-5- yl)phenyl)carbamate (70.0 mg, 121 μmol, 1.00 eq) in HCl/dioxane (2 M, 605 μL, 10.0 eq) was stirred at 25 °C for 4 h. The mixture was freeze-dried to give the title compound (16.0 mg, 34.1 μmol, 28.1% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.00 Hz, 1H) 7.56 - 7.54 (m, 1H), 7.26 (t, J = 7.88 Hz, 1H), 6.84 - 6.82 (m, 1H), 6.64 - 6.75 (m, 2H), 5.11 - 5.08 (m, 1H), 4.27 - 4.49 (m, 2H), 2.85 - 2.96 (m, 1H), 2.55 - 2.63 (m, 1H), 2.36 - 2.40 (m, 1H), 1.95 - 2.04 (m, 1H) (ESI+) m/z: 471.1 (M+H)+, (C22H17F3N6O3). 535 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 455 [1552] Synthesis of 3-(5-(5-(3-Aminophenyl)-1-methyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1553] A. tert-Butyl 5-amino-4-(5-(5-(3-((tert-butoxycarbonyl)amino)phenyl)-1- methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert- butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (300 mg, 628 μmol, 1.00 eq) and (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid (297 mg, 1.26 mmol, 2.00 eq) and K3PO4 (266 mg, 1.26 mmol, 2.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Pd(dtbpf)Cl2 (40.9mg, 62.8μmol, 0.10 eq) under N2. The mixture was stirred at 65 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC (Dichloromethane: Methanol = 10: 1, Rf = 0.45) to give the title compound (280 mg, 429 μmol, 68.3% yield, 90.5% purity in LCMS at 220 nm) as yellow oil. (ESI+) m/z: 590.3 (M+H)+, (C32H39N5O6). [1554] B.3-(5-(5-(3-Aminophenyl)-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(3-((tert- butoxycarbonyl)amino)phenyl)-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (280 mg, 474 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (245 mg, 1.42 mmol, 3.00 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 0% - 30.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (80.0 mg, 182 μmol, 38.4% yield, 94.8% purity in HPLC at 220 nm) was obtained as white solid. (ESI+) m/z: 416.3 (M+H)+, (C23H21N5O3). [1555] C.3-(5-(5-(3-Aminophenyl)-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; hydrogen chloride: To a solution of 3-(5-(5-(3-aminophenyl)-1- methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80.0 mg, 192 μmol, 536 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1.00 eq) in dioxane (3.00 mL) was added HCl/dioxane (2 M, 962 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (66.2 mg, 137 μmol, 71.2% yield, 93.6% purity in HPLC at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.12 (s, 1H),8.05 - 7.97 (m, 3H), 7.44 - 7.40 (m, 2H), 7.12 - 7.06 (m, 2H), 5.21 - 5.17 (m, 1H), 4.64 - 4.47 (m, 2H), 3.75 (s, 3H), 2.97 - 2.91 (m, 1H), 2.65 - 2.60 (m, 1H), 2.45 - 2.41 (m, 1H), 2.07 - 2.04 (m, 1H). (ESI+) m/z: 416.2 (M+H)+, (C23H21N5O3). EXAMPLE 456 [1556] Synthesis of 3-(5-(5-(4-Acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione;hydrochloride: [1557] A. tert-Butyl 4-(5-(5-(4-acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: A mixture of tert-butyl 5-amino-4-(5-(5- bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 419 μmol, 1.00 eq), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one (155 mg, 628 μmol, 1.50 eq), K3PO4 (267 mg, 1.26 mmol, 3.00 eq) and Pd(dtbpf)Cl2 (27.3 mg, 41.9 μmol, 0.10 eq) in dioxane (2.00 mL) and H2O (0.50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 16 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, DCM: MeOH = 10: 1, Rf = 0.50) to give the title compound (200 mg, 344 μmol, 55% yield, 88.8% purity in LCMS at 220 nm) as brown oil.1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.0 Hz, 2H), 7.90 (s, 1H), 7.64 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 4.69 (dd, J = 4.4, 10.0 Hz, 1H), 4.53 - 4.33 (m, 2H), 3.52 (s, 3H), 2.64 (s, 3H), 2.17 - 2.09 (m, 3H), 2.02 - 1.91 (m, 1H), 1.32 (s, 9H). (ESI+) m/z: 517.3 (M+H)+, (C29H32N4O5). 537 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1558] B.3-(5-(5-(4-Acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl 4-(5-(5-(4-acetylphenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (200 mg, 387 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (267 mg, 1.55 mmol, 4.00 eq). The mixture was stirred at 80 °C for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove ACN. The residue was diluted with NaHCO3 (50.0 mL) and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 5% - 35% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (100 mg, 200 μmol, 51.5% yield, 88.3% purity in LCMS at 220 nm) as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.63 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.70 - 7.56 (m, 4H), 7.42 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.42 - 4.23 (m, 2H), 3.63 (s, 3H), 2.94 - 2.86 (m, 1H), 2.64 (s, 3H), 2.62 - 2.59 (m, 1H), 2.38 - 2.33 (m, 1H), 2.04 - 1.94 (m, 1H). (ESI+) m/z: 443.1 (M+H)+, (C25H22N4O4). [1559] C.3-(5-(5-(4-Acetylphenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione;hydrochloride: To a solution of 3-(5-(5-(4-acetylphenyl)-1-methyl- 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 226 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (2 M, 565 μL, 5.00 eq). The mixture was stirred at 25 °C for 4 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (91.72 mg, 187.66 μmol, 97.99% purity, HCl) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.98 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.44 - 4.25 (m, 2H), 3.67 (s, 3H), 2.96 - 2.86 (m, 1H), 2.64 (s, 3H), 2.58 - 2.55 (m, 1H), 2.41 - 2.33 (m, 1H), 2.03 - 1.95 (m, 1H). (ESI+) m/z: 443.2 (M+H)+, (C25H22N4O4). EXAMPLE 457 [1560] Synthesis of 3-(5-(1-Methyl-5-(3-(methylamino)phenyl)-2-(trifluoromethyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: 538 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1561] A. tert-Butyl 5-amino-4-(5-(1-methyl-5-(3-(methylamino)phenyl)-2- (trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(5-bromo-1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 366 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.50 mL) was added N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (102 mg, 440 μmol, 1.20 eq), Pd(dtbpf)Cl2 (23.9 mg, 36.6 μmol, 0.10 eq) and K3PO4 (233 mg, 1.10 mmol, 3.00 eq) under N2. The mixture was stirred at 65 °C for 12 h. After the reaction was completed, the reaction mixture was filtered and the filtrated was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.50) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 29 - 59% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (150 mg, 260 μmol, 70.9% yield, 99.2% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.55 - 7.52 (m, 2H), 7.47 - 7.44 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.16 (s, 1H), 6.77 - 6.74 (m, 1H), 6.63 - 6.59 (m, 2H), 4.71 - 4.67 (m, 1H), 4.53 - 4.36 (m, 2H), 3.56 (s, 3H), 2.67 (s, 3H), 2.17 - 2.09 (m, 3H), 2.02 - 1.91 (m, 1H), 1.31 (s, 9H). (ESI+) m/z: 572.2 (M+H)+, (C29H32F3N5O4). [1562] B.3-(5-(1-Methyl-5-(3-(methylamino)phenyl)-2-(trifluoromethyl)-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5- (1-methyl-5-(3-(methylamino)phenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate (130 mg, 225μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (155 mg, 902 μmol, 4.00 eq). The mixture was stirred at 80 °C for 12 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 15 - 45% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) and by preparative- HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 28 - 58% acetonitrile in water containing 0.05% FA over 8 min at a flow rate of 25 mL/min) to give the title compound (50.0 mg, 100 μmol, 44.3% yield, 99.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.73 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 6.74 - 6.70 (m, 1H), 6.61 - 6.56 (m, 2H), 5.95 - 5.90 (m, 1H), 5.11 - 5.05 (m, 1H), 4.42 - 4.22 (m, 2H), 3.56 (s, 3H), 2.95 - 2.85 539 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (m, 1H), 2.66 (d, J = 5.2 Hz, 3H), 2.61 - 2.59 (m, 1H), 2.39 - 2.34 (m, 1H), 2.04 - 1.95 (m, 1H). (ESI+) m/z: 498.1 (M+H)+, (C25H22F3N5O3). [1563] C.3-(5-(1-Methyl-5-(3-(methylamino)phenyl)-2-(trifluoromethyl)-1H-imidazol- 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: To a solution of 3-(5-(1- methyl-5-(3-(methylamino)phenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (50.0 mg, 100 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (2 M, 500 μL, 10.0 eq). The mixture was stirred at 25 °C for 4 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (39.9 mg, 74.2 μmol, 74.2% yield, 99.3% purity in HPLC at 220 nm, 2HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.72 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.82 - 6.80 (m, 1H), 6.70 - 6.66 (m, 2H), 5.11 - 5.05 (m, 1H), 4.42 - 4.22 (m, 2H), 3.56 (s, 3H), 2.99 - 2.83 (m, 1H), 2.69 (s, 3H), 2.56 - 2.55 (m, 1H), 2.41 - 2.34 (m, 1H), 1.99 - 1.96 (m, 1H). (ESI+) m/z: 498.1 (M+H)+, (C25H24F3N5O3Cl2). EXAMPLE 458 [1564] Synthesis of 3-(1-Oxo-5-(5-(p-tolyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [1565] A.3-(1-Oxo-5-(5-(p-tolyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin- 2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(1-(trifluoromethyl)-1H-1,2,3-triazol- 4-yl)isoindolin-2-yl)piperidine-2,6-dione (100 mg, 169 μmol, 1.00 eq) in NMP (1.00 mL) was added 1-iodo-4-methyl-benzene (110 mg, 507 μmol, 3.00 eq) ,tetrabutylammonium;acetate (204 mg, 677 μmol, 206 μL, 4.00 eq) Pd(OAc)2 (3.80 mg, 16.9 μmol, 0.10 eq), then the mixture was stirred at 80 °C for 16 h under N2. The mixture was filtrated to give a filtrate. The filtrate was added H2O (5.0mL). The mixture was extracted with Dichloromethane: methyl alcohol = 15:1 (3 x 5 mL).The combined organic layers were dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: methyl alcohol = 20:1, Rf = 0.8). The mixture was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 32 - 62% acetonitrile in water containing 0.05% NH4HCO3 540 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT over 8 min at a flow rate of 25 mL/min) to give the title compound (8.03 mg, 17.0 μmol, 10.0% yield, 99.5% purity in HPLC at 220 nm) as off white solid.1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1 H), 7.78 (s, 1 H), 7.70 (d, J = 8.00 Hz, 1 H), 7.38 - 7.52 (m, 5 H), 5.10 - 5.07 (m, 1 H), 4.25 - 4.52 (m, 2 H) 2.84 - 2.97 (m, 1 H) 2.61 (m, 1 H) 2.42 (s, 3 H) 2.37 (m, 1 H) 1.93 - 2.03 (m, 1 H) (ESI+) m/z: 470.0 (M+H)+, (C23H18F3N5O3). EXAMPLE 459 [1566] Synthesis of 3-(5-(5-(4-Aminophenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1567] A. tert-Butyl (4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1- (trifluoromethyl)-1H-1,2,3-triazol-5-yl)phenyl)carbamate: A mixture of 3-(1-oxo-5-(1- (trifluoromethyl)-1H-1,2,3-triazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione (200 mg, 527 μmol, 1.00 eq), tert-butyl (4-iodophenyl)carbamate (505 mg, 1.58 mmol, 3.00 eq), Pd(OAc)2 (11.8 mg, 52.7 μmol, 0.10 eq) and tetrabutylammonium acetate (636 mg, 2.11 mmol, 642 μL, 4.00 eq) in NMP (5.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. After the reaction was completed, the reaction mixture was diluted with H2O (50.0 mL) and extracted with DCM (3 x 50.0 mL). The combined organic layers were washed with brine (3 x 50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 10 μm) and gradiente of 39 - 69% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (50.0 mg, 85.8 μmol, 16.3% yield, 97.9% purity in HPLC at 220 nm) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.74 (s, 1H), 7.79 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 5.13 - 5.06 (m, 1H), 4.48 - 4.27 (m, 2H), 2.93 - 2.84 (m, 1H), 2.61 - 2.59 (m, 1H), 2.40 - 2.35 (m, 1H), 2.02 - 1.95 (m, 1H), 1.49 (s, 9H). (ESI+) m/z: 515.2 (M-55)+, (C27H25F3N6O5). [1568] B.3-(5-(5-(4-Aminophenyl)-1-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl (4-(4-(2-(2,6- 541 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-(trifluoromethyl)-1H-1,2,3-triazol-5- yl)phenyl)carbamate (30.0 mg, 52.6 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl (12 M, 100 μL, 20.0 eq). The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 18 - 48% acetonitrile in water containing 0.05% HCl over 11 min at a flow rate of 25 mL/min) to give the title compound (9.56 mg, 20.0 μmol, 38.0% yield, 98.6% purity in HPLC at 220 nm) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.82 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 7.6 Hz, 2H), 5.15 - 5.06 (m, 1H), 4.51 - 4.26 (m, 2H), 2.96 - 2.86 (m, 1H), 2.60 - 2.56 (m, 1H), 2.43 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H). (ESI+) m/z: 471.1 (M+H)+, (C22H17F3N6O3). EXAMPLE 460 [1569] Synthesis of 3-(5-(5-(3-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1570] A. tert-Butyl 5-amino-4-(5-(5-(3-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of tert-butyl 5-amino-4-(5-(1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 1.25 mmol, 1.00 eq), 1-bromo-3-methoxybenzene (702 mg, 3.76 mmol, 475 μL, 3.00 eq), Pd(PPh3)2Cl2 (87.8 mg, 125 μmol, 0.10 eq) and tetrabutylammonium acetate (1.51 g, 5.01 mmol, 1.52 mL, 4.00 eq) in NMP (10.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 4 h under N2 atmosphere. The mixture was poured water (10.0 mL) and extracted with ethyl acetate(3 x 20.0 mL) to collecte the organic layer. The organic layers were washed with brine (2 x 20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum at 45 °C to get a residue. The residue was purified by preparative- TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.50) to give the title compound (400 mg, 664 μmol, 53.0% yield, 84% purity in LCMS at 220 nm) as a yellow oil. (ESI+) m/z: 506.4 (M+H)+, (C27H31N5O5). 542 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1571] B.3-(5-(5-(3-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione：A solution of tert-butyl 5-amino-4-(5-(5-(3-methoxyphenyl)-1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 498 μmol, 1.00 eq) and HBr (4.47 g, 18.2 mmol, 3.00 mL, 33% purity, 36.5 eq) in AcOH (3.00 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a CD18-Welch Utimate C18 (150 x 40 x 7 μm) and gradient of 6 - 36% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25.0 mL/min) to give the title compound (101.12 mg, 237 μmol, 47.7% yield, 98.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.81 (s, 1H), 7.74 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 6.96 - 9.94 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.81 - 6.79 (m, 1H), 5.12 - 5.07 (m, 1H), 4.45 - 4.26 (m, 2H), 3.90 (s, 3H), 2.91 - 2.87 (m, 1H), 2.61 - 2.55 (m, 1H), 2.39 - 2.33 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI+) m/z: 418.1 (M+H)+, (C22H19N5O4). EXAMPLE 461 [1572] Synthesis of 3-(5-(1-(3-Hydroxyphenyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride: [1573] A.3-(2-Bromo-1H-imidazol-1-yl)phenol：To a mixture of 2-bromo-1H-imidazole (500 mg, 3.40 mmol, 1.00 eq) in DCE (5.00 mL) was added(3- (3-((tert- butyldimethylsilyl)oxy)phenyl)boronic acid (2.14 g, 8.50 mmol, 2.50 eq), Cu(OAc)2 (617 mg, 3.40 mmol, 1.00 eq), 2-(2-pyridyl)pyridine (1.59 g, 10.2 mmol, 3.00 eq) and Na2CO3 (1.08 g, 10.2 mmol, 3.00 eq) under O2. The mixture was stirred at 70 °C for 12 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 500: 1 to 5: 1, Rf = 0.36 (TLC: Petroleum ether: Ethyl acetate = 1: 1)) to give the title compound (150 mg, 597.32 μmol, 17.5% yield, 95.2% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.53 (s, 1H), 7.52 - 7.31 (m, 1H), 7.08 (s, 1H) 6.91 - 6.86 (m, 2H), 6.79 - 6.78 (s, 1H). (ESI+) m/z: 240.9 (M+H)+, (C9H7BrN2O). 543 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1574] B.2-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)phenyl)-1H-imidazole：To a mixture of 3-(2-bromo-1H-imidazol-1-yl)phenol (150 mg, 627 μmol, 1.00 eq) in DMF (2.00 mL) was added TBS-Cl (141 mg, 941 μmol, 115 μL, 1.50 eq) and Imidazole (128 mg, 1.88 mmol, 3.00 eq). The mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was poured into H2O (5.00 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1,Rf = 0.43) to give the title compound (120 mg, 339 μmol, 54.1% yield, 100% purity) as yellow oil. (ESI+) m/z: 352.9 (M+H)+, (C15H21BrN2OSi). [1575] C.3-(5-(1-(3-Hydroxyphenyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a mixture of 2-bromo-1-(3-((tert- butyldimethylsilyl)oxy)phenyl)-1H-imidazole (100 mg, 283 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (261 mg, 707 μmol, 2.50 eq), K3PO4 (180 mg, 849 μmol, 3.00 eq) and Ru-Phos-Pd-G3 (18.4 mg, 28.3 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vaccum to give a residue. The product was purified by preparative-HPLC (using a CD24-XPT C18 (150 mm x 25 mm 7 μm) and gradient of 6 - 36% acetonitrile in water containing 0.5% NH4HCO3 over 10 min at a flow rate of 25.0 mL/min) to give the title compound (10.0 mg, 49.7 μmol, 8.7% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 10.1 (s, 1H), 7.97 (s, 1H), 7.84 - 7.83 (m, 2H), 7.80 - 7.78 (m, 1H), 7.73 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.32 - 7.28 (m, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.82 - 6.81 (m, 2H), 5.14 - 5.09 (m, 2H), 2.94 - 2.88 (m, 1H), 2.61 - 2.57 (m, 1H), 2.41 - 2.38 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI+) m/z: 403.0 (M+H)+, (C22H18O4N4). [1576] D.3-(5-(1-(3-Hydroxyphenyl)-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride: To a mixture of 3-(5-(1-(3-hydroxyphenyl)-1H- imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10.0 mg, 24.8 μmol, 1.00 eq) in dioxane (1.00 mL) was addded HCl/dioxane (1.0 M, 248 μL, 10.0 eq) .The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum. The product was pre-purified by preparative-HPLC (using a CD01-Phenomenex luna C18 (150 mm x 25 mm 10 μm) and gradient of 0 - 25% acetonitrile in water containing 0.5% HCl over 10 min at a flow rate of 25.0 mL/min) to give the title compound (10.16 mg, 23.10 μmol, 92.9% yield, 544 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 99.8% purity in HPLC at 220 nm, HCl) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 10.1 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.82 - 7.80 (m, 1H), 7.77 (s, 1H), 7.54 - 7.53 (m, 1H), 7.33 - 7.29 (m, 1H), 6.95 - 6.88 (m, 1H), 6.88 - 6.87 (m, 1H), 6.87 - 6.85 (m, 1H), 5.14 - 5.10 (m, 1H), 4.49 - 4.31 (m, 2H), 2.94 - 2.88 (m, 1H), 2.62 - 2.57 (m, 1H), 2.41 - 2.38 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI+) m/z: 403.0 (M+H)+, (C22H19O4N4Cl). EXAMPLE 462 [1577] Synthesis of 3-(5-(1-(3-(Methylamino)propyl)-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1578] A. tert-Butyl (3-(4-bromo-5-phenyl-1H-imidazol-1- yl)propyl)(methyl)carbamate: To mixture of 4-bromo-5-phenyl-1H-imidazole (500 mg, 2.24 mmol, 1.00 eq) in THF (10.0 mL) was added NaH (134 mg, 3.36 mmol, 60% purity, 1.50 eq) at 0 °C under N2, and then the mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then the mixture was added tert-butyl (3-chloropropyl)(methyl)carbamate (651 mg, 3.14 mmol, 1.40 eq) at 0 °C, and then the mixture was stirred at 80 °C for 40 h under N2 atmosphere. The reaction was quenched with aq.NH4Cl (10.0 mL) drop-wise at 0 °C. The resulting mixture was extracted with EA (3 x 15.0 mL). The combined organic phase was washed with brine (15.0 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *40 mm *10 um) and gradient of 34.0% - 64.0% acetonitrile in water containing 0.05% TFA over 25 min at a flow rate of 25 mL/min to give the title compound (190 mg, 478 μmol, 21.3% yield, 99.3% purity in HPLC at 220 nm) was obtained as yellow oil.1H NMR (400 MHz, DMSO- d6) δ 7.89 (m, 1H), 7.51 - 7.46 (m, 3H), 7.42 - 7.41 (m, 2H), 3.71 – 3.55 (m, 2H), 3.03 – 3.02 (m, 2H), 2.57 (s, 3H), 1.69 – 1.62 (m, 2H), 1.38 – 1.18 (m, 9H). (ESI+) m/z: 394.0 (M+H)+, (C18H24BrN3O2). [1579] B. tert-Butyl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-phenyl- 1H-imidazol-1-yl)propyl)(methyl)carbamate: To a solution of tert-butyl (3-(4-bromo-5- phenyl-1H-imidazol-1-yl)propyl)(methyl)carbamate (190 mg, 481 μmol, 1.00 eq) and 3-(1- oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (356 545 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT mg, 963 μmol, 2.00 eq) and K3PO4 (306 mg, 1.45 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (40.3 mg, 48.1 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by TLC( Dichloromethane: Methanol = 20: 1, Rf = 0.40) to give the title compound (100 mg, 177 μmol, 36.8% yield, 99.0% purity in LCMS at 220 nm) as white solid. (ESI+) m/z: 558.4 (M+H)+, (C31H35N5O5). [1580] C.3-(5-(1-(3-(Methylamino)propyl)-5-phenyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: To a solution of tert-butyl (3- (4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-phenyl-1H-imidazol-1- yl)propyl)(methyl)carbamate (100 mg, 179 μmol, 1.00 eq) in dioxane (5.00 mL) was added HCl/dioxane (2 M, 896 μL, 10.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a Phenomenex luna C18 (150 *25 mm *7 um) and gradient of 0% - 19.0% acetonitrile in water containing 0.05% HCl over 11 min at a flow rate of 25 mL/min to give the title compound (32.3 mg, 65.0 μmol, 36.2% yield, 99.5% purity in HPLC at 220 nm) was obtained as white solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (m, 1H), 9.31 - 9.17 (m, 1H), 9.04 - 8.96 (m, 2H), 7.68 - 7.60 (m, 5H), 7.58 - 7.53 (m, 2H), 7.52 - 7.44 (m, 1H), 5.11 - 5.06 (m, 1H), 4.42 - 4.22 (m, 2H), 4.14 – 4.11 (m, 2H), 2.89 - 2.81 (m, 3H), 2.60 - 2.58 (m, 1H), 2.47 - 2.45 (m, 3H), 1.99 - 1.93 (m, 3H). (ESI+) m/z: 458.1 (M+H)+, (C26H27N5O3). EXAMPLE 463 [1581] Synthesis of 3-(5-(5-(4-Aminophenyl)-1-methyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride: [1582] A. tert-Butyl 5-amino-4-(5-(1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: A mixture of 2-bromo-1-methyl-1H-imidazole (2.00 g, 12.4 mmol, 1.00 eq), tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin- 2-yl)pentanoate (5.52 g, 12.4 mmol, 1.00 eq), Ru-Phos-Pd-G3 (519 mg, 621 μmol, 0.05 eq) and K3PO4 (5.27 g, 24.8 mmol, 2.00 eq) in dioxane (40.0 mL) and H2O (2.00 mL) was 546 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 4 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30) to give the title compound (2.70 g, 5.49 mmol, 44.1% yield, 81% purity in LCMS at 220 nm) as a brown solid.1H NMR: (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.82 - 7.76 (m, 2H), 7.60 (s, 1H), 7.31 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 4.77 - 4.74 (m, 1H), 4.68 - 4.52 (m, 2H), 3.79 (s, 3H), 2.25 - 2.15 (m, 3H), 2.03 - 1.99 (m, 1H), 1.32 (s, 9H). (ESI+) m/z: 399.1 (M+H)+, (C21H26N4O4). [1583] B. tert-Butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-2-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1-methyl- 1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.60 g, 5.29 mmol, 1.00 eq) in ACN (30.0 mL) was added a solution of NBS (940 mg, 5.29 mmol, 1.00 eq) in ACN (5.00 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into H2O (100 mL), extracted with EtOAc (3 x 50.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol=100: 0 to 80: 1, TLC: Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (1.60 g, 2.85 mmol, 53.9% yield, 85% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.81 - 7.76 (m, 2H), 7.60 (s, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 4.77 - 4.74 (m, 1H), 4.68 - 4.52 (m, 2H), 3.70 (s, 3H), 2.25 - 2.15 (m, 3H), 2.03 - 1.99 (m, 1H), 1.32 (s, 9H). (ESI+) m/z: 477.1 (M+H)+, (C21H25BrN4O4). [1584] C. tert-Butyl 5-amino-4-(5-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1- methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: A mixture of tert-butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 534 μmol, 1.00 eq), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (253 mg, 1.07 mmol, 2.00 eq), Pd(dtbpf)Cl2 (34.8 mg, 53.4 μmol, 0.10 eq) and K3PO4 (226 mg, 1.07 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (2.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.30) to give the title compound (200 mg, 324 μmol, 60.7% yield, 95.6% purity in HPLC at 220 nm) as a yellow solid. (ESI+) m/z: 590.3 (M+H)+, (C32H39N5O6). [1585] D.3-(5-(5-(4-Aminophenyl)-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: A solution of tert-butyl 5-amino-4-(5-(5-(4-((tert- 547 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT butoxycarbonyl)amino)phenyl)-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate (200 mg, 324 μmol, 1.00 eq) and TsOH (223 mg, 1.30 mmol, 4.00 eq) in ACN (5.00 mL) was stirred at 80 °C for 32 h. The reaction mixture was filtered and concentrated in vacuum to give residue. The crude product was purified by preparative-HPLC (using a CD08-Phenomenex kinetex EVO C18 (150 x 30 x 5 μm) and gradient of 0 - 20% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 30.0 mL/min) to give the title compound (40.0 mg, 95.9 μmol, 29.6% yield, 99.7% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 416.1 (M+H)+, (C23H21N5O3). [1586] E.3-(5-(5-(4-Aminophenyl)-1-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrogen chloride: A solution of 3-(5-(5-(4-aminophenyl)-1- methyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen chloride (30.0 mg, 72.2 μmol, 1.00 eq) and HCl/dioxane (2 M, 361 μL, 10.0 eq) in dioxane (1.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give the title compound (25.18 mg, 55.1 μmol, 98.9% purity in HPLC at 220 nm, HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.20 - 5.16 (m, 1H), 4.63 - 4.46 (m, 2H), 3.73 (s, 3H), 2.99 - 2.89 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.40 (m, 1H), 2.05 - 2.02 (m, 1H). (ESI+) m/z: 416.1 (M+H)+, (C23H21N5O3). EXAMPLE 464 [1587] Synthesis of 3-(5-(1-Methyl-5-(3-(methylamino)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: [1588] A. tert-Butyl 5-amino-4-(5-(5-(4-(2-hydroxyethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg, 418 μmol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.50 mL) was added N-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (117 mg, 502 μmol, 1.20 eq), Pd(dtbpf)Cl2 (27.3 mg, 41.9 μmol, 0.10 eq) and K3PO4 (266 mg, 1.26 mmol, 3.00 eq) under N2. The mixture was stirred at 65 °C for 12 h. After the reaction was completed, the reaction mixture was filtered 548 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT and the filtrated was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.40) and by preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 13 - 43% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (150 mg, 296 μmol, 70.8% yield, 99.6% purity in LCMS at 220 nm) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.70 - 7.65 (m, 2H), 7.57 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 6.61 - 6.58 (m, 2H), 4.73 - 4.70 (m, 1H), 4.69 (t, J = 5.2Hz, 1H), 4.59 - 4.41 (m, 2H), 3.65 (s, 3H), 2.65 (s, 3H), 2.16 - 2.12 (m, 3H), 2.04 - 1.96 (m, 1H), 1.31 (s, 9H). (ESI+) m/z: 504.2 (M+H)+, (C28H33N5O4). [1589] B.3-(5-(1-Methyl-5-(3-(methylamino)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-(2- hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (130 mg, 257μmol, 1.00 eq) in ACN (2.00 mL) was added TsOH (191 mg, 1.11 mmol, 4.00 eq). The mixture was stirred at 80 °C for 12 h under N2. After the reaction was completed, the reaction mixture was poured into a solution of NaHCO3 (10.0 mL). The mixture was extracted with ethyl acetate (3 x 50.0 mL) and the combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18 150 x 25 mm x 7 μm) and gradiente of 0 - 30% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (40.0 mg, 93.1 μmol, 36.2% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO- d6) δ 10.9 (s, 1H), 9.06 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.74 - 6.70 (m, 1H), 6.61 - 6.56 (m, 2H), 5.13 - 5.07 (m, 1H), 4.46 - 4.26 (m, 2H), 3.64 (s, 3H), 2.96 - 2.86 (m, 1H), 2.65 (s, 3H), 2.57 - 2.53 (m, 1H), 2.41 - 2.36 (m, 1H), 2.02 - 1.97 (m, 1H). (ESI+) m/z: 430.1 (M+H)+, (C24H23N5O3). [1590] C.3-(5-(1-Methyl-5-(3-(methylamino)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride: To a solution of 3-(5-(1-methyl-5- (3-(methylamino)phenyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40.0 mg, 93.1 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (2 M, 465 μL, 10.0 eq). The mixture was stirred at 25 °C for 4 h. After the reaction was completed, the mixture was lyophilizated to give the title compound (37.3 mg, 78.4 μmol, 84.2% yield, 97.9% purity in HPLC at 220 nm, 2HCl) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.25 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 549 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.64 - 6.59 (m, 2H), 5.13 - 5.08 (m, 1H), 4.46 - 4.27 (m, 2H), 3.67 (s, 3H), 2.95 - 2.87 (m, 1H), 2.65 (s, 3H), 2.56 - 2.53 (m, 1H), 2.42 - 2.36 (m, 1H), 2.02 - 1.97 (m, 1H). (ESI+) m/z: 430.1 (M+H)+, (C24H25N5O3Cl2). EXAMPLE 465 [1591] Synthesis of 3-(5-(5-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1592] A. tert-Butyl 5-amino-4-(5-(5-(4-(benzyloxy)phenyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 751 μmol, 1.00 eq) and 1-(benzyloxy)-4-iodobenzene (698 mg, 2.25 mmol, 3.00 eq) and tetrabutylammonium acetate (905 mg, 3.00 mmol, 4.00 eq) in NMP (5.00 mL) was added Pd(PPh3)2Cl2 (52.7 mg, 75.1μmol, 0.10 eq) under N2. The mixture was stirred at 120 °C for 4 h under N2. The mixture was poured into aturated H2O aqeous (50.0 mL) and extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with saturated NaCl aqeous (3 x 100 mL), dried over Na2SO4 and concentrated under reduced pressure to get residue. The residue was purified by TLC (Dichloromethane: Methanol = 15: 1, Rf = 0.45) to give the title compound (200 mg, 238 μmol, 31.7% yield, 69.3% purity in LCMS at 220 nm) as brown oil. (ESI+) m/z: 582.4 (M+H)+, (C33H35N5O5). [1593] B. tert-Butyl 5-amino-4-(5-(5-(4-(benzyloxy)phenyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of Pd/C (40.0 mg, 10% purity) in TFE (5.00 mL) was added tert-butyl 5-amino-4-(5-(5-(4-(benzyloxy)phenyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (150 mg, 257 μmol, 1.00 eq) under N2.Then the reaction mixture was degassed purged with H2 for 3 times. Then the mixture was stirred at 25°C for 24 h under H2 (50 psi). The reaction mixture was filtered through diatomite and the filtrate was concentrated under vacuum to give a residue. The residue was purified by TLC (Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (110 mg, 214 μmol, 83.1% yield, 95.8% purity in LCMS at 220 nm) as brown oil. (ESI+) m/z: 492.2 (M+H)+, (C26H29N5O5). 550 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1594] C.3-(5-(5-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione: To a solution of tert-butyl 5-amino-4-(5-(5-(4-hydroxyphenyl)-1- methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (110 mg, 223 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (77.0 mg, 447 μmol, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative - HPLC (using a CD24-XPT C18 (150 *25 mm *7 um) and gradient of 10.0% - 40.0% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min to give the title compound (13.7 mg, 31.5 μmol, 14.1% yield, 95.9% purity in HPLC at 220 nm) was obtained as white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.97 (s, 1H), 7.74 (s, 1H), 7.67 - 7.65 (m, 1H), 7.55 - 7.52 (m, 1H), 7.28 – 7.26 (m, 2H), 6.94 – 6.92 (m, 2H), 5.11 - 5.07 (m, 1H), 4.45 - 4.26 (m, 2H), 3.91 (s, 3H), 2.95 - 2.86 (m, 1H), 2.61 - 2.58 (m, 1H), 2.38 - 2.32 (m, 1H), 2.01 – 1.96 (m, 1H). (ESI+) m/z: 418.1.(M+H)+, (C22H19N5O4). EXAMPLE 466 [1595] Synthesis of 3-(5-(5-(3-(2-Mercaptoethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1596] A. tert-Butyl 5-amino-4-(5-(5-(3-(2-hydroxyethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate：A mixture of tert-butyl 5-amino-4- (5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg, 837 μmol, 1.00 eq), (4-(2-hydroxyethyl)phenyl)boronic acid (166 mg, 1.01 mmol, 1.20 eq), Pd(dtbpf)Cl2 (54.6 mg, 83.8 μmol, 0.10 eq) and K3PO4 (355 mg, 1.68 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 19: 1; TLC, Dichloromethane: Methanol = 10 : 1, Rf = 0.30). to give the title compound (360 mg, 624 μmol, 74.5% yield, 90% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 519.2 (M+H)+, (C29H34N4O5) 551 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1597] B. tert-Butyl 4-(5-(5-(3-(2-(acetylthio)ethyl)phenyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a solution of PPh3 (327 mg, 1.25 mmol, 2.00 eq) in THF (5.00 mL) was added DIAD (252 mg, 1.25 mmol, 242 μL, 2.00 eq) dropwise at 0 °C under N2. The mixture was stirred at 0 °C for 30 min under N2, then a solution of tert-butyl 5-amino-4-(5-(5-(3-(2-hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (360 mg, 624 μmol, 1.00 eq) in THF (5.00 mL) and ethanethioic S-acid (95.1 mg, 1.25 mmol, 89.3 μL, 2.00 eq) was added to the mixture at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 0 to 20: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30) to give the title compound (260 mg, 395 μmol, 63.3% yield, 87.8% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 577.1 (M+H)+, (C31H36N4O5S). [1598] C.3-(5-(5-(3-(2-Mercaptoethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 4-(5-(5-(3-(2- (acetylthio)ethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5- oxopentanoate (260 mg, 395 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (545 mg, 3.17 mmol, 8.00 eq) under N2. The reaction mixture was stirred at 80 °C for 16 h under N2.The reaction mixture was concentrated in vacuum to give residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.40) and preparative-HPLC (using a CD24-XPT C18 (150 x 25 x 7 μm) and gradient of 12 - 42% acetonitrile in water containing 0.05% TFA over 8 min at a flow rate of 30.0 mL/min) to give the title compound (32.47 mg, 69.9 μmol, 17.6% yield, 99.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.73 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.49 - 7.43 (m, 3H), 7.34 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.41 - 4.23 (m, 2H), 3.61 (s, 3H), 2.91 - 2.87 (m, 3H), 2.77 - 2.74 (m, 2H), 2.65 - 2.55 (m, 1H), 2.45 - 2.40 (m, 1H), 2.21 - 2.17 (m ,1H), 2.05 - 2.02 (m, 1H). (ESI+) m/z: 461.1 (M+H)+, (C25H24N4O3S). 552 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EXAMPLE 467 [1599] Synthesis of 3-(5-(1-(4-Aminophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1600] A.4-Bromo-5-methyl-1H-1,2,3-triazole: To a solution of 5-methyl-1H-1,2,3- triazole (1.00 g, 12.0 mmol, 1.00 eq) in DCM (10.0 mL) was added NBS (2.36 g, 13.2 mmol, 1.10 eq). The mixture was stirred at 25 °C for 16 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1; TLC, Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.40) to give the title compound (1.30 g, 8.03 mmol, 66.6% yield, 100% purity in LCMS at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 15.0 (br, 1H), 2.21 (s, 3H). (ESI+) m/z: 161.9 (M+H)+, (C3H4BrN3). [1601] B.4-Bromo-5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole: To a solution of 4- bromo-5-methyl-1H-1,2,3-triazole (700 mg, 4.32 mmol, 1.00 eq) and 1-fluoro-4-nitrobenzene (731 mg, 5.19 mmol, 550 μL, 1.20 eq) in DMSO (10.0 mL) was added CsF (3.94 g, 25.9 mmol, 6.00 eq) and DIEA (3.35 g, 25.9 mmol, 4.52 mL, 6.00 eq). The mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was poured into water (125 mL) and filtered. The filtrate was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1; TLC, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.50) to give the title compound (170 mg, 542 μmol, 12.5% yield, 90.4% purity in LCMS at 220 nm) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 2.38 (s, 3H). (ESI+) m/z: 282.9 (M+H)+, (C9H7BrN4O2). [1602] C.3-(5-(5-Methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of 4-bromo-5-methyl-1-(4-nitrophenyl)triazole (150 mg, 529 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-2-yl)piperidine-2,6-dione (490 mg, 1.32 mmol, 2.50 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (44.3 mg, 52.9 μmol, 0.10 eq) and K3PO4 553 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (224 mg, 1.06 mmol, 2.00 eq). The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 20: 1, Rf = 0.25) and by preparative-TLC (Dichloromethane: Ethyl acetate = 1: 1, Rf = 0.40) to give the title compound (90.0 mg, 199 μmol, 37.7% yield, 99.1% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 447.1 (M+H)+, (C22H18N6O5). [1603] D.3-(5-(1-(4-Aminophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of Pd/C (50.0 mg, 10% purity) in THF (2.00 mL) was added 3-(5-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (90.0 mg, 201 μmol, 1.00 eq) under N2.The mixture was stirred at 25 °C for 12 h under H2 (15 Psi). After the reaction was completed, the reaction mixture was filtered through diatomite and the filtrate was concentrated under vacuum to give a residue. The residue was purified by Preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 8 - 38% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (42.3 mg, 100 μmol, 50.0% yield, 99.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 5.17 - 5.12 (m, 1H), 4.58 - 4.39 (m, 2H), 2.98 - 2.88 (m, 1H), 2.64 - 2.60 (m, 1H), 2.44 (s, 3H), 2.42 - 2.37 (m, 1H), 2.06 - 2.00 (m, 1H). (ESI+) m/z: 417.1 (M+H)+ (C22H20N6O3). EXAMPLE 468 [1604] Synthesis of 3-(5-(1-(3-Aminophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1605] A.4-Bromo-5-methyl-1H-1,2,3-triazole: To a solution of 5-methyl-1H-1,2,3- triazole (1.00 g, 12.0 mmol, 1.00 eq) in DCM (10.0 mL) was added NBS (2.36 g, 13.2 mmol, 1.10 eq). The mixture was stirred at 25 °C for 16 h under N2. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1; TLC, Petroleum ether: Ethyl acetate = 3: 1, Rf 554 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT = 0.40) to give the title compound (1.30 g, 8.03 mmol, 66.6% yield, 100% purity in LCMS at 220 nm) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 15.0 (br, 1H), 2.21 (s, 3H). (ESI+) m/z: 161.9 (M+H)+, (C3H4BrN3). [1606] B.4-Bromo-5-methyl-1-(3-nitrophenyl)-1H-1,2,3-triazole: To a solution of 4- bromo-5-methyl-1H-1,2,3-triazole (1.00 g, 6.17 mmol, 1.00 eq) and 1-fluoro-4-nitrobenzene (1.05g, 7.41 mmol, 788 μL, 1.20 eq) in DMSO (10.0 mL) was added CsF (5.63 g, 37.0 mmol, 6.00 eq) and DIEA (4.79 g, 37.0 mmol, 6.45 mL, 6.00 eq). The mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was poured into water (125 mL) and filtered. The filtrate was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatrography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1; TLC, Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.50) to give the title compound (170 mg, 409 μmol, 6.63% yield, 68.2% purity in LCMS at 220 nm) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 2.0 Hz, 1H), 8.47 - 8.44 (m, 1H), 8.16 - 8.12 (m, 1H), 7.94 (t, J = 8.4 Hz, 1H), 2.35 (s, 3H). (ESI+) m/z: 282.9 (M+H)+, (C9H7BrN4O2). [1607] C.3-(5-(5-Methyl-1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of 4-bromo-5-methyl-1-(3-nitrophenyl)-1H-1,2,3- triazole (100 mg, 353 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)isoindolin-2-yl)piperidine-2,6-dione (326 mg, 883 μmol, 2.50 eq) in dioxane (2.00 mL) and H2O (0.10 mL) was added Pd(dtbpf)Cl2 (23.0 mg, 35.3 μmol, 0.10 eq) and K3PO4 (149 mg, 706 μmol, 2.00 eq). The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (Ethyl acetate: Petroleum ether = 5: 1, Rf = 0.50) to give the title compound (40.0 mg, 72.4 μmol, 20.4% yield, 80.8% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 447.1 (M+H)+, (C22H18N6O5). [1608] D.3-(5-(1-(3-Aminophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione：To a solution of Pd/C (40.0 mg, 10% purity) in THF (2.00 mL) was added 3-(5-(5-methyl-1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (40.0 mg, 89.6 μmol, 1.00 eq) under N2.The mixture was stirred at 25 °C for 12 h under H2 (15 Psi). After the reaction was completed, the reaction mixture was filtered through diatomite and the filtrate was concentrated under vacuum to give a residue. 555 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT The residue was purified by Preparative-HPLC (using a Welch Xtimate C18150 x 25 mm x 7 μm) and gradiente of 9 - 39% acetonitrile in water containing 0.01% NH4HCO3 over 15 min at a flow rate of 25 mL/min) to give the title compound (2.65 mg, 6.15 μmol, 6.86% yield, 96.6% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 5.17 - 5.12 (m, 1H), 4.58 - 4.40 (m, 2H), 2.98 - 2.93 (m, 1H), 2.65 - 2.59 (m, 1H), 2.45 (s, 3H), 2.44 - 2.41 (m, 1H), 2.06 - 2.04 (m, 1H). (ESI+) m/z: 417.1 (M+H)+ (C22H20N6O3). EXAMPLE 469 [1609] Synthesis of 3-(5-(5-(4-(2-Mercaptoethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: [1610] A. tert-Butyl 5-amino-4-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5- oxopentanoate: To a solution of 4-iodo-1-methyl-1H-imidazole (5.00 g, 24.04 mmol, 1.00 eq) in dioxane (100 mL) and H2O (10.0 mL) was added tert-butyl 5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (13.89 g, 31.25 mmol, 1.30 eq), CataCxium A Pd G3 (1.75 g, 2.40 mmol, 0.10 eq) and K3PO4 (15.31 g, 71.12 mmol, 3.00 eq) under N2.The mixture was stirred at 80 °C for 12 h. The mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 100 mL), dried over by Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromathane: Methanol = 10: 1, Rf = 0.46) to give the title compound (3.50 g, 8.78 mmol, 36.5% yield, 96.9% purity in LCMS at 220 nm) as yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.96 (s, 1H), 7.96 (s, 1H), 7.67 – 7.64 (m, 2H), 7.56 (s, 1H), 7.18 (s,1H) ,4.76 -4.72 (m,1H), 4.63 (d, J = 17.6 Hz, 1H), 4.51 (d, J = 17.6 Hz, 1H), 3.66 (s, 3H), 2.22-2.02 (m, 3H), 2.00-1.95 (m,1H),1.33 (s, 9H), (ESI+) m/z = 399.2 (M+H)+, (C21H26N4O4). [1611] B. tert-Butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-(1-methyl- 556 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (3.00 g, 7.53 mmol, 1.00 eq) in ACN (30.0 mL) was added NBS (1.41 g, 7.91 mmol, 1.05 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was poured in H2O (60.0 mL) and extracted with ethyl acetate (3 x 50.0 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 50: 1 to 10: 1, Rf = 0.4) to give the title compound (1.80 g, 3.77 mmol, 60.0% yield, 94.2% purity in LCMS at 220 nm) as yellow solid.1H NMR: δ 8.11 (s, 1H), 8.06 - 8.04 (m, 1H),8.01 (s, 1H), 7.75 - 7.73 (m, 1H), 7.56 (s, 1H) 7.19 (s, 1H), 4.76 - 4.72 (m, 1H), 4.63 (d, J = 17.6 Hz, 1H), 4.51 (d, J = 17.6 Hz, 1H), 3.66 (s, 3H), 2.22 - 2.02 (m, 3H), 2.00 - 1.95 (m, 1H), 1.33 (s, 9H), (ESI+) m/z = 479.0 (M+H)+, (C21H25BrN4O4). [1612] C. tert-Butyl 5-amino-4-(5-(5-(4-(2-hydroxyethyl)phenyl)-1-methyl-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino- 4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (260 mg, 544 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (1.25 mL) was added (4-(2- hydroxyethyl)phenyl)boronic acid (135 mg, 817 μmol, 1.50 eq), Pd(dtbpf)Cl2 (35.5 mg, 54.4 μmol, 0.10 eq) and K3PO4 (346 mg, 1.63 mmol, 3.00 eq) under N2. The mixture was stirred at 65 °C for 16 h. After the reaction was completed, the reaction mixture was filtered and the filtrated was concentrated in vacuum to give a residue. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 10: 1, Rf = 0.40) to give the title compound (210 mg, 384 μmol, 70.6% yield, 95.0% purity in LCMS at 220 nm) as a yellow solid. (ESI+) m/z: 519.2 (M+H)+, (C29H34N4O5). [1613] D. tert-Butyl 4-(5-(5-(4-(2-(acetylthio)ethyl)phenyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate: To a solution of PPh3 (182 mg, 694 μmol, 2.00 eq) in THF (5.00 mL) was added DIAD (140 mg, 694 μmol, 134 μL, 2.00 eq) dropwise at 0 °C under N2. The mixture was stirred at 0 °C for 30 min under N2, then a solution of tert-butyl 5-amino-4-(5-(5-(4-(2-hydroxyethyl)phenyl)-1-methyl-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (180 mg, 347 μmol, 1.00 eq) in THF (5.00 mL) and ethanethioic S-acid (52.8 mg, 694 μmol, 49.6 μL, 2.00 eq) was added to the mixture at 0 °C under N2. The reaction mixture was stirred at 0°C for 1 h under N2. The reaction mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative-TLC (Dichloromethane: Methanol = 10: 1, Rf = 0.35) to give the title compound (120 mg, 158 μmol, 45.5% yield, 76% purity in LCMS at 220 nm) was obtained as yellow solid. (ESI+) m/z: 577.3 (M+H)+, (C31H36N4O5S). 557 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1614] E.3-(5-(5-(4-(2-Mercaptoethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl 4-(5-(5-(4-(2- (acetylthio)ethyl)phenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-amino-5- oxopentanoate (120 mg, 158 μmol, 1.00 eq) in ACN (5.00 mL) was added TsOH (286 mg, 1.66 mmol, 8.00 eq). The mixture was stirred at 80 °C for 30 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative-HPLC (using a Welch Xtimate C18 150 x 25 mm x 7 μm) and gradiente of 10 - 40% acetonitrile in water containing 0.05% TFA over 10 min at a flow rate of 25 mL/min) to give the title compound (12.1 mg, 25.7 μmol, 12.3% yield, 97.9% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.74 - 8.69 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.46 - 7.37 (m, 5H), 5.11 - 5.06 (m, 1H), 4.41 - 4.22 (m, 2H), 3.60 (s, 3H), 2.96 - 2.88 (m, 3H), 2.86 - 2.77 (m, 2H), 2.60 - 2.58 (m, 1H), 2.41 - 2.34 (m, 1H), 2.32 - 2.28 (m, 1H), 2.01 - 1.97 (m, 1H). (ESI+) m/z: 461.2 (M+H)+, (C25H24N4O3S). EXAMPLE 470 [1615] Synthesis of (S)-3-(1-Oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [1616] A. tert-Butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl)isoindolin-2-yl)pentanoate: To a solution of 4-bromo-5-phenyl-1-(2,2,2- trifluoroethyl)-1H-pyrazole (0.60 g, 1.97 mmol, 1.00 eq) and tert-butyl (S)-5-amino-5-oxo-4- (1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (873 mg, 1.97 mmol, 1.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added K3PO4 (834 mg, 3.93 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (164 mg, 196 μmol, 0.10 eq). The mixture was stirred at 65 °C for 12 h under N2. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatrography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and preparative-HPLC (using a Welch Ultimate C18 (200 mm x 40 mm x 10 μm) and gradient of 35-65% acetonitrile in water 558 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT containing 0.5% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (0.30 g, 514 μmol, 26.1% yield, 92.9% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 543.1 (M+H)+, (C28H29F3N4O4). [1617] B. (S)-3-(1-oxo-5-(5-Phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)isoindolin- 2-yl)piperidine-2,6-dione: A mixture of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(5-phenyl- 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)isoindolin-2-yl)pentanoate (0.30 g, 552 μmol, 1.00 eq) and TsOH (380.87 mg, 2.21 mmol, 4.00 eq) in ACN (6.00 mL) was stirred at 65 °C for 12 h under N2. Then the reaction mixture was poured into 10.0 mL of water and extracted with EtOAc (3 x 10.0 mL). The combined organic layer was washed with brine (10.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and then by preparative-HPLC (using a Welch Ultimate C18 (150 mm x 25 mm x 10 μm) and gradient of 29-59% acetonitrile in water containing 0.5% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (140 mg, 298 μmol, 54.4% yield, 99.7% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.11 (s, 1H), 7.56 - 7.54 (m, 4H), 7.40 - 7.34 (m, 3H), 7.30 - 7.24 (m, 1H), 5.09 - 5.05 (m, 1H), 4.94 - 4.87 (m, 2H), 4.36 - 4.17 (m, 2H), 2.90 - 2.86 (m, 1H), 2.59 - 2.50 (m, 1H), 2.38 - 2.34 (m, 1H), 2.00 - 1.94 (m, 1H). (ESI+) m/z: 469.1 (M+H)+, (C24H19F3N4O3). EXAMPLE 471 [1618] Synthesis of (R)-3-(1-Oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)isoindolin-2-yl)piperidine-2,6-dione: [1619] A.4-Bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole: To a solution of 4-bromo-1H- pyrazole (3.00 g, 20.4 mmol, 1.00 eq) and Cs2CO3 (19.9 g, 61.2 mmol, 3.00 eq) in DMF (10.0 mL) was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.21 g, 22.4 mmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. Then the reaction mixture was quenched with 5.00 mL of water and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: 559 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT EtOAc = 100: 1 to 10: 1, Rf = 0.40 (Petroleum ether: EtOAc = 10: 1)) to give the title compound (1.70 g, 7.42 mmol, 36.3% yield) as colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.55 (s, 1H), 4.68 (dd, J = 16.4, 8.4 Hz, 2H). (ESI+) m/z: 228.9 (M+H)+, (C5H4BrF3N2). [1620] B.4-Bromo-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole: To a solution of 4- bromo-1-(2,2,2-trifluoroethyl)pyrazole (500 mg, 2.18 mmol, 1.00 eq) and bromobenzene (342 mg, 2.18 mmol, 229 μL, 1.00 eq) in NMP (7.50 mL) was added Pd(OAc)2 (4.90 mg, 21.8 μmol, 0.01 eq), Davephos (17.1 mg, 43.6 μmol, 0.02 eq), Bu4NOAc (1.32 g, 4.37 mmol, 1.33 mL, 2.00 eq) and isobutric acid (57.7 mg, 655 μmol, 60.7 μL, 0.30 eq) under N2. The mixture was stirred at 100 °C for 16 h under N2. Then the reaction mixture was poured in to 10.0 mL of brine and extracted with EtOAc (3 x 10.0 mL). The combined organic layers were concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether: EtOAc = 10: 1, Rf = 0.60) to give the title compound (360 mg, 821 μmol, 37.6% yield, 69.5% purity in LCMS at 220 nm) as colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.56 - 7.51 (m, 3H), 7.40 - 7.35 (m, 2H), 4.69 (dd, J = 16.8, 8.4 Hz, 2H). (ESI+) m/z: 304.9 (M+H)+, (C11H8BrF3N2). [1621] C. tert-Butyl (R)-5-amino-5-oxo-4-(1-oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl)isoindolin-2-yl)pentanoate: To a solution of 4-bromo-5-phenyl-1-(2,2,2- trifluoroethyl)-1H-pyrazole (0.60 g, 1.97 mmol, 1.00 eq) and tert-butyl tert-butyl (R)-5- amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2- yl)pentanoate (873 mg, 1.97 mmol, 1.00 eq) in dioxane (10.0 mL) and H2O (1.00 mL) was added K3PO4 (834 mg, 3.93 mmol, 2.00 eq) and Ru-Phos-Pd-G3 (164 mg, 196 μmol, 0.10 eq). The mixture was stirred at 65 °C for 12 h under N2. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatrography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and preparative-HPLC (using a Welch Ultimate C18 (200 mm x 40 mm x 10 μm) and gradient of 31-61% acetonitrile in water containing 0.5% TFA over 15 min at a flow rate of 25 mL/min) to give the title compound (0.30 g, 514 μmol, 26.1% yield, 93.1% purity in HPLC at 220 nm) as a white solid. (ESI+) m/z: 543.1 (M+H)+, (C28H29F3N4O4). [1622] D. (R)-3-(1-Oxo-5-(5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)isoindolin- 2-yl)piperidine-2,6-dione: A mixture of tert-butyl (R)-5-amino-5-oxo-4-(1-oxo-5-(5-phenyl- 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)isoindolin-2-yl)pentanoate (0.30 g, 552 μmol, 1.00 eq) and TsOH (380.87 mg, 2.21 mmol, 4.00 eq) in ACN (6.00 mL) was stirred at 65 °C for 560 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 12 h under N2. Then the reaction mixture was poured into 10.0 mL of water and extracted with EtOAc (3 x 10.0 mL). The combined organic layer was washed with brine (10.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100: 1 to 50: 1; TLC, Dichloromethane: Methanol = 10: 1, Rf = 0.30) and then by preparative-HPLC (using a Welch Ultimate C18 (150 mm x 25 mm x 10 μm) and gradient of 29-59% acetonitrile in water containing 0.5% FA over 10 min at a flow rate of 25 mL/min) to give the title compound (100 mg, 212 μmol, 38.8% yield, 99.2% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.11 (s, 1H), 7.59 - 7.51 (m, 4H), 7.40 - 7.38 (m, 3H), 7.37 - 7.24 (m, 1H), 5.09 - 5.04 (m, 1H), 4.94 - 4.87 (m, 2H), 4.36 - 4.17 (m, 2H), 2.90 - 2.86 (m, 1H), 2.59 - 2.50 (m, 1H), 2.38 - 2.34 (m, 1H), 2.00 - 1.95 (m, 1H). (ESI+) m/z: 469.1 (M+H)+, (C24H19F3N4O3). EXAMPLE 472 [1623] Synthesis of (R)-3-(5-(1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1624] A.2,4-Dibromo-1-methyl-1H-imidazole: To a solution of 2,4,5-tribromo-1- methyl-imidazole (75.0 g, 235 mmol, 1.00 eq) in THF (2.25 L) was added EtMgBr (3.00 M, 86.2 mL, 258 mmol, 1.10 eq) slowly at 20 °C under N2 during 2 h. Then the reaction mixture was stirred at 20 °C for additional 2 h under N2.200 mL of water was added to the reaction mixture at 0 °C. The mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate = 3: 1)) to give the title compound (20.0 g, 83.3 mmol, 35.4% yield) as an off-white solid.1H NMR: (400 MHz, CDCl3) δ 6.95 (s, 1H), 3.61 (s, 3H). (ESI+) m/z: 239.0 (M+H)+, (C4H4Br2N2). [1625] B.4-Bromo-1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole: To a solution of 2,4-dibromo-1-methyl-imidazole (20.0 g, 83.3 mmol, 1.00 eq) in THF (200 mL) was added [4-(trifluoromethyl)phenyl]boronic acid (19.0 g, 100 mmol, 1.2 eq), K3PO4 (53.0 g, 250 mmol, 3.00 eq), Pd(OAc)2 (934 mg, 4.17 mmol, 0.05 eq) and tris(4- fluorophenyl)phosphane (1.31 g, 4.17 mmol, 0.05 eq). The mixture was stirred at 80 °C for 561 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 16 h under N2. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.55 (Petroleum ether: Ethyl acetate = 3: 1)) and reversed-phase HPLC (0.1% FA condition) to give the title compound (8.00 g, 26.2 mmol, 31.4% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.50 (s, 1H), 3.78 (s, 3H). (ESI+) m/z: 304.8 (M+H)+, (C11H8F3BrN2). [1626] C. tert-Butyl (R)-5-amino-4-(5-(1-methyl-2-(4-(trifluoromethyl)phenyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 4-bromo-1-methyl- 2-[4-(trifluoromethyl)phenyl]imidazole (659 mg, 2.16 mmol, 1.20 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added tert-butyl (4R)-5-amino-5-oxo-4-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]pentanoate (800 mg, 1.80 mmol, 1.00 eq), Pd(dtbpf)Cl2 (117 mg, 180 μmol, 0.10 eq) and K3PO4 (1.15 g, 5.40 mmol, 3.00 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into 20.0 mL of water and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1: 100, Rf = 0.60 (Petroleum ether: Ethyl acetate = 0: 1)) to give the title compound (600 mg, 1.10 mmol, 61.1% yield, 99.5% purity in HPLC at 220 nm) as yellow oil. (ESI+) m/z: 543.1 (M+H)+, (C28H29F3N4O4). [1627] D. (R)-3-(5-(1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl (4R)-5-amino-4-[5-[1- methyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (600 mg, 1.10 mmol, 1.00 eq) in ACN (12.0 mL) was added TsOH (1.14 g, 6.60 mmol, 6.00 eq). The mixture was stirred at 65 °C for 16 h. The reaction mixture was poured into 20.0 mL of water and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer were washed with brine (20.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.50) and preparative-HPLC (using a Phenomenex Luna C18 (200 mm x 40 mm 10 μm) and gradient of 8-38% acetonitrile in water containing 0.5% TFA over 12 min at a flow rate of 25.0 mL/min) to give the title compound (150.66 mg, 320 μmol, 28.7% yield, 99.5% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.11 - 8.03 (m, 4H), 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 13.2, 5.2 Hz, 1H), 4.45 (dd, J = 52.8, 562 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 17.2 Hz, 2H), 3.88 (s, 3H), 2.98 - 2.86 (m, 1H), 2.65 - 2.57 (m, 1H), 2.48 - 2.35 (m, 1H), 2.07 - 1.98 (m, 1H). (ESI+) m/z: 469.0 (M+H)+, (C24H19F3N4O3). EXAMPLE 473 [1628] Synthesis of (S)-3-(5-(1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: [1629] A.2,4-Dibromo-1-methyl-1H-imidazole: To a solution of 2,4,5-tribromo-1- methyl-imidazole (40.0 g, 125 mmol, 1.00 eq) in THF (1.20 L) was added EtMgBr (3.00 M, 46.0 mL, 138 mmol, 1.10 eq) slowly at 20 °C under N2 during 2 h. Then the reaction mixture was stirred at 20 °C for additional 2 h under N2.100 mL of water was added to the reaction mixture at 0 °C. The mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.50 (Petroleum ether: Ethyl acetate = 3: 1)) to give the title compound (11.0 g, 45.8 mmol, 36.5% yield) as an off-white solid.1H NMR: (400 MHz, CDCl3) δ 6.96 (s, 1H), 3.62 (s, 3H). (ESI+) m/z: 239.0 (M+H)+, (C4H4Br2N2). [1630] B.4-Bromo-1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole: To a solution of 2,4-dibromo-1-methyl-imidazole (80.0 g, 333 mmol, 1.00 eq) in THF (800 mL) was added [4-(trifluoromethyl)phenyl]boronic acid (76.0 g, 400 mmol, 1.2 eq), K3PO4 (29.0 g, 137 mmol, 3.00 eq), Pd(OAc)2 (514 mg, 2.29 mmol, 0.05 eq) and tris(2-furyl)phosphane (531 mg, 2.29 mmol, 0.05 eq). The mixture was stirred at 80 °C for 16 h under N2. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 5: 1, Rf = 0.55 (Petroleum ether: Ethyl acetate = 3: 1)) and reversed-phase HPLC (0.1% FA condition) to give the title compound (48.0 g, 157 mmol, 47.1% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.50 (s, 1H), 3.78 (s, 3H). (ESI+) m/z: 304.8 (M+H)+, (C11H8F3BrN2). [1631] C. tert-Butyl (S)-5-amino-4-(5-(1-methyl-2-(4-(trifluoromethyl)phenyl)-1H- imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 4-bromo-1-methyl- 2-(4-(trifluoromethyl)phenyl]imidazole (659 mg, 2.16 mmol, 1.20 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added tert-butyl (4S)-5-amino-5-oxo-4-[1-oxo-5-(4,4,5,5- 563 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]pentanoate (800 mg, 1.80 mmol, 1.00 eq), Pd(dtbpf)Cl2 (117 mg, 180 μmol, 0.10 eq) and K3PO4 (1.15 g, 5.40 mmol, 3.00 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into 20.0 mL of water and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 1: 100, Rf = 0.60 (Petroleum ether: Ethyl acetate = 0: 1)) to give the title compound (600 mg, 1.10 mmol, 60.7% yield, 98.9% purity in HPLC at 220 nm) as yellow oil. (ESI+) m/z: 543.1 (M+H)+, (C28H29F3N4O4). [1632] D. (S)-3-(5-(1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl (4S)-5-amino-4-[5-[1- methyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (600 mg, 1.10 mmol, 1.00 eq) in ACN (12.0 mL) was added TsOH (1.14 g, 6.60 mmol, 6.00 eq). The mixture was stirred at 65 °C for 16 h. The reaction mixture was poured into 20.0 mL of water and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer were washed with brine (20.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to get a residue. The residue was purified by preparative-TLC (SiO2, Dichloromethane: Methanol = 10: 1, Rf = 0.50) and preparative-HPLC (using a Phenomenex Luna C18 (200 mm x 40 mm 10 μm) and gradient of 8-38% acetonitrile in water containing 0.5% TFA over 12 min at a flow rate of 25.0 mL/min) to give the title compound (124.24 mg, 265 μmol, 23.9% yield, 100% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.09 - 8.03 (m, 4H), 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 13.2, 5.2 Hz, 1H), 4.44 (dd, J = 52.8, 17.2 Hz, 2H), 3.88 (s, 3H), 2.97 - 2.87 (m, 1H), 2.65 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H), 2.07 - 1.97 (m, 1H). (ESI+) m/z: 469.0 (M+H)+, (C24H19F3N4O3). EXAMPLE 474 [1633] Synthesis of (S)-3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: 564 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1634] A. tert-Butyl (S)-5-amino-4-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)- 1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 3-bromo-1-(difluoromethyl)-5- phenyl-1H-pyrazole (500 mg, 1.83 mmol, 1.00 eq) tert-butyl (R)-5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (813 mg, 1.83 mmol, 1.00 eq) and K3PO4 (777 mg, 3.66 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (2.00 mL) was added Ru-Phos-Pd-G3 (153 mg, 183 μmol, 0.10 eq) under N2.The mixture was stirred at 65 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 200: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.40). to give the title compound (750 mg, 1.40mmol, 76.7% yield, 95.6% purity in LCMS at 220 nm) as yellow solid.. (ESI+) m/z: 483.3 (M+H)+, (C27H28F2N4O4). [1635] B. (S)-3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl (R)-5-amino-4-(5-(1-(difluoromethyl)-5- phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (750 mg, 1.47 mmol, 1.00 eq) and TsOH (1.01 g, 5.88 mmol, 4.00 eq) in ACN (8.00 mL) under N2.The mixture was stirred at 65 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (200 x 40 mm x 10 μm) and gradient of 25.0% - 55.0% acetonitrile in water containing 0.50% TFA over 12 min at a flow rate of 25 mL/min) to give the title compound (248 mg, 567 μmol, 38.2% yield, 99.5% purity in HPLC at 220 nm) as white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.04 – 11.00 (m, 1H), 8.18 – 8.07 (m, 2H), 7.93 - 7.78 (m, 2H), 7.64 – 7.56 (m, 5H), 7.32 – 7.30 (m, 1H), 5.16 – 5.12 (m, 1H), 4.57 – 4.40 (m, 2H), 2.97 - 2.89 (m, 1H), 2.64 – 2.53 (m, 1H), 2.45 - 2.41 (m, 1H), 2.07 – 2.03 (m, 1H). (ESI+) m/z: 437.1 (M+H)+, (C23H18F2N4O3). EXAMPLE 475 [1636] Synthesis of (R)-3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione: 565 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1637] A. tert-Butyl (R)-5-amino-4-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)- 1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of 3-bromo-1-(difluoromethyl)-5- phenyl-1H-pyrazole (500 mg, 1.83 mmol, 1.00 eq) tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (813 mg, 1.83 mmol, 1.00 eq) and K3PO4 (777 mg, 3.66 mmol, 2.00 eq) in dioxane (10.0 mL) and H2O (2.00 mL) was added Ru-Phos-Pd-G3 (153 mg, 183 μmol, 0.10 eq) under N2.The mixture was stirred at 65 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 200: 1 to 20: 1, TLC: Dichloromethane: Methanol = 20: 1, Rf = 0.40). to give the title compound (850 mg, 1.59mmol, 76.7% yield, 95.4% purity in LCMS at 220 nm) as yellow solid.. (ESI+) m/z: 483.1 (M+H)+, (C27H28F2N4O4). [1638] B. (R)-3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of tert-butyl (S)-5-amino-4-(5-(1-(difluoromethyl)-5- phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (850 mg, 1.59 mmol, 1.00 eq) and TsOH (1.15 g, 6.66 mmol, 4.00 eq) in ACN (9.00 mL) under N2.The mixture was stirred at 65 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to get a residue at 45 °C. The residue was purified by preparative-HPLC (using a Phenomenex luna C18 (200 x 40 mm x 10 μm) and gradient of 25.0% - 55.0% acetonitrile in water containing 0.50% TFA over 12 min at a flow rate of 25 mL/min) to give the title compound (268 mg, 601 μmol, 36.3% yield, 100% purity in HPLC at 220 nm) as white solid. 1H NMR: (400 MHz, DMSO-d6) δ 11.01 – 11.00 (m, 1H), 8.18 – 8.08 (m, 2H), 7.87 - 7.65 (m, 2H), 7.64 – 7.56 (m, 5H), 7.32 – 7.30 (m, 1H), 5.16 – 5.12 (m, 1H), 4.57 – 4.40 (m, 2H), 2.97 - 2.89 (m, 1H), 2.64 – 2.53 (m, 1H), 2.45 - 2.41 (m, 1H), 2.07 – 2.03 (m, 1H). (ESI+) m/z: 437.1 (M+H)+, (C23H18F2N4O3). EXAMPLE 476 [1639] Synthesis of 3-(5-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: 566 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT [1640] A.1-Ethyl-4,5-diphenyl-1,3-dihydro-2H-imidazol-2-one: To a solution of 2- hydroxy-1,2-diphenyl-ethanone (1.00 g, 4.71 mmol, 1.00 eq) in ethylene glycol (1.50 mL) was added ethylurea (2.08 g, 23.6 mmol, 5.00 eq). The mixture was stirred at 165 °C for 1 h. The reaction mixture was colled to 20 °C and then added into H2O (20.0 mL), extracted with dichloromethane (3 x 10.0 mL). The organic phase was washed with brine (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuum to give a residue. The residue was triturated with MeCN (2 mL) at 20 oC for 5 mins. The precipitated was filtered and the filter cake was concentrated in vacuum to give the title compound (283 mg, 1.00 mmol, 21.3% yield, 92.5% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.51 - 7.45 (m, 3H), 7.42 - 7.37 (m, 2H), 7.21 - 7.16 (m, 2H), 7.15 - 7.07 (m, 3H), 3.44 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H) . (ESI+) m/z: 236.1 (M+1)+, (C17H16N2O). [1641] B.2-Bromo-1-ethyl-4,5-diphenyl-1H-imidazole: To a solution of 3-ethyl-4,5- diphenyl-1H-imidazol-2-one (283 mg, 1.00 mmol, 1.0 eq) in toluene (3.00 mL) was degassed and purged with N2 for 3 times, and then was added POBr3 (435 mg, 1.50 mmol, 153 μL, 1.50 eq). The mixture was stirred at 110 °C for 6 h under N2 atmosphere. The reaction mixture was colled to 20 °C and then added into saturated aqueous solution of NaHCO3 (20.0 mL), extracted with dichloromethane (3 x 10.0 mL). The organic phase was washed with brine (3 x 50.0 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 1/0 to 20/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.70) to give the title compound (162 mg, 494 μmol, 49.3% yield, 99.7% purity in LCMS at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.59 - 7.50 (m, 3H), 7.48 - 7.40 (m, 2H), 7.30 (d, J = 7.2 Hz, 2H), 7.09 - 7.09 (m, 1H), 7.22 - 7.08 (m, 2H), 3.77 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). (ESI+) m/z: 328.8 (M+1)+, (C17H15BrN2). [1642] C.3-(5-(1-Ethyl-4,5-diphenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione: To a solution of 2-bromo-1-ethyl-4,5-diphenyl-imidazole (142 mg, 433 μmol, 1.00 eq) in dioxane (1.50 mL) and H2O (75.0 μL) was added 3-[1-oxo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (320 mg, 865 μmol, 2.00 eq) and K3PO4 (184 mg, 865 μmol, 2.00 eq) degassed and purged with N2 for 3 times, and then was added RuPhos Pd G3 (36.2 mg, 43.3 μmol, 0.10 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was filtered, washed with dichloromethane (20.0 mL) and the filtrate was concentrated in vacuum to give the residue. 567 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT The residue was purified by column chromatography (SiO2, Dichloromethane/Methanol = 1/0 to 20/1, TLC: Dichloromethane/Methanol = 20/1, Rf = 0.30) and then purified by Prep-HPLC (column: CD01-Phenomenex luna C18150 x 25 x 10um; mobile phase: [water(TFA)-ACN]; gradient: 20%-50% B over 10 min) to give the title compound (97.6 mg, 199 μmol, 45.9% yield, 99.8% purity in HPLC at 220 nm) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.09 (s, 1H), 7.99 (s, 2H), 7.69 - 7.58 (m, 3H), 7.58 - 7.50 (m, 2H), 7.46 - 7.38 (m, 2H), 7.37 - 7.23 (m, 3H), 5.19 (dd, J = 5.2, 13.6 Hz, 1H), 4.65 - 4.59 (m, 1H), 4.53 - 4.47 (m, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.02 - 2.87 (m, 1H), 2.64 (br dd, J = 1.2, 17.6 Hz, 1H), 2.48 - 2.35 (m, 1H), 2.05 (br d, J = 3.2 Hz, 1H), 1.08 - 0.91 (m, 3H). (ESI+) m/z: 491.2 (M+1)+, (C30H26N4O3). EXAMPLE 477 [1643] HiBit Assays [1644] Procedure A [1645] CSNK1A1-HiBit KI HEK293(LgBit) Cells (Promega Catalog # CS3023103; Lot# 0000449125) and HiBit-GSPT1 KI HEK293(LgBit) Cells (Promega Catalog # CS302381; Lot# 0000381455) were maintained in DMEM (Thermo Fisher Scientific, Catalog # 11965126) containing 10% Fetal Bovine Serum (Thermo Fisher Scientific, Catalog # 16140071) 1% Penicillin-Streptomycin (Thermo Fisher Scientific, Catalog # 25200056) and 200 µg/ml Hygromycin (Thermo Fisher Scientific, Catalog # 10687010). Cells were maintained at 37 °C in a 5% CO2 environment. [1646] Compounds were spotted onto Cornin 384-Well, Cell Culture-Treated, Flat-Bottom, Low Flange Microplate (Fisher Scientific, Catalog # 07-201-013) using a Tecan D300e digital dispenser. Ten-point dose response curves spanning from 10 µM to 0.005 µM with a 0.1% DMSO tolerance were used. [1647] Cells were dissociated from tissue 182cm2 Tissue Culture Flask (CellTreat Catalog# 229351) by washing the cells with PBS (Fisher Scientific Catalog # BP3994) followed by dissociation with Trypsin-EDTA (0.25%) (Thermo Scientific Catalog # 25200056). Trysin was neutralized and cells were resuspended with DMEM+10% FBS. Cells were centrifuged for 5 minutes at 1200 RPMs. Cell culture media was aspirated off and cells were resuspended with DMEM+10% FBS. Cell density was determined using a Denovix CellDrop BF cell counter. Cell density was adjusted to 1 x 106 cells/ml. 40µl of cells was added to compound treated tissue culture plates and incubated for six hours at 37 °C. After six hours, cell culture plates were removed from tissue culture incubator and cooled to room 568 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT temperature. 40µl of Nano-GloHiBiT Lytic Detection Reagent (Promega, Catalog # N3040) was added to each well. Plates were placed on an orbital shaker (600 rpm) for 20 minutes. Luminescence was measured using an Envsion plate reader (Perkin Elmer). DC50 curves and were generated using a 4-parameter curve fit with GraphPad Prism software (Prism . [1648] Procedure B [1649] Molt 4_hGSPT1_HiBIT N-terminus tagged cells were generated using CRISPR technology. Cells were maintained in RPMI media (Thermo Fisher Scientific, Catalog # 11875-093) containing 10% Fetal Bovine Serum (Thermo Fisher Scientific, Catalog # 16140071) 1% Penicillin-Streptomycin (Thermo Fisher Scientific, Catalog # 25200056). Cells were maintained at 37 °C in a 5% CO2 environment. [1650] Compounds were spotted onto Cornin 384-Well, Cell Culture-Treated, Flat-Bottom, Low Flange Microplate (Fisher Scientific, Catalog # 07-201-013) using a Tecan D300e digital dispenser. Ten-point dose response curves spanning from 10 µM to 0.005 µM with a 0.1% DMSO tolerance were used. [1651] Cells were centrifuged for 5 minutes at 1200 RPMs. Cell culture media was aspirated off and cells were resuspended with RPMI+10% FBS. Cell density was determined using a Denovix CellDrop BF cell counter. Cell density was adjusted to 1 x 106 cells/ml. 40 µl of cells was added to compound treated tissue culture plates and incubated for six hours at 37 °C. After six hours, cell culture plates were removed from tissue culture incubator and cooled to room temperature. 40 µl of Nano-GloHiBiT Lytic Detection Reagent (Promega, Catalog # N3040) was added to each well. Plates were placed on an orbital shaker (600 rpm) for 20 minutes. Luminescence was measured using an Envsion plate reader (Perkin Elmer). IC50 curves and Ymin were generated using a 4-parameter curve fit with GraphPad Prism software (Prism Corporation). [1652] Results [1653] Results from the HiBiT assay (DC50 (nM) and Ymin (% remaining)) are shown below. The compounds were tested by one of the two methods (Procedure A or Procedure B). 569 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 570 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 571 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 572 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 573 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 574 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT A = <25 nM, B = ≥25 nM, C = 0 – 10 % remaining, D = >10 – 25 % remaining, E = >25 – 75 % remaining, F = >75 – 100 % remaining 575 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 576 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 577 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT A = <25 nM, B = ≥25 nM, C = 0 – 10 % remaining, D = >10 – 25 % remaining, E = >25 – 75 % remaining, F = >75 – 100 % remaining [1654] This disclosure is not to be limited in scope by the embodiments disclosed in the examples which are intended as single illustrations of individual aspects, and any equivalents are within the scope of this disclosure. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. [1655] Various references such as patents, patent applications, and publications are cited herein, the disclosures of which are hereby incorporated by reference herein in their entireties. 578 1103861084\1\AMERICAS

Claims

ATTY DKT. NO.129824.00006 INVO 108 PCT WHAT IS CLAIMED IS: 1. A compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein: X11, X12, and X13 are each independently CR, CRx, N, NR, or NRx; X14 is N or C; wherein when X14 is N, exactly one of X11, X12, and X13 is N, NR, or NRx and when X14 is C, exactly two of X11, X12, and X13 are N, NR, or NRx; and wherein when Ar is aryl or heteroaryl, at least one of X11, X12, and X13 must be CRx or NRx; Ar is aryl; heteroaryl optionally substituted with one or more alkyl group; -C0-C4- alkylene-NH-heterocyclyl wherein the heterocyclyl is optionally substituted with one or more alkyl groups which are independently selected; or -C0-C4-alkylene-NH-heteroaryl wherein the heteroaryl is optionally substituted with one or more alkyl groups which are independently selected; each Rx is independently cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups which are independently selected; heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups which are independently selected; aryl optionally substituted with one or more groups selected from alkyl, halo, or alkyloxy which are independently selected; or -C0-C4-alkylene-C(O)- heterocyclyl; and each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. 2. The compound of claim 1, wherein the compound of Formula V is selected from: acceptable salt thereof. 579 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 3. The compound of claim 2, wherein the compound of Formula a pharmaceutically acceptable salt thereof. 4. The compound of any one of claims 1-3, wherein Ar is C0-C4-alkylene-NH- heterocyclyl wherein the heterocyclyl is optionally substituted with one or more alkyl groups which are independently selected or C0-C4-alkylene-NH-heteroaryl wherein the heteroaryl is optionally substituted with one or more alkyl groups which are independently selected; or a pharmaceutically acceptable salt thereof. 5. The compound of any one of claims 1-3, wherein Ar is C2-alkylene-NH- heterocyclalkyl wherein the heterocycloalkyl is optionally substituted with one or more alkyl groups which are independently selected or C2-alkylene-NH-heteroaryl wherein the heteroaryl is optionally substituted with one or more alkyl groups which are independently selected; or a pharmaceutically acceptable salt thereof. 6. The compound of any one of claims 1-5, wherein R is unsubstituted alkyl; or a pharmaceutically acceptable salt thereof. 7. The compound of any one of claims 1-2, wherein Rx is cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 8. The compound of any one of claims 1-2 and 7, wherein Rx is cycloalkylalkyl wherein the cycloalkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 9. The compound of any one of claims 1-2 and 7, wherein Rx is cycloalkylalkyl wherein the alkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; or a pharmaceutically acceptable salt thereof. 10. The compound of any one of claims 1-2, wherein Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups which are independently selected; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 11. The compound of any one of claims 1-2 and 10, wherein Rx is heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one C1- C3alkyl group which are independently selected and wherein the heterocycloalkyl is a 4- to 7- 580 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 12. The compound of any one of claims 1-2, wherein Rx is aryl optionally substituted with one or more groups independently selected from alkyl, halo, and alkyloxy; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 13. The compound of any one of claims 1-2 and 12, wherein Rx is unsubstituted aryl; or a pharmaceutically acceptable salt thereof. 14. The compound of any one of claims 1-2 and 12, wherein Rx is aryl optionally substituted with one or more groups independently selected from methyl, Cl, F, and methoxy; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 15. The compound of any one of claims 12-14, wherein Rx is phenyl optionally substituted with one or more groups independently selected from alkyl, halo, and alkyloxy; optionally wherein only one Rx is present; or a pharmaceutically acceptable salt thereof. 16. The compound of any one of claims 1-2 and 7-15, wherein Ar is aryl; or a pharmaceutically acceptable salt thereof. 17. The compound of claim 16, wherein Ar is phenyl; or a pharmaceutically acceptable salt thereof. 18. A compound of Formula I and I’: or a pharmaceutically acceptable salt thereof, wherein: X and Ar are selected from (i) or (ii): (i) X is O; and Ar is alkyl, heteroaryl, is phenyl fused to a heterocyclyl ring, cycloalkyl, indanyl, phenyl, or heterocycloalkyl; or (ii) X is S; and Ar is aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl or a 5-7 membered heterocycloalkenyl; wherein the alkyl, heteroaryl, phenyl fused to a heterocyclyl ring, cycloalkyl, indanyl, phenyl, phenylalkyl, heterocycloalkyl (alone or as part of another group), aryl, C5- 7cycloalkyl, C5-7cycloalkenyl, 5-7 membered heterocyclyl, and 5-7 membered heterocycloalkenyl, each of Ar, are each optionally substituted; E is according to any one of the following formulae: 581 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT wherein R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein R5-R7 are each independently H or alkyl; and R is H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted; with the proviso that the compound is not 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3-(1-oxo-5-(5-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-phenylthiazol-4-yl) isoindolin-2-yl) piperidine-2, 6-dione; 3-(1-oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(5-(2-ethyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3-(5-(2-isobutyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(2-isopropyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-cyclopropyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; or 3-(5-(2-(difluoromethyl)-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein: 582 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT (i) X is O; and Ar is alkyl, heteroaryl, is phenyl fused to a heterocyclyl ring, cycloalkyl, indanyl, phenyl, phenylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or (ii) X is S and Ar is aryl; wherein the alkyl of Ar is optionally substituted with heterocycloalkyl or phenyl; the aryl, heteroaryl, phenyl fused to a heterocyclyl ring, and phenyl, each of Ar, is substituted with 1, 2, or 3 R8; and each R8 is independently selected from H; halo; OR’ where R’ is H, alkyl, or haloalkyl; -CN; alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo and OR’ where R’ is H, alkyl, or haloalkyl; -C(O)R' where R’ is alkyl; -CONR'R" where R’ and R” are independently H or alkyl or R’ and R” together with the nitrogen to which they are attached form heterocycloalkyl (optionally substituted with alkyl); cycloalkyl; 2-oxo-1,2-dihydropyridin-1-yl; heterocycloalkyl (optionally substituted with alkyl); heteroaryl; or phenyl; the cycloalkyl of Ar is optionally substituted with 1, 2, or 3 groups independently selected from halo; OR’ where R’ is alkyl; and alkyl optionally substituted with 1, 2, or 3 halo; the heterocycloalkyl of Ar, is optionally substituted with alkyl optionally substituted with 1, 2, or 3 groups halo which are independently selected; benzyl; or -C(O)R’ where R’ is alkyl; and the alkyl of R is optionally substituted with 1, 2, or 3 halo which are independently selected or substituted with cycloalkyl or heterocycloalkyl; wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo; wherein the heterocycloalkyl is optionally substituted with 1 or 2 alkyl which are independently selected. 20. The compound of claim 18 or 19, according to Formula Ia: or a pharmaceutically acceptable salt thereof, wherein: Ar is phenyl substituted with 1, 2, or 3 R8;and R is independently alkyl, cycloalkyl or heterocycloalkyl; where the alkyl of R is optionally substituted with OR’ where R’ is alkyl or with 1, 2, or 3 halo groups. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein: Ar is phenyl substituted with 1, 2, or 3 R8;and 583 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT R is independently methyl, isopropyl, tert-butyl, trifluoromethyl, methoxymethyl, cyclopropyl or 4-pyranyl; or R is C1-C3 alkyl or cyclopropyl. 22. The compound of claim 18 that has Formula Ib: or a pharmaceutically acceptable salt thereof, wherein: Ar is heteroaryl or is phenyl fused to a heterocyclyl ring; and R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl wherein the alkyl is optionally substituted with 1, 2, or 3 halo which are independently selected. 23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein: Ar is heteroaryl; and R is independently H or alkyl wherein the alkyl is optionally substituted with 1, 2, or 3 halo which are independently selected. 24. The compound of claim 22 or claim 23, or a pharmaceutically acceptable salt thereof, wherein: Ar is thienyl, pyridyl, pyrrolyl, pyrazolyl, indolyl, benzofuryl, pyridopyrazolyl, benzimidazolyl or indazolyl; and R is independently H, methyl, difluoromethyl, or trifluoromethyl. 25. The compound of any one of claims 22-24, wherein: Ar is: , , , , , 584 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT R is independently H, methyl, difluoromethyl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 26. The compound of claim 22, wherein: Ar is phenyl fused to a heterocyclyl ring; and R is independently H, alkyl, or haloalkyl; or a pharmaceutically acceptable salt thereof. 27. The compound of claim 26, wherein: Ar is: R is independently H, methyl, difluoromethyl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 28. The compound of claim 18 or 19, where the compound is according to Formula Ib: or a pharmaceutically acceptable derivative thereof, wherein i) Ar is phenyl and is substituted with at least one R8 that is not H; or ii) Ar is phenyl substituted with 1, 2, or 3 R8 and R is alkyl substituted with cycloalkyl where the cycloalkyl is optionally substituted with one or two halo; or iii) Ar is phenyl substituted with1, 2, or 3 R8 and R is alkyl substituted with heterocycloalkyl where the heterocycloalkyl is optionally substituted with one or two alkyl; 585 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT iv) Ar is phenyl substituted with1, 2, or 3 R8 and when are each CR4, then at least one R4 is not H (preferably at least one R4 is halo). 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein at least one R8 is heterocycloalkyl (in some embodiments, piperazinyl, morpholinyl, methyl- substituted piperidinyl) where the heterocycloalkyl is optionally substituted with alkyl); - CONR'R" where R’ and R” are independently H or alkyl or R’ and R” together with the nitrogen to which they are attached form heterocycloalkyl (in some embodiments, pyrrolidinyl) where the heterocycloalkyl is optionally substituted with alkyl); 2-oxo-1,2- dihydropyridin-1-yl; heteroaryl (in some embodiments, pyrazolyl); OR’ where R’ is H or alkyl optionally substituted with 1, 2, or 3 halo which are independently selected (in some embodiments, methoxy, -OCHF2); halo (fluoro, chloro); -CN; or alkyl optionally substituted with OR’ where R’ is alkyl. 30. The compound of claim 18 or 19, where the compound is according to: or a pharmaceutically acceptable derivative thereof, wherein Ar is cycloalkyl (in some embodiments, cyclopentyl, cyclohexyl), heterocycloalkyl (in some embodiments, piperidinyl, pyranyl, furanyl, tetrahydro-2H-thiopyranyl), or alkyl optionally substituted with heterocycloalkyl (in some embodiments, isopropyl, piperidinyl); and the cycloalkyl of Ar is optionally substituted with 1, 2, or 3 groups independently selected from halo; OR’ where R’ is alkyl; and alkyl optionally substituted with 1, 2, or 3 halo; and the heterocycloalkyl of Ar, is optionally substituted with alkyl optionally substituted with 1, 2, or 3 groups halo which are independently selected; benzyl; or -C(O)R’ where R’ is alkyl. 31. A compound of Formula II: 586 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT or a pharmaceutically acceptable salt thereof, wherein: E is according to any one of the following formulae: , R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Het is heteroaryl; alkyl; OR’ where R’ is alkyl; cycloalkyl optionally substituted with 1 or 2 groups independently selected from halo; heterocycloalkyl optionally substituted with benzyl; heterocycloalkylalkyl; or aryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, and heteroaryl are each optionally substituted; with the proviso that the compound is not 3-(5-(3-methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione; 3-(1-oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6- dione; or 3-(1-oxo-5-(3-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6- dione. 32. The compound of claim 31, wherein the alkyl of Het is optionally substituted with 1, 2, or 3 groups independently selected from halo; OR’ where R’ is H or alkyl; NR’R” where R’ and R” are independently H or alkyl or where R’ and R” together with the nitrogen to which they are attached form 4-, 5-, 587 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 6-, or 7-membered heterocycloalkyl; -CO2R’ where R’ is alkyl; and -NR"C(O)R' where R” is H and R’ is alkyl; wherein the aryl and heteroaryl of Het are substituted with 1, 2, or 3 R9; where each R9 is independently H; halo; -CN; alkyl optionally substituted with 1, 2, or 3 halo which are independently selected; OR’ where R’ is H or alkyl; -CO2R’ where R’ is alkyl; or heterocycloalkyl (optionally substituted with alkyl). 33. The compound of claim 31 or 32, wherein Het is pyridyl, thiazolyl or pyrazinyl; or a pharmaceutically acceptable salt thereof. 34. The compound of any one of claims 31-33, wherein Het is pyridyl; or a pharmaceutically acceptable salt thereof. 35. The compound of any one of claims 31-34, wherein Het is 2-pyridyl; or a pharmaceutically acceptable salt thereof. 36. The compound of any one of claims of 31-33, wherein Het is 4-thiazolyl, 5-methyl- 2-pyridyl, 2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro-2-pyridyl, 6- methoxy-2-pyridyl, 2-pyrazinyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl or 5-methoxy-2-pyridyl; or a pharmaceutically acceptable salt thereof. 37. The compound of any one of claims 31-36, wherein Het is 5-methyl-2-pyridyl, 2- pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro-2-pyridyl, 6-methoxy-2- pyridyl, 4-methoxycarbonyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl or 5-methoxy-2-pyridyl; or a pharmaceutically acceptable salt thereof 38. The compound of any one of claims 18-30 that is according to: optionally wherein R5 is H; or a pharmaceutically acceptable salt thereof. 39. The compound of any one of claims 31-37 that is according to: optionally wherein R5 is H; or a pharmaceutically acceptable salt thereof. 588 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 40. The compound of any one of claims 18-21 that is according to: 42. A compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein: Ar is aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl, a 5-7 membered heterocycloalkenyl, or phenyl fused to a heterocyclyl ring; wherein the aryl, heteroaryl, C5-7cycloalkyl, C5-7cycloalkenyl, a 5-7 membered heterocyclyl, a 5-7 membered heterocycloalkenyl, or phenyl fused to a heterocyclyl ring, each of Ar, are each optionally substituted; R is H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl; E is according to any one of the following formulae: , R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 589 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein R5-R7 are each independently H or alkyl; and R is H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted; with the proviso that the compound is not 3-(1-oxo-5-(4-phenyl-4H-1,2,4-triazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; or 3-(5-(1-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione. 43. The compound of claim 42, wherein the compound is or a pharmaceutically acceptable salt thereof. 44. The compound of claim 42, wherein the compound is: or a pharmaceutically acceptable salt thereof, wherein: 45. The compound of any one of claims 42-44, wherein Ar is aryl, heteroaryl, C5- 7cycloalkyl, or phenyl fused to a heterocyclyl ring and R is H, optionally substituted alkyl, or cycloalkyl; or a pharmaceutically acceptable salt thereof. 46. The compound of any one of claims 42-45, wherein Ar is aryl, heteroaryl, C5- 7cycloalkyl, or phenyl fused to a heterocyclyl ring and R is H, optionally substituted alkyl, or cycloalkyl; wherein the aryl of Ar is optionally substituted with 1, 2, or 3 R8a wherein R8a is independently selected from OR’ where R’ is H, alkyl, or haloalkyl; alkyl optionally 590 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT substituted with 1, 2, or 3 groups independently selected from halo and OR’ where R’ is H, alkyl, or haloalkyl; -NR’R” where R’ and R” are independently H or alkyl; and halo; and the alkyl of R is optionally substituted with 1, 2, or 3 halo; or a pharmaceutically acceptable salt thereof. 47. The compound of any one of claims 42-46, wherein Ar is phenyl optionally substituted with 1 R8a selected from OR’ where R’ is H or alkyl; alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo; -NH2; and halo; or a pharmaceutically acceptable salt thereof. 48. The compound of any one of claims 42-46, wherein Ar is pyridyl, benzothiazolyl, benzofuranyl, indolyl, or cyclohexyl; or a pharmaceutically acceptable salt thereof. 49. The compound of any one of claims 42-46, wherein , ; or a pharmaceutically acceptable salt thereof. 50. The compound of any one of claims 42-49, wherein R is alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo; or a pharmaceutically acceptable salt thereof. 51. The compound of claim 50, wherein R is unsubstituted alkyl or alkyl substituted with 1, 2, or 3 fluoro; or a pharmaceutically acceptable salt thereof. 52. The compound of claim 42, wherein the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. 591 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 53. The compound of claim 42, wherein the compound is alkyl; or a pharmaceutically acceptable salt thereof. 54. A compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: X2, X3, X4, X5, X6, and X7 are independently selected from CR10 and N; X1 is O, NR11 or C(R10)2; wherein (a) at least two of X3-X6 are CR10; (b) when X1 is C(R10)2, X2 is N and when X2 is CR10, X1 is O or NR11; and (c) when X7 is CR10, X2 is N and when X2 is CR10, X7 is N; R9 is alkyl, halo, or aryl; R10 is independently selected from H, alkyl, alkoxy, and aryl; R11 is H, alkyl, or aryl wherein the aryl is optionally substituted with alkoxy or amino; n is 1 or 2; E is according to any one of the following formulae: 592 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT wherein R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1 and Y2 is S and the other is CR3, where R3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4 are each independently N or CR4, where each R4 is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein R5-R7 are each independently H or alkyl; with the proviso that the compound is not 3-(1-oxo-6-(pyrazolo[1,5-a]pyrimidin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1-ethyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; or 3-(6-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione. 55. The compound of claim 54, wherein X3-X6 are CH; or a pharmaceutically acceptable salt thereof. 56. The compound of claim 54, wherein one of X3-X6 is N and the others are CH; or a pharmaceutically acceptable salt thereof. 57. The compound of claim 54, wherein Ring pharmaceutically acceptable salt thereof. 593 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 58. The compound of claim 54, wherein Ring A is pharmaceutically acceptable salt thereof. 59. The compound of claim 54, wherein Ring pharmaceutically acceptable salt thereof. 3 1 4 X X X X5 X6 X2 60. The compound of claim 54, wherein Ring A is and pharmaceutically acceptable salt thereof. 61. The compound of claim 54, wherein Ring pharmaceutically acceptable salt thereof. 594 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 62. The compound of any one of claims 54, 55, and 61, wherein Ring pharmaceutically acceptable salt thereof. 64. The compound of claim 54, wherein the compound is , , 595 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT acceptable salt thereof. 65. The compound of claim 54, wherein the compound is salt thereof. 66. The compound of claim 54, wherein the compound is wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. 67. The compound of any one of claims 1-66, wherein E is: 69. The compound of any one of claims 1-66, wherein E is selected from: 596 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. 70. The compound of any one of claims 1-69, wherein E is according to: wherein R5 is H or alkyl; or a pharmaceutically acceptable salt thereof. 71. The compound of claim 70, wherein R5 is H. 72. The compound of any one of claims 67-69, wherein one or two R4 are independently halo and the other of the R4 are each H; optionally wherein one R4 is halo and the other of the R4 are each H; or a pharmaceutically acceptable salt thereof. 73. A compound or a pharmaceutically acceptable salt thereof, of any of Examples 1- 476. 74. A pharmaceutical composition, comprising the compound of any one of claims 1-73 and a pharmaceutically acceptable carrier. 75. A method of degrading CK1α in a cell or a subject, comprising contacting the cell with or administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 76. A method of inhibiting Card11/BCL10/MALT1 (CBM) complex activation in a subject, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 597 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 77. A method of regulating cellular proliferation in a subject or treating a subject having a proliferative disease, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 78. A method of treating a subject having cancer, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 79. The method of claim 78, wherein the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome, (MDS) (including 5q-MDS), colon cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B- cell lymphoma or mantle cell lymphoma (MCL). 80. The method of claim 78 or claim 79, wherein the cancer is a B-cell lymphoma. 81. The method of claim 78 or claim 79, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL). 82. The method of claim 80, wherein the DLBCL is ABC DLBCL. 83. The method of claim 82, wherein the cancer is a BTK inhibitor resistant cancer, optionally wherein the BTK inhibitor resistant cancer is ibrutinib resistant cancer. 84. The method of claim 83, wherein BTK inhibitor resistant cancer is resistant to one or more of acalabrutinib, zanubrutinib, pirtobrutinib, spebrutinib, evobrutinib, olmutinib, tirabrutinib, elsubrutinib (ABBV-105), tolebrutinib (SAR 442168), fenebrutinib, vacabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068 and DTRMWXHA-12. 85. The method of claim 83, wherein the BTK inhibitor resistant cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, or chronic graft-versus-host disease. 86. A method of degrading CK1α and GSPT1 in a cell or a subject, comprising contacting the cell with or administering to the subject the compound of any one of claims 1- 73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 87. A method of treating AML, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, stomach cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testis cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, hepatocellular carcinoma, a 598 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT lymphoma, or gastric cancer in a subject, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 88. A method of treating a subject having an autoimmune disorder, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 89. The method of claim 88, wherein the autoimmune disorder is Addison disease, Celiac disease - sprue (gluten-sensitive enteropathy), dermatomyositis, Graves’ disease, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, or type I diabetes. 90. The method of claim 88 or 89, further comprising administering to the subject a second active agent. 91. The method of claim 90, wherein the second active agent is a checkpoint inhibitor, such as an anti-CTLA-4, an anti-PD-1 or anti-PD-L1 antibody; optionally wherein the second active agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tramelimumab, or a combination thereof. 92. The method of claim 77, wherein the proliferative disease to be treated is melanoma including unresectable or metastatic melanoma, BRAF 600 mutation positive, and melanoma with lymph node involvement; non-small cell lung cancer including metastatic non-small cell lung cancer; renal cell carcinoma; Hodgkin lymphoma including relapsed/refractory Hodgkin lymphoma; squamous cell carcinoma of the head and neck including metastatic disease; urothelial carcinoma including metastatic disease; colorectal cancer including metastatic disease; or hepatocellular carcinoma. 93. A method of treating a RAS-driven cancer in a subject, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 94. The method of claim 93, wherein the RAS-driven cancer is a RAS-mutant cancer; optionally wherein the RAS-driven cancer is lung cancer, head and neck cancer, pancreatic cancer, breast cancer, colorectal cancer, gastrointestinal cancer, melanoma, myeloid cancer, bladder cancer, cervical cancer, ovarian cancer or uterine cancer. 95. The method of claim 93, wherein the RAS-driven cancer is a KRASG12D-driven cancer. 599 1103861084\1\AMERICAS ATTY DKT. NO.129824.00006 INVO 108 PCT 96. A method of preventing acquired resistance to erlotinib in EGFR-mutant non-small cell lung cancer in a subject, comprising administering to the subject the compound of any one of claims 1-73 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 74. 600 1103861084\1\AMERICAS
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Citations (98)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5033252A (en) 1987-12-23 1991-07-23 Entravision, Inc. Method of packaging and sterilizing a pharmaceutical product
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6740634B1 (en) 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof
WO2015200795A1 (en) 2014-06-27 2015-12-30 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon other e3 ubiquitin ligases
US20180215731A1 (en) 2017-01-31 2018-08-02 Arvinas, Inc. Cereblon ligands and bifunctional compounds comprising the same
WO2018169777A1 (en) 2017-03-14 2018-09-20 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
US20190017998A1 (en) 2015-12-28 2019-01-17 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases
WO2019043214A1 (en) 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Glutarimide
WO2019043217A1 (en) 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Dihydrobenzimidazolones
US20190076541A1 (en) 2016-05-10 2019-03-14 C4 Theraprutics, Inc. Heterocyclic degronimers for target protein degradation
WO2019078522A1 (en) 2017-10-20 2019-04-25 한국화학연구원 Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient
US20190233433A1 (en) 2018-01-26 2019-08-01 Yale University Imide-based modulators of proteolysis and associated methods of use
WO2019173224A1 (en) 2018-03-05 2019-09-12 Biotheryx, Inc. Deuterated compounds and chimeras and uses thereof
WO2019204354A1 (en) 2018-04-16 2019-10-24 C4 Therapeutics, Inc. Spirocyclic compounds
WO2019241271A1 (en) 2018-06-13 2019-12-19 Biotheryx, Inc. Fused thiophene compounds
WO2020006233A1 (en) 2018-06-29 2020-01-02 Dana-Farber Cancer Institute, Inc. Immunomodulatory compounds
US20200155690A1 (en) 2014-04-14 2020-05-21 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
WO2020118098A1 (en) 2018-12-05 2020-06-11 Vividion Therapeutics, Inc. Substituted isoindolinones as modulators of cereblon-mediated neo-substrate recruitment
US20200206201A1 (en) 2018-12-28 2020-07-02 Vividion Therapeutics, Inc. Cereblon modulators and uses thereof
US20200207733A1 (en) 2017-09-04 2020-07-02 C4 Therapeutics, Inc. Dihydroquinolinones for medical treatment
WO2020181232A1 (en) 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Heterocyclic compounds for medical treatment
WO2020263832A1 (en) 2019-06-24 2020-12-30 Dana-Farber Cancer Institute, Inc. E3 ligase binders and uses thereof
US20210009559A1 (en) 2018-03-26 2021-01-14 C4 Therapeutics, Inc. Cereblon binders for the degradation of ikaros
WO2021041664A1 (en) 2019-08-27 2021-03-04 The Regents Of The University Of Michigan Cereblon e3 ligase inhibitors
WO2021069705A1 (en) 2019-10-09 2021-04-15 Monte Rosa Therapeutics Isoindolinone compounds
WO2021086830A1 (en) 2019-10-28 2021-05-06 Celgene Corporation Use of biomarkers to predict clinical sensitivity to 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide
WO2021105334A1 (en) 2019-11-27 2021-06-03 Captor Therapeutics S.A. Piperidine-2, 6-dione derivatives which bind to cereblon, and methods of use thereof
US20210177825A1 (en) 2016-03-16 2021-06-17 H. Lee Moffitt Cancer Center And Research Institute, Inc. Small molecules against cereblon to enhance effector t cell function
WO2021143822A1 (en) 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Bicyclic imide derivative, preparation method thereof, and application thereof in medicine
WO2021143816A1 (en) 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Fused imide derivative, preparation method therefor and medical use thereof
WO2021147889A1 (en) 2020-01-20 2021-07-29 康朴生物医药技术（上海）有限公司 Isoindoline derivative, and pharmaceutical composition and use thereof
WO2021188537A1 (en) 2020-03-17 2021-09-23 Dana-Farber Cancer Institute, Inc. Selective small molecule degraders of cereblon
US20210403454A1 (en) 2020-06-24 2021-12-30 Celgene Corporation Cereblon binding compounds, compositions thereof, and methods of treatment therewith
WO2022007659A1 (en) 2020-07-06 2022-01-13 北京诺诚健华医药科技有限公司 Heterocyclic immunomodulator
WO2022017365A1 (en) 2020-07-20 2022-01-27 江苏恒瑞医药股份有限公司 Sulfur-containing isoindoline derivative, and preparation method therefor and medical use thereof
WO2022029573A1 (en) * 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022029138A1 (en) 2020-08-03 2022-02-10 Captor Therapeutics S.A. Low molecular weight protein degraders and their applications
WO2022066835A1 (en) 2020-09-23 2022-03-31 St. Jude Children's Research Hospital, Inc. Substituted n-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)arylsulfonamide analogs as modulators of cereblon protein
WO2022073469A1 (en) 2020-10-07 2022-04-14 Cullgen (Shanghai) , Inc. Compounds and methods of treating cancers
WO2022144416A1 (en) 2020-12-30 2022-07-07 Captor Therapeutics S.A. Novel compounds which bind to cereblon, and methods of use thereof
WO2022148358A1 (en) 2021-01-05 2022-07-14 江苏恒瑞医药股份有限公司 Cyclohexadiimide derivative substituted by fused heterocyclyl, and preparation method therefor and pharmaceutical application thereof
WO2024054832A1 (en) * 2022-09-09 2024-03-14 Innovo Therapeutics, Inc. CK1α AND DUAL CK1α / GSPT1 DEGRADING COMPOUNDS
WO2024192146A2 (en) * 2023-03-14 2024-09-19 Southern Research Institute Compounds for the treatment of cystic fibrosis

Patent Citations (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US4414209A (en) 1972-04-20 1983-11-08 Allen & Hanburys Limited Micronized aerosol steroids
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5033252A (en) 1987-12-23 1991-07-23 Entravision, Inc. Method of packaging and sterilizing a pharmaceutical product
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US6376461B1 (en) 1993-06-24 2002-04-23 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US6699500B2 (en) 1996-10-31 2004-03-02 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6740634B1 (en) 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20200155690A1 (en) 2014-04-14 2020-05-21 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
WO2015200795A1 (en) 2014-06-27 2015-12-30 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon other e3 ubiquitin ligases
US20190017998A1 (en) 2015-12-28 2019-01-17 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases
US20210177825A1 (en) 2016-03-16 2021-06-17 H. Lee Moffitt Cancer Center And Research Institute, Inc. Small molecules against cereblon to enhance effector t cell function
US20190076541A1 (en) 2016-05-10 2019-03-14 C4 Theraprutics, Inc. Heterocyclic degronimers for target protein degradation
US20180215731A1 (en) 2017-01-31 2018-08-02 Arvinas, Inc. Cereblon ligands and bifunctional compounds comprising the same
WO2018169777A1 (en) 2017-03-14 2018-09-20 Biotheryx, Inc. Compounds targeting proteins, compositions, methods, and uses thereof
WO2019043217A1 (en) 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Dihydrobenzimidazolones
WO2019043214A1 (en) 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Glutarimide
US20200207733A1 (en) 2017-09-04 2020-07-02 C4 Therapeutics, Inc. Dihydroquinolinones for medical treatment
US20200207764A1 (en) 2017-09-04 2020-07-02 C4 Therapeutics, Inc. Dihydrobenzimidazolones for medical treatment
WO2019078522A1 (en) 2017-10-20 2019-04-25 한국화학연구원 Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient
US20190233433A1 (en) 2018-01-26 2019-08-01 Yale University Imide-based modulators of proteolysis and associated methods of use
US20220112211A1 (en) 2018-01-26 2022-04-14 Yale University Imide-based modulators of proteolysis and associated methods of use
WO2019173224A1 (en) 2018-03-05 2019-09-12 Biotheryx, Inc. Deuterated compounds and chimeras and uses thereof
US20210009559A1 (en) 2018-03-26 2021-01-14 C4 Therapeutics, Inc. Cereblon binders for the degradation of ikaros
WO2019204354A1 (en) 2018-04-16 2019-10-24 C4 Therapeutics, Inc. Spirocyclic compounds
US20210032245A1 (en) 2018-04-16 2021-02-04 C4 Therapeutics, Inc. Spirocyclic compounds
WO2019241271A1 (en) 2018-06-13 2019-12-19 Biotheryx, Inc. Fused thiophene compounds
US20210284624A1 (en) 2018-06-29 2021-09-16 Dana-Farber Cancer Institute, Inc. Immunomodulatory compounds
WO2020006233A1 (en) 2018-06-29 2020-01-02 Dana-Farber Cancer Institute, Inc. Immunomodulatory compounds
WO2020118098A1 (en) 2018-12-05 2020-06-11 Vividion Therapeutics, Inc. Substituted isoindolinones as modulators of cereblon-mediated neo-substrate recruitment
US20200206201A1 (en) 2018-12-28 2020-07-02 Vividion Therapeutics, Inc. Cereblon modulators and uses thereof
US20220062248A1 (en) 2018-12-28 2022-03-03 Vividion Therapeutics, Inc. Cereblon modulators and uses thereof
WO2020181232A1 (en) 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Heterocyclic compounds for medical treatment
WO2020263832A1 (en) 2019-06-24 2020-12-30 Dana-Farber Cancer Institute, Inc. E3 ligase binders and uses thereof
WO2021041664A1 (en) 2019-08-27 2021-03-04 The Regents Of The University Of Michigan Cereblon e3 ligase inhibitors
WO2021069705A1 (en) 2019-10-09 2021-04-15 Monte Rosa Therapeutics Isoindolinone compounds
WO2021086830A1 (en) 2019-10-28 2021-05-06 Celgene Corporation Use of biomarkers to predict clinical sensitivity to 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide
WO2021105334A1 (en) 2019-11-27 2021-06-03 Captor Therapeutics S.A. Piperidine-2, 6-dione derivatives which bind to cereblon, and methods of use thereof
WO2021143822A1 (en) 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Bicyclic imide derivative, preparation method thereof, and application thereof in medicine
WO2021143816A1 (en) 2020-01-16 2021-07-22 江苏恒瑞医药股份有限公司 Fused imide derivative, preparation method therefor and medical use thereof
WO2021147889A1 (en) 2020-01-20 2021-07-29 康朴生物医药技术（上海）有限公司 Isoindoline derivative, and pharmaceutical composition and use thereof
WO2021188537A1 (en) 2020-03-17 2021-09-23 Dana-Farber Cancer Institute, Inc. Selective small molecule degraders of cereblon
US20210403454A1 (en) 2020-06-24 2021-12-30 Celgene Corporation Cereblon binding compounds, compositions thereof, and methods of treatment therewith
WO2022007659A1 (en) 2020-07-06 2022-01-13 北京诺诚健华医药科技有限公司 Heterocyclic immunomodulator
WO2022017365A1 (en) 2020-07-20 2022-01-27 江苏恒瑞医药股份有限公司 Sulfur-containing isoindoline derivative, and preparation method therefor and medical use thereof
WO2022029573A1 (en) * 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022029138A1 (en) 2020-08-03 2022-02-10 Captor Therapeutics S.A. Low molecular weight protein degraders and their applications
WO2022066835A1 (en) 2020-09-23 2022-03-31 St. Jude Children's Research Hospital, Inc. Substituted n-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)arylsulfonamide analogs as modulators of cereblon protein
WO2022073469A1 (en) 2020-10-07 2022-04-14 Cullgen (Shanghai) , Inc. Compounds and methods of treating cancers
WO2022144416A1 (en) 2020-12-30 2022-07-07 Captor Therapeutics S.A. Novel compounds which bind to cereblon, and methods of use thereof
WO2022146151A1 (en) 2020-12-30 2022-07-07 Captor Therapeutics S.A. Novel compounds which bind to cereblon, and methods of use thereof
WO2022148358A1 (en) 2021-01-05 2022-07-14 江苏恒瑞医药股份有限公司 Cyclohexadiimide derivative substituted by fused heterocyclyl, and preparation method therefor and pharmaceutical application thereof
WO2024054832A1 (en) * 2022-09-09 2024-03-14 Innovo Therapeutics, Inc. CK1α AND DUAL CK1α / GSPT1 DEGRADING COMPOUNDS
WO2024192146A2 (en) * 2023-03-14 2024-09-19 Southern Research Institute Compounds for the treatment of cystic fibrosis

Non-Patent Citations (42)

* Cited by examiner, † Cited by third party
Title
"Ansel Introduction to Pharmaceutical Dosage Forms", 1999
"Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines", JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 92, no. 3, 2000, pages 205 216
BEDSAUL ET AL., FRONT. ONC., vol. 8, 2018
BIDERE ET AL., NATURE, vol. 458, no. 7234, 2009, pages 7234 - 96
BISWAS ET AL., FRONTIERS IN IMMUNOLOGY, vol. 13, 2022, pages 875320
BOWMAN ET AL., SCI. SIGNAL., vol. 8, no. 361, 2016, pages 9
BUCHWALD ET AL., SURGERY, vol. 88, 1980, pages 507
CHARLINSKI ET AL., CANCERS, vol. 13, 2021, pages 4666
CHEONG ET AL., CLIN. INVEST., vol. 125, no. 4, 2015, pages 1401 - 1418
CHEONG ET AL., MOL. CELL. ONC., vol. 3, no. 3, 2016, pages 1045117
DI PILATO ET AL., NATURE, vol. 570, no. 7759, 2019, pages 112 - 116
GEHRING ET AL., CELL REPORTS, vol. 29, 2019, pages 873 - 888
GOODSON, MEDICAL APPLICATIONS OF CONTROLLED RELEASE, vol. 2, 1984, pages 115 - 138
HAMILTON G S, BIOLOGICALS, vol. 43, no. 5, September 2015 (2015-09-01), pages 318 - 32
HUART ET AL., J. BIOL. CHEM., vol. 284, no. 47, 2009, pages 32384 - 32394
HUART ET AL., PLOS ONE, vol. 7, no. 8, 2012, pages 43391
JENS T. CARSTENSEN: "Drug Stability: Principles & Practice", 1995, MARCEL DEKKER, pages: 379 - 80
JIANG ET AL., CELL COMMUN. SIGNALING, vol. 16, 2018, pages 23
JUILLAND ET AL., CURR. OPIN. HEMAT., vol. 23, no. 4, 2016, pages 402 - 409
KIM E GKIM K M, BIOMOL. THER. (SEOUL, vol. 23, no. 6, November 2015 (2015-11-01), pages 493 - 509
KOCIK ET AL., CANCERS, vol. 11, 2019, pages 1014
LANGER, SCIENCE, vol. 249, 1990, pages 1527 - 1533
LANTERMANN ET AL., CANCER RES., vol. 75, no. 22, 2015, pages 4937 - 4948
LIANG ET AL., MOD. PATHOL., vol. 23, no. 3, 2010, pages 389 - 91
MANNI ET AL., FRONT. ONCOL, vol. 11, 2021
MANNI ET AL., FRONT. ONCOL., vol. 11, 2021
NISHIGUCHI ET AL., J. MED. CHEM., vol. 64, 2021, pages 7296 - 7311
OLSEN DJORGENSEN J T, FRONT. ONCOL., vol. 4, 16 May 2014 (2014-05-16), pages 105
PETERS CBROWN S, BIOSCI. REP., vol. 35, no. 4, 12 June 2015 (2015-06-12), pages 00225
POWELL ET AL., ACS CHEM. BIOL., vol. 15, 2020, pages 2722 - 2730
ROSENBAUM ET AL., NAT. COMMUN, vol. 10, no. 1, 2019, pages 2352
ROSENBAUM ET AL., NAT. COMMUN., vol. 10, no. 1, 2019, pages 2352
SABA ET AL., CANCER RES., vol. 77, no. 24, 2017, pages 7038 - 7048
SAUDEK ET AL., N. ENGL. J. MED., vol. 321, 1989, pages 574
SEFTON, CRC CRIT. REF. BIOMED. ENG., vol. 14, 1987, pages 201
SPINELLO ET AL., INT. J. MOL. SCI, vol. 22, 2021, pages 3716
TABE ET AL., CLIN. CANCER RES, vol. 15, no. 3, 2009, pages 933 - 942
TABE ET AL., CLIN. CANCER RES., vol. 15, no. 3, 2009, pages 933 - 942
WU ET AL., MOL. CELL. BIOL., vol. 32, no. 23, 2012, pages 4821 - 4832
YIN ET AL., CELL. MOL. LIFE SCI, vol. 79, 2022, pages 112
YIN ET AL., CELL. MOL. LIFE SCI., vol. 79, 2022, pages 112
ZHANG ET AL., ONCOGENE, vol. 37, 2018, pages 363 - 376

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