Protein degrading compounds

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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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 X14are 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\AMERICASATTY 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\AMERICASATTY 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-C10means one to ten carbons). 7 1103861084\1\AMERICASATTY 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-C10means 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-OCH3and –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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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., -CF3and –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\AMERICASATTY 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\AMERICASATTY 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 R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and 13 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT Z1-Z4are each independently N or CR4, where each R4is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andwherein R5-R7are 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 R8is 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\AMERICASATTY 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 R8and R is independently methyl, isopropyl, tert-butyl, trifluoromethyl, methoxymethyl, cyclopropyl or 4-pyranyl; or R is C1-C3alkyl 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\AMERICASATTY 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\AMERICASATTY 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 isor a pharmaceutically acceptable derivative thereof, wherein i) Ar is phenyl and is substituted with at least one R8that is not H; or ii) Ar is phenyl substituted with 1, 2, or 3 R8and 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 R8and 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 R8and whenand Z1-Z3are each CR4, then at least one R4is not H (preferably at least one R4is halo).

[0066] In one embodiment of Formula Ib, including any of the foregoing, at least one R8is 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\AMERICASATTY 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:R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 18 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is 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 R9is 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\AMERICASATTY 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 ispharmaceutically 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 iswherein R5is 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 iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. In a further embodiment, R5is H; or a pharmaceutically acceptable salt thereof. 20 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0079] In one embodiment of Formula I, Ia, or Ib, including any of the foregoing, the compoundoptionally wherein R5is H; or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment of Formula II, including any of the foregoing, the compound isoptionally wherein R5is H; or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment of Formula I or Ia, including any of the foregoing, the compoundpharmaceutically acceptable salt thereof.

[0082] In one embodiment of Formula I or Ib, including any of the foregoing, the compoundoptionally wherein R5is 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTE 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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; R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is 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-R7are 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTwherein R5is H or alkyl.

[0119] In embodiment 21, provided is the compound of any one of embodiments 1-16, wherein E has the structure:wherein R5is H or alkyl.

[0120] In embodiment 22, provided is the compound of embodiment 21, wherein R5is 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\AMERICASATTY 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\AMERICASATTY 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., -CF3and –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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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 R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andwherein R5-R7are 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0160] In one embodiment, the compound of Formulaa pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formulapharmaceutically 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 R8awherein R8ais 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 R8aselected 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 R8aselected 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\AMERICASATTY 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 iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. 38 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0171] In one embodiment of Formula III, including any of the foregoing, the compound iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment of Formula III, including any of the foregoing, the compound iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

[0173] In one embodiment of Formula III, including any of the foregoing, the compound iswherein R5is 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 X7are independently selected from CR10and N; X1is O, NR11or C(R10)2; 39 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT wherein (a) at least two of X3-X6are CR10; (b) when X1is C(R10)2, X2is N and when X2is CR10, X1is O or NR11; and (c) when X7is CR10, X2is N and when X2is CR10, X7is N; R9is alkyl, halo, or aryl; R10is independently selected from H, alkyl, alkoxy, and aryl; R11is 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 R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andwherein R5-R7are 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\AMERICASATTY 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 Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A isof Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically 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-X6are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, one of X3-X6is N and the others are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X3is N and X4-X6are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X4is N and X3and X5-X6are CH; or a 41 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X5is N and X3-X4and X6are CH; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, X6is N and X3- X5are CH. ; or a pharmaceutically acceptable salt thereof

[0177] In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A ispharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A is

[0178] In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring42 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof.

[0179] In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof.pharmaceutically acceptable salt thereof. 43 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0181] In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringof Formula IV is Ringpharmaceutically acceptable salt thereof.

[0182] In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring44 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ringpharmaceutically 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 Ringpharmaceutically acceptable salt thereof. In one embodiment of Formula IV is Ring A ispharmaceutically acceptable salt45 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTpharmaceutically acceptable salt thereof.

[0185] In one embodiment of Formula IV, including any of the foregoing, the compound iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, thepharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compoundwherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

[0186] In one embodiment of Formula IV, including any of the foregoing, the compound iswherein R5is 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTwherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

[0187] In one embodiment of Formula IV, including any of the foregoing, the compound isacceptable salt thereof.

[0188] In one embodiment of Formula IV, including any of the foregoing, the compound iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

[0189] In one embodiment of Formula IV, including any of the foregoing, the compound iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

[0190] In one embodiment of Formula IV, including any of the foregoing, the compound iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compoundwherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of 47 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT the foregoing, the compoundwherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compoundwherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula IV, including any of the foregoing, the compound iswherein R5is 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 X13are each independently CR, CRx, N, NR, or NRx; X14is N or C; wherein when X14is N, exactly one of X11, X12, and X13is N, NR, or NRxand when X14is C, exactly two of X11, X12, and X13are N, NR, or NRx; and wherein when Ar is aryl or heteroaryl, at least one of one of X11, X12, and X13must be CRxor 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT each Rxis 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\AMERICASATTY 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, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis cycloalkylalkyl wherein the cycloalkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis cycloalkylalkyl wherein the alkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, 50 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT including any of the foregoing, Rxis cycloalkylalkyl optionally substituted with two halo groups which are independently selected; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis cycloalkylalkyl optionally substituted with two fluoro; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0199] In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0200] In one embodiment, the compound of Formula V is selected from: , , and ; Rxis 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 Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0202] In one embodiment of Formula V, including any of the foregoing, Rxis -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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT selected; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis -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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0203] In one embodiment of Formula V, including any of the foregoing, Rxis unsubstituted -CH2-cyclopropyl or -CH2-cyclobutyl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0204] In one embodiment of Formula V, including any of the foregoing,; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0205] In one embodiment of Formula V, including any of the foregoing, Rxis 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, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one C1-C3alkyl group and wherein the 52 1103861084\1\AMERICASATTY 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0206] In one embodiment of Formula V, including any of the foregoing, Rxis heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups and Ar is aryl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups and Ar is phenyl; optionally wherein only one Rxis 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 Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. 53 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0209] In one embodiment of Formula V, including any of the foregoing,optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0210] In one embodiment of Formula V, including any of the foregoing, Rxis 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, Rxis unsubstituted aryl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis aryl optionally substituted with one or more groups selected from methyl, Cl, F, and methoxy; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis aryl substituted with one alkyl group; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis aryl substituted with two alkyl groups; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis aryl substituted with one alkoxy group. In one embodiment of Formula V, including any of the foregoing, Rxis aryl substituted with one halo group; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis aryl substituted with one halo group wherein the halo group is Cl or F; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0211] In one embodiment of Formula V, including any of the foregoing, Rxis phenyl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0212] In one embodiment of Formula V, including any of the foregoing, Rxis aryl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar is aryl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis phenyl 54 1103861084\1\AMERICASATTY 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0213] In one embodiment of Formula V, including any of the foregoing, Rxis aryl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar is heteroaryl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0214] In one embodiment of Formula V, including any of the foregoing, Rxis phenyl optionally substituted with one or more groups selected from alkyl, halo, and alkyloxy and Ar; optionally wherein only one Rxis 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 Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. 55 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0217] In one embodiment of Formula V, including any of the foregoing, Rxis,pharmaceutically acceptable salt thereof.

[0218] In one embodiment of Formula V, including any of the foregoing, Rxis C(O)- heterocycloalkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis C1-C3-C(O)-heterocycloalkyl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis C2-C(O)-heterocycloalkyl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

[0219] In one embodiment of Formula V, including any of the foregoing, Rxis C0-C4- C(O)-heterocyclyl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0220] In one embodiment of Formula V, including any of the foregoing, Rxis C0-C4-C(O)- heterocyclyl and Ar is aryl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. In one embodiment of Formula V, including any of the foregoing, Rxis C0-C4-C(O)-heterocyclyl and Ar is phenyl; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof. 56 1103861084\1\AMERICASATTY 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 Rxis 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 Rxis present; or a pharmaceutically acceptable salt thereof.

[0223] In one embodiment of Formula V, including any of the foregoing, Rxisoptionally wherein only one Rxis 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\AMERICASATTY 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; R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is 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-Z4are each independently N or CR4, where each R4is 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-Z4are N.

[0226] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), E iswherein at least one of Z1-Z3is CR4wherein R4is 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), Z1and R1, together with the atoms to which they are attached, form a fused phenyl ring; R2is absent; and E has the formula:58 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT where A is a cyclic amide or cyclic imide or a derivative thereof; and Z2and Z3are each independently N or CR4, where each R4is 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 R5is H or alkyl; R6and R7are 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), R5is H or lower alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5is H or methyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5is H. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R5is methyl.

[0230] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R6and R7are each independently H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R6and R7are each independently H or methyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R6and R7both 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-R7are 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT where R5is 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), R1and R2are each independently H, alkyl, alkenyl or alkynyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R1and R2are each independently H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R1and R2are each independently H or methyl. In another embodiment of Formula (I), (II), (P-I), (P- II), (III), (IV), or (V), R1and R2are each H.

[0236] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R3is H, alkyl, alkenyl or alkynyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R3is H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P- II), (III), (IV), or (V), R3is H or methyl. In another embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), R3is H.

[0237] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R4is H, alkyl, alkenyl or alkynyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), R4is H or alkyl. In another embodiment of Formula (I), (I’), (II), (P-I), (P- II), (III), (IV), or (V), R4is H or methyl. In another embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), R4is H.

[0238] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Y1is S and Y2is CR3. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Y1is S and Y2is CH. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Y1is CR3and Y2is S. In another embodiment of Formula (I), (I’), (II), (P- I), (P-II), (III), (IV), or (V), Y1is CH and Y2is S.

[0239] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z1is N and Z2-Z4are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z1is N and Z2-Z4are CH. 60 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT

[0240] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z2is N and Z1, Z3and Z4are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z2is N and Z1, Z3and Z4are CH.

[0241] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z3is N and Z1, Z2and Z4are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z3is N and Z1, Z2and Z4are CH.

[0242] In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z4is N and Z1-Z3are CR4. In another embodiment of Formula (I), (I’), (II), (P-I), (P-II), (III), (IV), or (V), Z4is N and Z1-Z3are 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 R5is 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 R5is 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\AMERICASATTY 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 R5and 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT92 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTEXAMPLES 8-31

[0375] The compounds of Example 8-31 were prepared according to the following synthetic scheme:93 1103861084\1\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT96 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT97 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT98 1103861084\1\AMERICASATTY 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\AMERICASATTY 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 Na2SO4and 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\AMERICASATTY 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\AMERICASATTY 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 Na2SO4and 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 Na2SO4and 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\AMERICASATTY 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\AMERICASATTY 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 Na2SO4and 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\AMERICASATTY 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 NaHCO3solution (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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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 Na2SO3aqueous 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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 Na2SO4and 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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 Na2SO4and 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 NaHCO3solid. 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\AMERICASATTY 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\AMERICASATTY 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 - 1.68127 1103861084\1\AMERICASATTY 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\AMERICASATTY 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 N2for 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\AMERICASATTY 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\AMERICASATTY 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 N2atmosphere. 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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 H2there 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\AMERICASATTY 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\AMERICASATTY 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 H2for 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 N2atmosphere. 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\AMERICASATTY 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....

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 X13are each independently CR, CRx, N, NR, or NRx; X14is N or C; wherein when X14is N, exactly one of X11, X12, and X13is N, NR, or NRxand when X14is C, exactly two of X11, X12, and X13are N, NR, or NRx; and wherein when Ar is aryl or heteroaryl, at least one of X11, X12, and X13must be CRxor 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 Rxis 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT 3. The compound of claim 2, wherein the compound of Formulaa 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 Rxis cycloalkylalkyl wherein the alkyl and cycloalkyl portions are independently optionally substituted with one or more halo groups; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-2 and 7, wherein Rxis cycloalkylalkyl wherein the cycloalkyl of cycloalkylalkyl is optionally substituted with one or more halo groups which are independently selected; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-2 and 7, wherein Rxis 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 Rxis heterocycloalkylalkyl wherein the heterocycloalkyl of heterocycloalkylalkyl is optionally substituted with one or more alkyl groups which are independently selected; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-2 and 10, wherein Rxis 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT membered ring comprising at least one heteroatom selected from O and N; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-2, wherein Rxis aryl optionally substituted with one or more groups independently selected from alkyl, halo, and alkyloxy; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1-2 and 12, wherein Rxis unsubstituted aryl; or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1-2 and 12, wherein Rxis aryl optionally substituted with one or more groups independently selected from methyl, Cl, F, and methoxy; optionally wherein only one Rxis present; or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 12-14, wherein Rxis phenyl optionally substituted with one or more groups independently selected from alkyl, halo, and alkyloxy; optionally wherein only one Rxis 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTwherein R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andwherein R5-R7are 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\AMERICASATTY 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 R8is 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\AMERICASATTY 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTR 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 R8that is not H; or ii) Ar is phenyl substituted with 1, 2, or 3 R8and 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 R8and R is alkyl substituted with heterocycloalkyl where the heterocycloalkyl is optionally substituted with one or two alkyl; 585 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT iv) Ar is phenyl substituted with1, 2, or 3 R8and whenare each CR4, then at least one R4is not H (preferably at least one R4is halo).

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein at least one R8is 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT or a pharmaceutically acceptable salt thereof, wherein: E is according to any one of the following formulae: ,R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is 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\AMERICASATTY 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 R9is 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 R5is H; or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 31-37 that is according to:optionally wherein R5is H; or a pharmaceutically acceptable salt thereof. 588 1103861084\1\AMERICASATTY 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: ,R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 589 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andwherein R5-R7are 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 isor 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 R8awherein R8ais independently selected from OR’ where R’ is H, alkyl, or haloalkyl; alkyl optionally 590 1103861084\1\AMERICASATTY 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 R8aselected 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 iswherein R5is H or alkyl; or a pharmaceutically acceptable salt thereof. 591 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT 53. The compound of claim 42, wherein the compound isalkyl; 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 X7are independently selected from CR10and N; X1is O, NR11or C(R10)2; wherein (a) at least two of X3-X6are CR10; (b) when X1is C(R10)2, X2is N and when X2is CR10, X1is O or NR11; and (c) when X7is CR10, X2is N and when X2is CR10, X7is N; R9is alkyl, halo, or aryl; R10is independently selected from H, alkyl, alkoxy, and aryl; R11is 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTwherein R1and R2are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; one of Y1and Y2is S and the other is CR3, where R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z1-Z4are each independently N or CR4, where each R4is independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andwherein R5-R7are 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-X6are CH; or a pharmaceutically acceptable salt thereof.

56. The compound of claim 54, wherein one of X3-X6is N and the others are CH; or a pharmaceutically acceptable salt thereof.

57. The compound of claim 54, wherein Ringpharmaceutically acceptable salt thereof. 593 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT 58. The compound of claim 54, wherein Ring A ispharmaceutically acceptable salt thereof.

59. The compound of claim 54, wherein Ringpharmaceutically acceptable salt thereof. 314 XXX X5X6 X2 60. The compound of claim 54, wherein Ring A is andpharmaceutically acceptable salt thereof.

61. The compound of claim 54, wherein Ringpharmaceutically acceptable salt thereof. 594 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCT 62. The compound of any one of claims 54, 55, and 61, wherein Ringpharmaceutically acceptable salt thereof.

64. The compound of claim 54, wherein the compound is, , 595 1103861084\1\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTacceptable salt thereof.

65. The compound of claim 54, wherein the compound issalt thereof.

66. The compound of claim 54, wherein the compound iswherein R5is 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\AMERICASATTY DKT. NO.129824.00006 INVO 108 PCTwherein R5is 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 R5is H or alkyl; or a pharmaceutically acceptable salt thereof.

71. The compound of claim 70, wherein R5is H.

72. The compound of any one of claims 67-69, wherein one or two R4are independently halo and the other of the R4are each H; optionally wherein one R4is halo and the other of the R4are 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\AMERICASATTY 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\AMERICASATTY 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\AMERICASATTY 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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