CK1alpha and dual CK1alpha / GSPT1 degrading compounds

Abstract

The invention provides a compound for inducing degradation of CK1 alpha or CK1 alpha / GSPT1 as a molecular glue, and a pharmaceutically acceptable derivative thereof. The invention also provides pharmaceutical compositions comprising the compounds and methods of using the compounds to treat subjects suffering from proliferative diseases.

Description

Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 375,167, filed on September 9, 2022, the content of which is incorporated herein by reference in its entirety. Field of the Invention

[0002] The present invention provides compounds and compositions for degrading CK1α protein or degrading CK1α and GSPT1 proteins. The compounds and compositions can be used for treating proliferative diseases, including cancer and autoimmune diseases. Background of the Invention

[0003] Recently, a great deal of research has been devoted to discovering compounds that can bind two different proteins without necessarily inhibiting the function of either protein. Such compounds are referred to as "molecular glue". Of particular interest is when the molecular glue causes one of the target proteins to degrade upon contact with it. This strategy has proven useful for modulating the activity of proteins that have hitherto been considered "undruggable".

[0004] For example, some molecular glues bind to E3 ubiquitin ligases. The E3 ubiquitin ligase specifically ubiquitinates substrate proteins and then causes them to be degraded by the proteasome. Cereblon is a key component of the E3 ubiquitin ligase complex and is therefore an attractive target for molecular glues. Cereblon is reprogrammed by compounds such as thalidomide, lenalidomide, and pomalidomide (immunomodulatory drugs (imids)) to induce the degradation of new substrate proteins, including IKZF1 (Ikaros) and IKAF3 (Aiolos) (see, e.g., Charlinski et al. Cancers, 2021, 13, 4666). Thus, molecular glues that bind to cereblon can ubiquitinate target proteins and then cause them to be degraded by the proteasome. Extensive research has been conducted in the field of cereblon-binding compounds, and many such compounds have been discovered (see, e.g., WO 2022 / 066835, WO 2020 / 118098, WO 2021 / 041664, WO2019 / 078522, WO 2021 / 188537, WO 2021 / 105334, WO 2022 / 144416, WO 2021 / 143816, WO2022 / 017365, WO 2022 / 146151, WO 2022 / 148358, WO 2021 / 147889, WO 2021 / 143822, WO2020 / 181232, WO 2019 / 043214, WO 2020 / 263832, WO 2020 / 006233, WO 2015 / 200795, WO2019 / 043217, WO 2019 / 204354, US Patent Publication Nos. US2022 / 0062248, US2019 / 0017998, US2020 / 0206201, US 2020 / 0155690, US2021 / 0009559, US2018 / 0215731, US2021 / 0177825, US2019 / 0076541, US2021 / 0403454, US2021 / 0284624, US2021 / 0032245, US2020 / 0207764, US2022 / 0112211, US2019 / 0233433, US 2020 / 0207733).

[0005] Casein kinase 1α (“CK1α”) is a protein in the CK1 protein family that regulates signaling pathways related to membrane trafficking, cell cycle progression, chromosome segregation, apoptosis, autophagy, cell metabolism, and differentiation, including development, circadian rhythm, and immune responses, as well as neurodegenerative diseases 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 diseases. Mechanistically, CK1α is required for the activation of the Card11 / BCL10 / MALT1 (CBM) complex induced by BCR (via BTK) and TCR (see, e.g., Gehring et al., Cell Reports 2019, 29, 873 - 888; Bidere et al., Nature 2009, 458, 7234; Yin et al. Cell. Mol. Life Sci. 2022, 79, 112). CBM activation is associated with the progression of a variety of lymphoid malignancies, including non - Hodgkin lymphoma (NHL) (see, e.g., Bedsaul et al. Front. Oncol. 2018, 9, Article 2105), diffuse large B - cell lymphoma (DLBCL) (including ABC DLBCL) (see, e.g., Thys et al., Front. Oncol. 2018, 8, Article 498; Bidere et al., Nature 2009, 458(7234), 92 - 96), mucosa - associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma (MCL), adult T - cell leukemia / lymphoma (ATLL), and Sézary syndrome (see, e.g., Juilland et al., Curr. Opin. Hemat. 2016, 23(4), 402 - 409). Specifically, CK1α has been shown to maintain B - cell signaling in MCL (see, e.g., Manni et al., Front. Oncol. 2021, 11, Article 733848), and MALT1 inhibition has been shown to be an effective strategy for the treatment of treatment - naive and ibrutinib - resistant chronic lymphocytic leukemia (CLL) (see, e.g., Saba et al., Cancer Res. 2017, 77(24), 7038 - 7048).In immuno - oncology, it has been demonstrated that modulating the CBM complex primes regulatory T cells for immune checkpoint therapy of tumors (see, e.g., DiPilato et al., Nature 2019, 570(7759), 112 - 116), while MALT1 activity is associated with T - cell immunosuppression (see, e.g., Rosenbaum et al., Nat. Commun. 2019, 10(1), 2352). It has also been shown that inhibiting MALT1 can improve autoimmune pathogenesis (see, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320).

[0006] It has also been confirmed that the depletion of CK1α caused by siRNA or kinase inhibitors stabilizes the tumor suppressor p53 and inhibits cell - cycle progression (see, e.g., Huart et al., J. Biol. Chem. 2009, 284(47), 32384 - 32394). Briefly, CK1α binds to MDM2, which is a p53 E3 ubiquitin ligase (see, e.g., Wu et al. Mol. Cell. Biol. 2012, 32(23), 4821 - 4832). The binding of the CK1α - MDM2 active complex to p53 promotes p53 degradation, thus preventing the expression of the cell - cycle progression inhibitor p21 (see, e.g., Kocik et al., Cancers 2019, 11, 1014). Therefore, the degradation of CK1α stabilizes p53 and induces growth arrest (see, e.g., Huart et al., PLoS One 2012, 7(8), e43391). Studies have shown that elevated p53 activity has anti - proliferative and pro - apoptotic effects 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 and is currently being explored as a therapeutic target for the treatment of acute myeloid leukemia (AML). Recent studies have found some molecular glues that can degrade GSPT1 without degrading CK1α (see, e.g., Powell et al., ACS Chem. Biol. 2020, 15, 2722 - 2730) or can degrade GSPT1 without degrading IKZF1 (Ikaros) (see, e.g., Nishiguchi et al., J. Med. Chem. 2021, 64, 7296 - 7311).

[0008] Therefore, there is a need for molecular glues that can degrade CK1α or CK1α / GSPT1. Such molecular glues offer therapeutic options for treating a variety of proliferative diseases, including cancer and autoimmune diseases. Summary of the Invention

[0009] The present invention provides compounds and compositions capable of degrading CK1α or CK1α / GSPT1. In one embodiment, the compound is a molecular glue that binds E3 ubiquitin ligase and CK1α. In another embodiment, the compound is a molecular glue that binds cereblon and CK1α.

[0010] In one embodiment, the compound that can be used in the compositions and methods provided by the present invention has a structure shown in Formula I or II:

[0011] The variables Ar, E and X 1 -X 5 All are as defined elsewhere in this invention.

[0012] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound provided by the present invention and a pharmaceutically acceptable carrier.

[0013] In another embodiment, the present invention provides a method for degrading CK1α or CK1α / GSPT1 using the compound or composition provided by the present invention. The method provided by the present invention includes a method for treating a disease mediated by CK1α or CK1α / GSPT1. In one embodiment, the CK1α disease is B-cell lymphoma or BTK inhibitor-resistant cancer. In another embodiment, the CK1α / GSPT1 disease is AML or breast cancer. In another embodiment, the CK1α degrader provided by the present invention is combined with a checkpoint inhibitor (including CTLA-4, PD-1 or PD-L1 inhibitors, such as anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibodies) for the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0014] To facilitate understanding of the disclosure described herein, certain terms are defined below.

[0015] Unless otherwise defined, all technical terms and scientific terms used in the present invention have the same meaning as those generally understood by those of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated herein by reference in their entirety. If there are multiple definitions for a term in the present invention, the definition in this section shall prevail unless otherwise stated.

[0016] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0017] As used herein, "subject" is an animal, such as a mammal, including a human, such as a patient.

[0018] As used herein, biological activity refers to the activity of a compound in vivo or the physiological response generated by a compound, composition, or other mixture after administration in vivo. Thus, biological activity encompasses the therapeutic effects and pharmacokinetic behavior of such compounds, compositions, and mixtures. Biological activity can be observed in in vitro systems designed to test such activity.

[0019] As used in the present invention, pharmaceutically acceptable derivatives of a compound include, but are not limited to, its salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates, or hydrates. Such derivatives can be readily prepared by those skilled in the art using known derivatization methods for this purpose. The compounds prepared can be administered to animals or humans without significant toxic effects and have pharmaceutical activity 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-methylglucosamine, procaine, N-benzylphenethylamine, 1-p-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; alkaline 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, disodium hydrogen phosphate and disodium phosphate; and also include, but are not limited to, mineral acid salts such as, but not limited to, hydrochloride salts and sulfate salts; and organic acid salts such as, but not limited to, acetate salts, lactate salts, malate salts, tartrate salts, citrate salts, ascorbate salts, succinate salts, butyrate salts, valerate salts, mesylate salts, and fumarate salts. Pharmaceutically acceptable esters include, but are not limited to, alkyl esters, alkenyl esters, alkynyl esters, aryl esters, aralkyl esters, and cycloalkyl esters of acidic groups, said acidic groups including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boric acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the formula C═C(OR), where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula C═C(OC(O)R), where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of the compound with one or more solvent or water molecules, or complexes with 1 to about 100, or 1 to about 10, or 1 to about 2, 1 to about 3, or 1 to about 4 solvent or water molecules.

[0020] "Treatment" or "treating" as used in the present invention refers to any manner that can ameliorate or otherwise beneficially alter one or more symptoms of a disease or disorder. Treatment or treating also includes any pharmaceutical use of the compositions described in the present invention, such as for treating diseases mediated by CK1α or CK1α / GSPT1.

[0021] As used herein, improving the symptoms of a particular disease or disorder by administering a particular compound or pharmaceutical composition refers to any alleviation that can be attributed to or is associated with the administration of the compound or pharmaceutical composition, whether permanent or temporary, lasting or transient.

[0022] As used herein, unless otherwise indicated, the term "manage" includes preventing recurrence of the particular disease or disorder in a subject having the disease or disorder, and / or prolonging the period of remission in a subject having the disease or disorder. These terms include modulating the threshold, development, and / or duration of the disease or disorder, or altering the manner in which a subject responds to the disease or disorder.

[0023] As used herein, DC 50 refers to the amount, concentration, or dose of a particular test compound that achieves 50% of the maximum response in an assay measuring such a response.

[0024] When a group moiety is written in its conventional chemical formula from left to right, it also includes chemically identical groups resulting from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0025] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group, which may include divalent and polyvalent groups, having a specified number of carbon atoms (i.e., C1-C 10 representing 1 to 10 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0026] Unless otherwise indicated, the term "alkenyl" by itself or as part of another substituent refers to a straight-chain (i.e., unbranched) or branched hydrocarbon group having one or more carbon-carbon double bonds, which may include divalent and polyvalent groups, having a specified number of carbon atoms (i.e., C1-C 10 representing 1 to 10 carbon atoms). 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 higher homologs and isomers.

[0027] Unless otherwise indicated, the term "alkynyl" by itself or as part of another substituent refers to a straight-chain (i.e., unbranched) or branched hydrocarbon group having one or more carbon-carbon triple bonds, which may include divalent and polyvalent groups, having a specified number of carbon atoms (i.e., C1-C 10(representing 1 to 10 carbon atoms). Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers.

[0028] The term "alkylene", either alone or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Generally, an alkyl (or alkylene) group has 1 to 24 carbon atoms, including groups having 10 or fewer carbon atoms. "Lower alkyl" or "lower alkylene" are alkyl or alkylene groups with shorter chains, generally having 6 or fewer carbon atoms.

[0029] The terms "alkoxy", "alkylamino", and "alkylthio" (or thioalkoxy) are used in their conventional meanings and refer to alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0030] The term "heteroalkyl", alone or in combination with another term, means, unless otherwise stated, a straight or branched hydrocarbon group composed of heteroatoms selected from the group consisting of O, N, P, Si, and S, where the N and S atoms may optionally be oxidized, and the N atom may have alkyl substituents to satisfy valency and / or may optionally be quaternized. The heteroatoms O, N, P, Si, and S can be located at any internal 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 can be adjacent, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene", either alone or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For alkylene and heteroalkylene linking groups, the direction of writing the general formula of the linking group does not imply the direction of the linking group. For example, the formula –C(O)2R'- represents both –C(O)2R'- and –R'C(O)2-.

[0031] Unless otherwise specified, the terms "cycloalkyl" and "heterocycloalkyl", alone or in combination with other terms, respectively denote the cyclic forms of "alkyl" and "heteroalkyl", including bicyclic, tricyclic and bridged bicyclic groups. In addition, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is connected to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, bicyclo[2.2.2]octyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, 1-azabicyclo[2.2.2]octyl or 2-azabicyclo[2.2.2]octyl, etc.

[0032] Unless otherwise specified, the term "halogen" by itself or as part of other substituents refers to fluorine, chlorine, bromine or iodine atoms. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0033] Unless otherwise specified, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or polycyclic (in one embodiment, 1 to 3 rings) fused together or covalently linked. The term "heteroaryl" is an aryl group containing 1 to 4 heteroatoms selected from N, O and S in the ring, where the N and S atoms are each optionally oxidized and the N atom is optionally quaternized. The heteroaryl group can be linked to the rest 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-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituent group part of the aryl and heteroaryl ring systems can be selected from the group of acceptable substituent group parts described in the present invention. The term "heteroarylium" refers to a heteroaryl group bearing a positive charge on one or more heteroatoms.

[0034] As used herein, the term "oxo" refers to an oxygen atom double-bonded to a carbon atom.

[0035] Each of the above terms (e.g., "alkyl", "heteroalkyl", "aryl", and "heteroaryl") is intended to include both substituted and unsubstituted forms of the indicated group. Non-limiting examples of the substituent groups for each group are provided below.

[0036] The substituent group moieties of alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl, in one embodiment, are 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 0 to the number of hydrogen atoms in the group. In one embodiment, the substituent group moieties of cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups further include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. R', R", R"' and R"", in one embodiment, are each independently H, 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 aralkyl groups. For example, when the compounds provided herein contain more than one R group, each R group is independently selected, and when there are more than one R', R", R"' and R"" groups, each R', R", R"' and R"" group is also independently selected. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a ring consisting of 4, 5, 6 or 7 atoms. For example, -NR'R" is intended to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the discussion of the above substituent group moieties, those skilled in the art will understand that the term "alkyl" is intended to include groups in which a carbon atom is attached to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and –CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0037] The substituent group moieties of the aryl and heteroaryl groups, in one embodiment, are selected from deuterium, halogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, 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, the number thereof ranging from 0 to the total number of hydrogen atoms on the aromatic ring system; and wherein R', R", R"' and R"", in one embodiment, are independently selected from H, 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 the compounds provided by the present invention include more than one R group, for example, each R group is independently selected, and when there are more than one R', R", R"' and R"" groups, each R', R", R"' and R"" group is also independently selected respectively.

[0038] Two substituent group moieties on adjacent atoms of the aryl ring or heteroaryl ring may optionally form a ring represented by the formula -Q'-C(O)-(CRR') q -Q”- wherein Q' and Q” are independently –NR-, -O-, -CRR'- or a single bond respectively, and q is an integer from 0 to 3. Alternatively, two substituent group moieties on adjacent atoms of the aryl ring or heteroaryl ring may optionally be substituted by a substituent represented by 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 respectively, and r is an integer from 1 to 4. One of the single bonds of the newly formed ring may optionally be replaced by a double bond. Alternatively, two substituent group moieties on adjacent atoms of the aryl ring or heteroaryl ring may optionally be substituted by the formula –(CRR') s -X'-(CR”R”') d- replaced by the indicated substituents, where s and d are each independently an integer from 0 to 3, and X' is –O–, –NR'–, –S–, –S(O)–, –S(O)2–, or –S(O)2NR'–. In one embodiment, the substituent groups R, R', R", and R'" are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0039] As used herein, the terms "heteroatom" or "ring heteroatom" are intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0040] As used in the present invention, a prodrug refers to a compound that, after administration in vivo, is metabolized through one or more steps or processes or undergoes a chemical change or otherwise is converted into the biologically, pharmaceutically, or therapeutically active form of the compound under physiological conditions. In addition, a prodrug can be converted into the biologically, pharmaceutically, or therapeutically active form of the compound by chemical or biochemical methods in an in vitro environment. For example, when a prodrug is placed in a transdermal patch reservoir having a suitable enzyme or chemical reagent, the prodrug can be converted into the compounds of the present invention.

[0041] Certain compounds provided by the present invention can exist in non-solvated forms as well as solvated forms, including hydrated forms. Generally, the solvated forms are equivalent to the non-solvated forms and are encompassed within the scope of the present invention. Certain compounds provided by the present invention can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0042] Certain compounds provided by the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereoisomers, tautomers, geometric isomers, and individual isomers are all encompassed within the scope of the present invention. The compounds provided by the present invention do not include compounds known in the art to be too unstable to be synthesized and / or isolated.

[0043] The compounds provided by the present invention may also contain unnatural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, the compounds can be radiolabeled with radioactive isotopes (e.g., tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C)). All isotopic variants of the compounds provided by the present invention, whether radioactive or not, are encompassed within the scope of the present invention. II. Compounds for Compositions and Methods

[0044] In one embodiment, the present invention provides compounds for use in the compositions and methods provided by the present invention, which have the structures shown in Formula I or II:

[0045] wherein Ar is aryl, heteroaryl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, a heterocyclic group composed of 5-7 atoms, or a heteroallenyl group composed of 5-7 atoms; E is a group moiety that binds to an E3 ubiquitin ligase; X 1 -X 2 are each independently N or C; and X 3 -X 5 are each independently CR, N, NR, S or O, wherein each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic group; or two R groups located at adjacent positions on the ring together form an alkylene group; or R and Ar located at adjacent positions on the 5-atom ring together form a fused ring.

[0046] In one embodiment, the present invention provides compounds for use in the compositions and methods provided by the present invention, which have the structures shown in Formula I or II:

[0047] wherein Ar is aryl, heteroaryl, C 5-7 cycloalkyl, or a heterocyclic group composed of 5-7 atoms; E is a group moiety that binds to an E3 ubiquitin ligase; X 1 -X 2 are each independently N or C; and X 3 -X 5 are each independently CR, N, NR, S or O, wherein each R is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl; or two R groups located at adjacent positions on the ring together form an alkylene group.

[0048] In another embodiment, the present invention provides compounds for use in the compositions and methods provided by the present invention, which have the structures shown in Formula I or II:

[0049] wherein Ar is aryl; E is a group moiety that binds to an E3 ubiquitin ligase; X 1 -X 2 are each independently N or C; and X 3 -X 5 are each independently CR, N, NR, S or O, wherein each R is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl; or two R groups located at adjacent positions on the ring together form an alkylene group.

[0050] In another embodiment, X 3 -X 5 are each independently CR, N, NR, or S. In another embodiment, X 3 -X 5 are each independently CR, N, or NR.

[0051] In another embodiment, the compound represented by Formula II is selected, provided that when X 1 is C, X 2 , X 4 and X 5 are N respectively, and X 3 is CH, then E is not an isatin moiety. In another embodiment, the compound represented by Formula II is selected, provided that when X 4 and X 5 are N respectively, then X 2 is not N.

[0052] In another embodiment, the compound represented by Formula II is selected, provided that when X 1 and X 2 are C respectively, X 3 is NMe, X 4 is N, and X 5 is CH, then E is not an isatin moiety. In another embodiment, the compound represented by Formula II is selected, provided that when X 4 is N, then X 3 is not NMe. In another embodiment, the compound represented by Formula II is selected, provided that when X 3 is NMe, then X 4 is not N.

[0053] In another embodiment, the compound represented by Formula II is selected, provided that when X 1 and X 2 are C respectively, X 3 is CH, X 4 is N, and X 5 is NMe, then Ar is not 5-fluoro-2-pyridyl. In another embodiment, the compound represented by Formula II is selected, provided that when X 1 and X 2 are C respectively, X 3 is CH, X 4 is N, and X 5 is NMe, then Ar is not a heteroaryl.

[0054] In another embodiment, the compound represented by Formula I is selected, provided that when X 1 is N, X 2 is C, X 3 and X 4Are CH and X respectively 5 When X is N, Ar is not cyclopropyl. In another embodiment, a compound of formula I is selected, provided that when X 1 is N, X 2 is C, X 3 and X 4 Are CH and X respectively 5 is N, then Ar is not cycloalkyl.

[0055] In another embodiment, a compound of formula II is selected, provided that when X 1 is N, X 2 is C, X 3 and X 4 Are CH and X respectively 5 is N, then Ar is not phenyl. In another embodiment, a compound of formula II is selected, provided that when X 1 is N, X 2 is C, X 3 and X 4 Are CH and X respectively 5 is N, then Ar is not aryl.

[0056] In another embodiment, a compound of formula II is selected, provided that when X 1 and X 3 Are N, X 2 is C, and X 4 and X 5 Are CH respectively, then Ar is not phenyl. In another embodiment, a compound of formula II is selected, provided that when X 1 and X 3 Are N, X 2 is C, and X 4 and X 5 Are CH respectively, then Ar is not aryl.

[0057] In another embodiment, a compound of formula II is selected, provided that the ring containing X 1 -X 5 Is not 1,2,3-triazole-1,4-diyl.

[0058] In another embodiment, a compound of formula I and II is selected, provided that Ar is not tetrahydropyran-2-yl. In another embodiment, a compound of formula I and II is selected, provided that Ar is not tetrahydropyranyl.

[0059] In another embodiment, the compound represented by Formula I is not 3-[1,3-dihydro-1-oxo-5-(5-phenyl-4-oxazolyl)-2H-isoindol-2-yl]-2,6-piperidinedione. In another embodiment, the compound represented by Formula II is not 3-[1,3-dihydro-1-oxo-5-(2-phenyl-4-oxazolyl)-2H-isoindol-2-yl]-2,6-piperidinedione. In another embodiment, the compound represented by Formula II is not 3-[1,3-dihydro-1-oxo-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-2H-isoindol-2-yl]-2,6-piperidinedione.

[0060] In certain embodiments, the compounds provided by the present invention contain multiple E groups. In another embodiment, the compounds provided by the present invention have one of the structures represented by the following formula:

[0061] wherein Ar, E, and X 1 -X 5 are each as defined elsewhere in the present invention.

[0062] In one embodiment, X 1 is C, and X 2 is N. In another embodiment, X 1 is N, and X 2 is C. In another embodiment, X 1 and X 2 are each C, respectively, and the compound has the following structure:

[0063] wherein Ar, E, and X 3 -X 5 are each as defined elsewhere in the present invention.

[0064] In another embodiment, the compounds provided by the present invention have one of the structures represented by the following formula:

[0065] In another embodiment, X 1 and X 2 are each C, X 5 is NR, and the compound has the following structure:

[0066] wherein Ar, E, X 3 and X 4 are each as defined elsewhere in the present invention.

[0067] In another embodiment, X 1 and X 2 are each C, X 3 is CR, X 4 is N, and X 5 is NR, and the compound has the following structure:

[0068] wherein Ar, E, and R are each as defined elsewhere in the present invention. In another embodiment, X 3 is CH, and the compound has the following structure:

[0069] wherein Ar, E, and R are each as defined elsewhere in the present invention. In another embodiment, the compound has the following structure:

[0070] wherein Ar and E are each as defined elsewhere in the present invention.

[0071] In another embodiment, X 1 and X 2 are each C, X 3 is N, X 4 is CR, and X 5 is NR, and the compound has the following structure:

[0072] wherein Ar, E, and R are each as defined elsewhere in the present invention. In another embodiment, X 4 is CH, and the compound has the following structure:

[0073] wherein Ar, E, and R are each as defined elsewhere in the present invention. In another embodiment, the compound has the following structure:

[0074] wherein Ar and E are each as defined elsewhere in the present invention.

[0075] In another embodiment, the compound has the following structure:

[0076] wherein R, Ar, and E are each as defined elsewhere in the present invention.

[0077] In another embodiment, the compound has the following structure:

[0078] wherein Ar and E are each as defined elsewhere in the present invention.

[0079] In another embodiment, the compound has the following structure:

[0080] wherein R, Ar, and E are each as defined elsewhere in the present invention.

[0081] In another embodiment, the compound has the following structure:

[0082] wherein R, Ar, and E are each as defined elsewhere in the present invention.

[0083] In another embodiment, the compound has the following structure:

[0084] wherein R, Ar, and E are each as defined elsewhere in the present invention.

[0085] In another embodiment, the compound has the following structure: wherein X 1 、X 3 、X 4 、R, Ar, and E are each as defined elsewhere in the present invention.

[0086] In another embodiment, each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic group; or two R groups located at adjacent positions on the ring together form an alkylene group. In another embodiment, each R is independently H, alkyl, alkenyl, or alkynyl. In another embodiment, each R is independently H, alkyl, cycloalkyl, heterocyclic group, or aryl; or two R groups located at adjacent positions on the ring together form an alkylene group. In another embodiment, each R is independently H, alkyl, cycloalkyl, or aryl; or two R groups located at adjacent positions on the ring together form a lower alkylene group. In another embodiment, each R is independently H, or alkyl; or two R groups located at adjacent positions on the ring together form a lower alkylene group. In another embodiment, each R is independently H, alkyl or haloalkyl. In another embodiment, each R is independently H, methyl, ethyl, isopropyl, difluoromethyl, fluoromethyl, trifluoromethyl, 2,2-difluoro-1-ethyl, 2,2,2-trifluoro-1-ethyl, difluoropropyl, cyclopropyl, trideuteriomethyl, ethyl, 2-hydroxy-2-methylpropyl, cyclohexyl, 1,3-dioxanyl, 4-pyranyl, or phenyl; or two R groups located at adjacent positions on the ring together form a propylene group. In another embodiment, each R is independently H, methyl, difluoromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoro-1-ethyl, cyclopropyl, trideuteriomethyl, ethyl, 2-hydroxy-2-methylpropyl, cyclohexyl, 4-pyranyl, or phenyl; or two R groups located at adjacent positions on the ring together form a propylene group. In another embodiment, each R is independently H, methyl, difluoromethyl, fluoromethyl, trifluoromethyl, cyclopropyl, trideuteriomethyl, ethyl, 2-hydroxy-2-methylpropyl, or phenyl; or two R groups located at adjacent positions on the ring together form a propylene group. In another embodiment, each R is independently H, methyl, difluoromethyl, or 2,2,2-trifluoro-1-ethyl. In another embodiment, each R is independently H, or methyl. In another embodiment, each R is H. In another embodiment, each R is methyl.

[0087] In another embodiment, E is a group moiety that binds to cereblon. In another embodiment, E comprises a group moiety derived from an imide, amide, thioamide or thioimide. In another embodiment, E comprises a phthalimido group, or an analogue or derivative thereof. In another embodiment, E comprises a phthalimido-glutarimide group, or an analogue or derivative thereof. In another embodiment, E comprises a thalidomide, lenalidomide or pomalidomide group moiety, or an analogue or derivative thereof.

[0088] In another embodiment, E has a structure represented by one of the following formulas:

[0089] wherein A is a cyclic amide or cyclic imide, or a derivative thereof; R 1 and R 2 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl; one of Y 1 and Y 2 is S and the other is CR 3 wherein R 3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl; and Z 1 -Z 4 are each independently N or CR 4 wherein each R 4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl. In one embodiment, at most two of Z 1 -Z 4 are N. In another embodiment, Z 1 and R 1 together with the atoms to which they are attached form a fused benzene ring; R 2 is absent; and E has a structure represented by the following formula:

[0090] wherein A is a cyclic amide or cyclic imide, or a derivative thereof; and Z 2 and Z 3 are each independently N or CR 4 wherein each R 4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl.

[0091] In one embodiment, A is a cyclic imide having the following structure:

[0092] wherein R 5 is H or alkyl; R 6 and R 7 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic group; and m is an integer from 1 to 4.

[0093] In another embodiment, R 5 is H or lower alkyl. In another embodiment, R 5 is H or methyl. In another embodiment, R 5 is H. In another embodiment, R5 is methyl.

[0094] In another embodiment, R 6 and R 7 are each independently H or alkyl. In another embodiment, R 6 and R 7 are each independently H or methyl. In another embodiment, R 6 and R 7 are each H.

[0095] In another embodiment, m is 1, 2 or 3. In another embodiment, m is 2 or 3. In another embodiment, m is 2. In another embodiment, m is 3.

[0096] In another embodiment, A has the following structure:

[0097] wherein R 5 -R 7 are each selected as described elsewhere in the present invention.

[0098] In another embodiment, A has the following structure:

[0099] wherein R 5 is selected as described elsewhere in the present invention.

[0100] In another embodiment, A has one of the following structures, the absolute stereochemistry of which is shown below:

[0101] In another embodiment, R 1 and R 2 are each independently H, alkyl, alkenyl or alkynyl. In another embodiment, R 1 and R 2 are each independently H or alkyl. In another embodiment, R 1 and R 2 are each independently H or methyl. In another embodiment, R 1 and R 2 are each H.

[0102] In another embodiment, R 3 is H, alkyl, alkenyl or alkynyl. In another embodiment, R 3 is H or alkyl. In another embodiment, R 3 is H or methyl. In another embodiment, R 3 is H.

[0103] In another embodiment, R 4 is H, alkyl, alkenyl or alkynyl. In another embodiment, R 4 is H or alkyl. In another embodiment, R 4 is H or methyl. In another embodiment, R 4 is H.

[0104] In another embodiment, Y 1 is S, and Y 2 is CR 3 . In another embodiment, Y 1 is S, and Y 2 is CH. In another embodiment, Y 1 is CR 3 , and Y 2 is S. In another embodiment, Y 1 is CH, and Y 2 is S.

[0105] In another embodiment, Z 1 is N, and Z 2 -Z 4 are respectively CR 4 . In another embodiment, Z 1 is N, and Z 2 -Z 4 are respectively CH.

[0106] In another embodiment, Z 2 is N, and Z 1 , Z 3 and Z 4 are respectively CR 4 . In another embodiment, Z 2 is N, and Z 1 , Z 3 and Z 4 are respectively CH.

[0107] In another embodiment, Z 3 is N, and Z 1 , Z 2 and Z 4 are respectively CR 4 . In another embodiment, Z 3 is N, and Z 1 , Z 2 and Z 4 are respectively CH.

[0108] In another embodiment, Z 4 is N, and Z 1 -Z 3 are respectively CR 4 . In another embodiment, Z4 is N, and Z 1 -Z 3 are each CH, respectively.

[0109] In another embodiment, E is an immunomodulatory drug (imid). In another embodiment, E is selected from:

[0110] wherein R 5 is as defined elsewhere in the present invention.

[0111] In another embodiment, E has the following structure:

[0112] wherein R 5 is as defined elsewhere in the present invention. In another embodiment, E is selected from:

[0113] In another embodiment, Ar is aryl, heteroaryl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, a heterocyclic group composed of 5-7 atoms with at least one N atom in the ring, or a hetero cycloalkenyl group composed of 5-7 atoms with at least one N atom in the ring.

[0114] In one embodiment, Ar is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, optionally substituted pyrido pyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted benzofuranyl, optionally substituted imidazo pyridyl, optionally substituted benzopyrazolyl, optionally substituted pyrrolo pyridyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted thieno pyridyl, optionally substituted dihydrobenzofuranyl, optionally substituted benzopyridazinyl, optionally substituted benzopyranyl, optionally substituted benzothienyl, optionally substituted triazolo pyrimidinyl, optionally substituted piperidinyl, optionally substituted cyclohexenyl, optionally substituted tetrahydropyridyl, optionally substituted tetrahydrofuranyl, optionally substituted dihydrofuranyl, optionally substituted morpholinyl, optionally substituted tetrahydroisoquinolinyl, optionally substituted azo yl, optionally substituted isoquinolinyl, optionally substituted cycloheptenyl, optionally substituted indenyl, optionally substituted dihydronaphthyl, optionally substituted 8-azabicyclooctyl, optionally substituted adamantyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl.

[0115] In one embodiment, Ar is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted pyridopyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted dihydrobenzofuranyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl. In another embodiment, Ar is optionally substituted phenyl, optionally substituted biphenyl, or optionally substituted naphthyl.

[0116] In another embodiment, Ar is phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, pyridopyrazolyl, isoxazolyl, indolyl, isoindolyl, thienyl, dihydrobenzofuranyl, dihydroindenyl, cyclopropyl, or cyclohexyl, and each group of Ar is optionally substituted with one or more substituents, and the one or more substituents are each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 , where: R 8 is alkyl, OR 13 or NR 14 R 15 ; R 9 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or COR 16 ; R 10 and R 11 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or COR 17 ; R 12 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 18 or NR 14 R 15 ; each R 13 , R 14 and R 15 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 16 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 17is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 18 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and n is 0, 1 or 2.

[0117] In another embodiment, Ar is phenyl, biphenyl, or naphthyl, each of which is optionally substituted with one or more substituents, and the one or more substituents are each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 , where: R 8 is alkyl, OR 13 or NR 14 R 15 ; R 9 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or COR 16 ; R 10 and R 11 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or COR 17 ; R 12 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 18 or NR 14 R 15 ; each R 13 , R 14 and R 15 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 16 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 17 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 18is an alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl; and n is 0, 1 or 2.

[0118] In one embodiment, Ar is substituted with 1 to 5, or 1 to 3, or 1 or 2 substituents. In another embodiment, Ar is unsubstituted.

[0119] In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 。 In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclicalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 。 In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclicalkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 。

[0120] In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridinyl-oxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

[0121] In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridinyl-oxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

[0122] In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 1-pyrazolyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, and SO2-(1-pyrrolidinyl).

[0123] In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, and SO2-(1-pyrrolidinyl).

[0124] In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2, and NMe2.

[0125] In another embodiment, Ar is unsubstituted phenyl, unsubstituted 4-biphenyl, or unsubstituted 1-naphthyl. In another embodiment, Ar is unsubstituted phenyl.

[0126] In another embodiment, Ar is thienyl, and the thienyl is optionally substituted with one or more substituents, each of the one or more substituents being independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 。

[0127] In another embodiment, Ar is thienyl, and the thienyl is optionally substituted with one or more substituents, each of the one or more substituents being independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 。

[0128] In another embodiment, Ar is thienyl, and the thienyl is optionally substituted with one or more substituents, each of the one or more substituents being independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 。

[0129] In another embodiment, Ar is thienyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-methoxybenzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

[0130] In another embodiment, Ar is thienyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, and SO2-(1-pyrrolidinyl).

[0131] In another embodiment, Ar is thienyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridinyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2, and NMe2.

[0132] In another embodiment, Ar is unsubstituted thienyl.

[0133] In another embodiment, Ar is a pyrazolyl group, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 。

[0134] In another embodiment, Ar is a pyrazolyl group, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclicalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 。

[0135] In another embodiment, Ar is a pyrazolyl group, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclicalkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 。

[0136] In another embodiment, Ar is a pyrazolyl group, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-methoxybenzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl and SO2-(1-pyrrolidinyl).

[0137] In another embodiment, Ar is a pyrazolyl group, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

[0138] In another embodiment, Ar is a pyrazolyl group, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2 and NMe2.

[0139] In another embodiment, Ar is an unsubstituted pyrazolyl group.

[0140] In another embodiment, the compounds provided by the present invention have the following structure:

[0141] wherein R 5 , Ar, and X 1 -X 5 are each as defined elsewhere in the present invention.

[0142] In another embodiment, the compounds provided by the present invention have the following structure:

[0143] wherein R 5 , Ar, and X 1 -X 5 are each as defined elsewhere in the present invention.

[0144] In another embodiment, the compounds provided by the present invention have the following structure:

[0145] wherein X 3 , X 4 , R, Ar, and R 5 are each as defined elsewhere in the present invention.

[0146] In another embodiment, the compounds provided by the present invention have the following structure:

[0147] wherein X 4 , R, Ar, and R 5 are each as defined elsewhere in the present invention.

[0148] In another embodiment, the compounds provided by the present invention have the following structure:

[0149] wherein X 4 , R, Ar, and R 5 are each as defined elsewhere in the present invention.

[0150] In another embodiment, the compounds provided by the present invention have the following structure:

[0151] wherein R, R 5 , and Ar are each as defined elsewhere in the present invention.

[0152] In another embodiment, the compounds provided by the present invention have the following structure:

[0153] wherein Ar is as defined elsewhere in the present invention.

[0154] In another embodiment, the compounds provided by the present invention have the following structure:

[0155] Wherein Ar is as defined elsewhere in the present invention. In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

[0156] In another embodiment, the compounds provided by the present invention have the following structure:

[0157] Wherein R, R 5 and Ar are all as defined elsewhere in the present invention.

[0158] In another embodiment, the compounds provided by the present invention have the following structure:

[0159] Wherein Ar is as defined elsewhere in the present invention.

[0160] In another embodiment, the compounds provided by the present invention have the following structure:

[0161] wherein Ar is as defined elsewhere in the present invention. In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 、OR 9 、NR 10 R 11 and S(O) n R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

[0162] In another embodiment, the compounds provided by the present invention have the following structure:

[0163] wherein R, R 5 and Ar are all as defined elsewhere in the present invention.

[0164] In another embodiment, the compounds provided by the present invention have the following structure:

[0165] wherein Ar is as defined elsewhere in the present invention.

[0166] In another embodiment, the compounds provided by the present invention have the following structure:

[0167] wherein Ar is as defined elsewhere in the present invention. In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 , OR 9 , NR 10 R 11 and S(O)2R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2 and NMe2.

[0168] In another embodiment, the compounds provided by the present invention have the following structure:

[0169] wherein R, Ar and R 5 are all as defined elsewhere in the present invention.

[0170] In another embodiment, the compounds provided by the present invention have the following structure:

[0171] wherein Ar and R 5 are all as defined elsewhere in the present invention.

[0172] In another embodiment, the compounds provided by the present invention have the following structure:

[0173] wherein Ar is as defined elsewhere in the present invention.

[0174] In another embodiment, the compounds provided by the present invention have the following structure:

[0175] wherein Ar is as defined elsewhere in the present invention. In another embodiment, Ar is phenyl, and the phenyl is optionally substituted with one or more substituents, and the one or more substituents are each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 . In another embodiment, Ar is phenyl, and the phenyl is optionally substituted with one or more substituents, and the one or more substituents are each independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 1-pyrazolyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

[0176] In another embodiment, the compounds provided by the present invention have the following structure:

[0177] wherein X 5 , R, Ar and R 5 are all as defined elsewhere in the present invention.

[0178] In another embodiment, the compounds provided by the present invention have the following structure:

[0179] wherein Ar and R 5 are all as defined elsewhere in the present invention.

[0180] In another embodiment, the compounds provided by the present invention have the following structure:

[0181] wherein Ar is as defined elsewhere in the present invention.

[0182] In another embodiment, the compounds provided by the present invention have the following structure:

[0183] wherein Ar is as defined elsewhere in the present invention. In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 , OR 9 , NR 10 R 11 and S(O)2R 12 . In another embodiment, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

[0184] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from:

[0185] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from:

[0186] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from:

[0187] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from:

[0188] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from:

[0189] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from:

[0190] In another embodiment, the compounds provided by the present invention for use in the compositions and methods provided by the present invention are selected from: III. Synthesis of Compounds

[0191] The compounds provided by the present invention can be synthesized from commercially available starting materials using standard methods well known to those skilled in the art. In one embodiment, the compounds provided by the present invention are synthesized according to one of the methods shown below.

[0192] In another embodiment, a compound library can be synthesized according to the methods shown below (see, for example, WO 2021 / 226269, WO 2020 / 127685, WO 2010 / 068242):

[0193] wherein R 20 is a substituent on Ar, as defined in the present invention, and x is an integer from 1 to 5, or 1 to 3, or 1 or 2.

[0194] In another embodiment, a compound library can be synthesized according to the methods shown below (see, for example, WO 2014 / 151945, WO 2010068242):

[0195] wherein R 20is a substituent on Ar, as defined in the present invention, and x is an integer from 1 to 5, or from 1 to 3, or 1 or 2.

[0196] In another embodiment, the compound library can be synthesized according to the methods shown below (see, for example, WO 2014 / 151945, WO 2010068242):

[0197] wherein R 20 is a substituent on Ar, as defined in the present invention, and x is an integer from 1 to 5, or from 1 to 3, or 1 or 2.

[0198] In another embodiment, the compound library can be synthesized according to one of the methods shown below:

[0199] wherein R is Ar as defined in the present invention. IV. Pharmaceutical Compositions

[0200] The pharmaceutical compositions provided by the present invention comprise a therapeutically effective amount of one or more compounds provided by the present invention and a pharmaceutically acceptable carrier, diluent or excipient.

[0201] The compounds can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release preparations or elixirs, for oral administration, or sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patches and dry powder inhalers. Generally, the above compounds can be formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0202] In the composition, an effective concentration of one or more compounds or pharmaceutically acceptable salts is mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective for delivering an amount after administration to treat, prevent or improve one or more symptoms and / or progression of the diseases or disorders disclosed in the present invention.

[0203] Generally, the composition is formulated for single-dose administration. To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle so as to alleviate or improve the disorder being treated. Pharmaceutical carriers or vehicles suitable for the administration of the compounds provided by the present invention include any such carriers known to those skilled in the art as being suitable for a particular mode of administration.

[0204] In addition, the compound can be formulated as the sole pharmaceutically active ingredient in a composition or in combination with other active ingredients. Liposome suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, are also suitable as pharmaceutically acceptable carriers. These can all be prepared by methods known to those skilled in the art. For example, liposome formulations can be prepared according to methods known in the art. Briefly, liposomes such as multilamellar vesicles (MLV) can be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. A solution of the compound provided by the present invention in phosphate buffered saline (PBS) lacking divalent cations is added to the flask, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, precipitated by centrifugation, and then resuspended in PBS.

[0205] The active compound is contained in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutic effect without causing adverse side effects to the subject being treated. The therapeutically effective concentration can be determined empirically by testing the compound in the in vitro and in vivo systems described in the present invention and then extrapolating the human dose therefrom. In some embodiments, the active compound is administered in a manner that achieves a pharmaceutically effective concentration. In some embodiments, companion diagnostics (see, for example, Olsen D and Jorgensen J T, Front. Oncol., 2014 May 16, 4:105, doi:10.3389 / fonc.2014.00105) are used to determine the therapeutic concentration and safety of the active compound in a particular subject or group of subjects.

[0206] The concentration of the active compound in the pharmaceutical composition depends on the absorption, tissue distribution, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the dosing regimen and the amount administered, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of the diseases or disorders disclosed in the present invention.

[0207] In certain embodiments, the therapeutically effective dose should result in a serum concentration of the active ingredient of from about 0.1 ng / mL to about 50 - 100 μg / mL. In one embodiment, the pharmaceutical composition provides a dose of from about 0.001 mg to about 2000 mg of the compound / kg body weight / day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg of the basic active ingredient / dosage unit form or combination of basic ingredients / dosage unit form, and in certain embodiments, from about 10 to about 500 mg of the basic active ingredient / dosage unit form or combination of basic ingredients / dosage unit form.

[0208] The active ingredient can be administered in one dose or divided into multiple small doses and administered at regular intervals. It should be understood that the precise dosage and duration of treatment depend on the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that the concentration and dosage values may also vary with the severity of the condition to be alleviated. It should also be understood that for any particular subject, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described in the present invention are only examples and are not intended to limit the scope or practice of the claimed composition.

[0209] Accordingly, an effective concentration or amount of one or more of the compounds or pharmaceutically acceptable salts thereof described in the present invention is mixed with a pharmaceutical carrier or vehicle suitable for systemic, topical or local administration to form a pharmaceutical composition. The amount of the compound contained can effectively improve one or more symptoms, or treat, delay the progression, or prevent. The concentration of the active compound in the composition depends on the absorption, tissue distribution, inactivation, excretion rate of the active compound, the dosing regimen, the dosage administered, the specific formulation, and other factors known to those skilled in the art.

[0210] The composition is intended to be administered by suitable routes, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, cutaneous, transdermal, buccal, rectal, topical, local, nasal or inhalation. For oral administration, capsules and tablets can be formulated. The composition is in liquid, semi-liquid or solid form and is formulated in a manner suitable for each route of administration.

[0211] Solutions or suspensions for parenteral, intradermal, subcutaneous or local application may include any of the following ingredients: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerol, propylene glycol, dimethylacetamide or other synthetic solvents; antimicrobial agents such as benzyl alcohol and methylparaben; 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 adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, pens, disposable syringes, or single-dose or multi-dose vials made of glass, plastic or other suitable materials.

[0212] In cases where the compound exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include but are not limited to using co-solvents (e.g., dimethyl sulfoxide (DMSO)), using surfactants (e.g., ) or dissolving in an aqueous sodium bicarbonate solution.

[0213] After mixing or adding the compounds, the resulting mixture can be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on various factors, including the intended mode of administration and the solubility of the compounds in the selected carrier or vehicle. The effective concentration is sufficient to improve the symptoms of the disease, disorder or condition being treated and can be determined empirically.

[0214] The pharmaceutical compositions are provided in unit dosage forms for administration to humans and animals, for example, in the form of tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-in-water emulsions, containing a suitable amount of the compound or its pharmaceutically acceptable salt. The pharmaceutically therapeutically active compounds and their salts are formulated and administered in unit dosage form or in multiple dosage form. The unit dosage form used in the present invention refers to physically discrete units suitable for human and animal subjects and individually packaged as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound, together with the required pharmaceutical carrier, vehicle or diluent, sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. The unit dosage form can be administered in its fraction or multiple. The multiple dosage form is a plurality of identical unit dosage forms packaged in a single container and administered in discrete unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or pint or gallon bottles. Thus, the multiple dosage form is a plurality of unit dosages not separated in the package.

[0215] Sustained release formulations can also be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds provided by the present invention, said matrices being in the form of shaped articles, such as films or microcapsules. Examples of sustained release matrices include iontophoretic patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (e.g., LUPRON DEPOT TM )(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. Although polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for more than 100 days, some hydrogels release proteins for a shorter time. When the encapsulated compound remains in the body for a long time, it may denature or aggregate due to exposure to moisture at 37°C, resulting in loss of biological activity and possible change in its structure. A reasonable stabilization strategy can be designed according to the mechanism of action involved. For example, if it is found that the aggregation mechanism is through the formation of intermolecular S--S bonds by thiol-disulfide exchange, stabilization can be achieved by modifying the thiol residues, lyophilizing from acidic solutions, controlling the moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0216] Dosage forms or compositions can be prepared that contain from 0.005% to 100% of an active ingredient, with the remainder consisting of a non-toxic carrier. For oral administration, by incorporating any commonly used excipients, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, sodium carboxymethylcellulose cross-linked, glucose, sucrose, magnesium carbonate or sodium saccharin, a pharmaceutically acceptable non-toxic composition is formed. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, etc. Methods for preparing these compositions are known to those skilled in the art. The contemplated compositions can contain from about 0.001% - 100% of the active ingredient, and in certain embodiments, contain from about 0.1% - 85% or about 75 - 95% of the active ingredient.

[0217] The active compound or a pharmaceutically acceptable salt thereof can be prepared with a carrier that protects the compound from rapid elimination from the body, such as a sustained release formulation or a coating.

[0218] The composition can include other active compounds to obtain a desired combination of properties. The compounds provided by the present invention or pharmaceutically acceptable salts thereof as described herein can also be advantageously used together with another pharmacological agent known in the art for therapeutic or prophylactic purposes, said pharmacological agent being valuable in the treatment of one or more of the above diseases or medical conditions (e.g., diseases related to oxidative stress). It should be understood that such combination therapy constitutes another aspect of the compositions and treatment methods provided by the present invention.

[0219] The lactose-free compositions provided by the present invention can contain excipients well known in the art and are excipients listed, for example, in the United States Pharmacopeia (USP) SP(XXI) / NF(XVI). Generally, the 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, pregelatinized starch, and magnesium stearate.

[0220] The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing the compounds provided by the present invention. For example, in the pharmaceutical field, the addition of water (e.g., 5%) is widely accepted as a way to simulate long-term storage to determine characteristics such as shelf life or the stability of a formulation over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In fact, water and heat can accelerate the decomposition of certain compounds. Thus, the effect of water on a formulation can be very important because moisture and / or humidity are typically encountered during the manufacture, handling, packaging, storage, shipping, and use of a formulation.

[0221] The anhydrous pharmaceutical compositions and dosage forms provided by the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient containing a primary or secondary amine are anhydrous if substantial contact with moisture and / or humidity is expected during manufacture, packaging, and / or storage.

[0222] The preparation and storage of anhydrous pharmaceutical compositions should maintain their anhydrous nature. Thus, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in a suitable prescription kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs. A. Oral Dosage Forms

[0223] Oral pharmaceutical dosage forms include solids, gels, or liquids. Solid dosage forms include tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges, and tablets, and these dosage forms can be coated with enteric coatings, sugar coatings, or film coatings. Capsules can be hard gelatin capsules or soft gelatin capsules, and granules and powders can be combined with other ingredients known to those skilled in the art to be provided in non-effervescent or effervescent forms.

[0224] In certain embodiments, the formulation is a solid dosage form, such as a capsule or a tablet. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents.

[0225] Examples of binders include microcrystalline cellulose, tragacanth, glucose solution, gum arabic, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium stearate 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 silica. Disintegrants include sodium carboxymethylcellulose cross-linked, sodium starch glycolate, crospovidone, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Colorants include, for example, any approved water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on hydrated alumina. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners (e.g., saccharin), as well as any number of spray-dried flavoring agents. Flavoring agents include natural flavorings extracted from plants (e.g., fruits), and mixtures of synthetic compounds that 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 phthalate. Film coatings include hydroxyethyl cellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0226] If oral administration is desired, the compounds can be formulated into compositions that protect them from the acidic environment of the stomach. For example, the compositions can be formulated with enteric coatings to maintain their integrity in the stomach and release the active compounds in the intestine. The compositions can also be formulated in combination with antacids or other such ingredients.

[0227] When the dosage unit form is a capsule, in addition to materials of the above types, it can also contain a liquid carrier, such as a fatty oil. In addition, the dosage unit form can contain various other materials that can modify the physical form of the dosage unit, such as coatings of sugar and other enteric solvents. The compounds can also be administered as ingredients in elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc. In addition to the active compound, the syrup can contain sucrose as a sweetening agent and certain preservatives, dyes, as well as colorants and flavoring agents.

[0228] The active substance can also be mixed with other active substances that do not impair the desired action, or with substances that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is the compound described in the present invention or a pharmaceutically acceptable salt thereof. Higher concentrations of the active ingredient can be included, up to about 98% by weight of the active ingredient.

[0229] Pharmaceutically acceptable carriers included in tablets include binders, lubricants, diluents, disintegrants, colorants, flavorants, and wetting agents. Enteric-coated tablets, due to having an enteric coating, can resist the action of gastric acid and dissolve or disintegrate in the neutral or alkaline intestine. Sugar-coated tablets are compressed tablets coated with different layers of pharmaceutically acceptable substances. Film-coated tablets are compressed tablets coated with a polymer or other suitable coating. Multiple-compressed tablets are compressed tablets made through more than one compression cycle using the aforementioned pharmaceutically acceptable substances. Colorants can also be used in the above dosage forms. Flavorants and sweeteners can both be used in compressed tablets, sugar-coated tablets, multiple-compressed tablets, and chewable tablets. Flavorants and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0230] 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 oil-in-water or water-in-oil. In some embodiments, suspensions are suspensions of microparticles or nanoparticles. In some embodiments, emulsions are emulsions of microparticles or nanoparticles.

[0231] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugar (e.g., sucrose) and may contain preservatives. Emulsions are a two-phase system in which one liquid is dispersed in the form of small spheres in 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 liquid oral dosage forms) include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules (to be reconstituted into liquid oral dosage forms) include organic acids and a source of carbon dioxide. Colorants and flavorants can be used in all of the above dosage forms.

[0232] Solvents include glycerol, sorbitol, ethanol, and syrup. Examples of preservatives include glycerol, methyl paraben, and propyl paraben, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, magnesium aluminum silicate, and gum arabic. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrup, glycerol, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene dodecyl ether. Organic additives include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include any approved water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavorings extracted from plants (e.g., fruits), and mixtures of synthetic compounds that produce a pleasant taste.

[0233] For solid dosage forms, a solution or suspension of, for example, propylene carbonate, vegetable oil, or triglyceride is encapsulated in a gelatin capsule. Such solutions and their preparation and encapsulation are disclosed in U.S. Patent Nos. US4,328,245, US4,409,239, and US4,410,545. For liquid dosage forms, a solution (e.g., a solution of polyethylene glycol) is diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate measurement for dosing.

[0234] Alternatively, liquid or semi-solid oral formulations can 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 the compounds provided by the present invention, dialkylated mono- or poly-alkyl diols (including, but not limited to, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol), and one or more antioxidants (e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates).

[0235] Other formulations include, but are not limited to, aqueous alcoholic solutions containing pharmaceutically acceptable acetals. The alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxy groups, including but not limited to propylene glycol and ethanol. The acetals include, but are not limited to, bis(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0236] In all embodiments, tablet and capsule formulations can be coated as known to those skilled in the art to modify or maintain the dissolution of the active ingredient. Thus, for example, both tablets and capsules can be coated with conventional enterically digestible coatings (e.g., phenyl salicylate, waxes, and cellulose acetate phthalate). B. Injectables, Solutions, and Emulsions

[0237] The present invention also contemplates parenteral administration, typically characterized by injection, or by subcutaneous, intramuscular or intravenous injection. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, in solid forms suitable for solution or suspension in a 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 include, for example, water, saline, dextrose, glycerol or ethanol. Additionally, if desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubilizing enhancers, and other such reagents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. The present invention also contemplates implantable sustained release or controlled release systems in order to maintain a constant dosage level. Briefly, the compounds provided by the present invention are dispersed within a solid inner matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicones, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (e.g., hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate), which solid inner matrix is surrounded by an outer polymeric membrane, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicones, polydimethylsiloxanes, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ethylene terephthalate ionomers, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyl glycol ether copolymers, which outer polymers are insoluble in body fluids. The compounds diffuse through the outer polymeric membrane in a rate controlling step. The percentage of the active compound contained in such parenteral compositions highly depends on its specific properties as well as the activity of the compound and the needs of the subject.

[0238] Parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration. Parenteral dosage forms include ready-to-inject sterile solutions, sterile dry soluble products (e.g., lyophilized powders) that can be immediately mixed with a solvent prior to use, including tablets for subcutaneous injection, ready-to-inject sterile suspensions, sterile dry insoluble products that can be immediately mixed with a vehicle prior to use, and sterile emulsions. Solutions can be aqueous or non-aqueous.

[0239] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents (e.g., glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof).

[0240] Pharmaceutically acceptable carriers for parenteral formulations include aqueous media, non-aqueous media, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, complexing or chelating agents, and other pharmaceutically acceptable substances.

[0241] Examples of aqueous media include sodium chloride injection, Ringers Injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringers injection. Non-aqueous parenteral media include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations must be added to parenteral formulations packaged in multi-dose containers, and such antimicrobial agents include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 Complexing or chelating agents for metal ions include EDTA. Pharmaceutical carriers also include water-miscible media such as ethanol, polyethylene glycol, and propylene glycol, and pH regulators such as sodium hydroxide, hydrochloric acid, citric acid, or lactic acid.

[0242] Adjust the concentration of the pharmaceutically active compound such that the 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.

[0243] Unit dose parenteral formulations are packaged in ampoules, vials, or syringes with needles. All formulations for parenteral administration must be sterile, as is known and practiced in the art.

[0244] Exemplarily, intravenous or intra-arterial infusion of a sterile aqueous solution containing the active compound is an effective mode of administration. Another embodiment is injection, as needed, of a sterile aqueous or oily solution or suspension containing the active substance to produce the desired pharmacological effect.

[0245] Injectables are designed for both local and systemic administration. Generally, for the tissue being treated, a therapeutically effective dose is formulated to contain an active compound at a concentration of at least about 0.1% w / w to at most about 90% w / w or more, such as more than 1% w / w. The active ingredient can be administered in one dose or divided into multiple smaller doses administered at intervals. It should be understood that the precise dose and duration of treatment depend on the tissue being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that the concentration and dose values can also vary with the age of the individual being treated. It should also be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the formulation, and the concentration ranges described in the present invention are merely exemplary and are not intended to limit the scope or practice of the claimed formulation.

[0246] The compound can be suspended in micronized or other suitable form or derivatized to produce a more soluble active product or a prodrug. The form of the resulting mixture depends on 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 to relieve the symptoms of the disorder and can be determined empirically. C. Lyophilized powder

[0247] The present invention also provides a lyophilized powder, which can be reconstituted into solutions, emulsions and other mixtures for administration. The lyophilized powder can also be reconstituted and formulated into solids or gels.

[0248] Sterile lyophilized powder is prepared by dissolving the compound provided by the present invention or a pharmaceutically acceptable salt thereof in a suitable solvent. The solvent can contain excipients, which can improve the stability of the powder or the reconstituted solution prepared from the powder or other pharmacological components. Excipients that can be used include, but are not limited to, dextran, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose or other suitable reagents. The solvent can also contain buffers, such as citrate, sodium phosphate or potassium phosphate, or other such buffers known to those skilled in the art. In one embodiment, the pH value is about neutral. Subsequently, the solution is aseptically filtered and then lyophilized under standard conditions known to those skilled in the art to provide the desired formulation. Generally, the resulting solution is dispensed into vials for lyophilization. Each vial will contain a single dose (including but not limited to 10 - 1000 mg or 100 - 500 mg) or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as stored at about 4°C to room temperature.

[0249] The lyophilized powder is reconstituted with water to obtain a formulation for parenteral administration. When reconstituting, about 1 - 50 mg, about 5 - 35 mg, or about 9 - 30 mg of the lyophilized powder is added to each mL of sterile water or other suitable vehicle. The exact amount depends on the compound selected. The amount can be determined empirically. D. Topical / Transdermal Administration

[0250] The topical mixture is prepared as described for topical and systemic administration. The resulting mixture can be a solution, suspension, emulsion, etc., and is formulated into creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, douches, sprays, suppositories, bandages, skin patches, or any other suitable formulation for topical administration.

[0251] The compound or a pharmaceutically acceptable salt thereof can be formulated into an aerosol for topical administration, for example, by inhalation (see, e.g., U.S. Patent Nos. US4,044,126, US4,414,209, and US4,364,923, which describe aerosols for delivering steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or a solution for a nebulizer, or as a fine powder for insufflation, used alone or in combination with an inert carrier (e.g., lactose). In such cases, the particle diameter of the formulation is less than 50 microns or less than 10 microns.

[0252] The compound can be formulated for topical or transdermal administration, for example, topically applied to the skin and mucous membranes (e.g., intraocular) in the form of gels, creams, and lotions, and administered intravitreally, intracisternally, or intraspinally. Topical administration is suitable for transdermal delivery, as well as for ocular or mucosal administration, or for inhalation therapy. Nasal solutions of the active compound can also be used alone or in combination with other pharmaceutically acceptable excipients.

[0253] These solutions, especially those for ophthalmic use, can be formulated as 0.01% - 10% isotonic solutions with a pH of about 5 - 7 and containing appropriate salts. E. Compositions for Other Routes of Administration

[0254] The present invention also contemplates other routes of administration, such as topical administration, transdermal patches, and rectal administration.

[0255] For example, drug dosage forms for rectal administration are rectal suppositories, capsules, and tablets for systemic action. The rectal suppositories used in the present invention refer to solid suppositories inserted into the rectum, which melt or soften at body temperature and release one or more pharmacological or therapeutic active ingredients. Pharmaceutically acceptable substances used in rectal suppositories are matrices or vehicles and agents that increase the melting point. Examples of matrices include cocoa butter (cocoa oil), glycerogelatin, polyethylene glycol (polyethylene glycol), and suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids. Combinations of various matrices can be used. Agents that increase the melting point of the suppository include cetyl and wax. Rectal suppositories can be prepared by a compression method or a molding method. The exemplary weight of a rectal suppository is about 2 g to 3 g.

[0256] Tablets and capsules for rectal administration are both prepared using the same pharmaceutically acceptable substances and the same methods as oral dosage forms. F. Sustained-release compositions

[0257] The active ingredients provided by the present invention can be administered by controlled release methods or delivery devices well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. US 3,845,770, US 3,916,899, US 3,536,809, US 3,598,123, and U.S. Patent Nos. US 4,008,719, US 5,674,533, US 5,059,595, US 5,591,767, US 5,120,548, US 5,073,543, US 5,639,476, US 5,354,556, US 5,639,480, US 5,733,566, US 5,739,108, US 5,891,474, US 5,922,356, US 5,972,891, US 5,980,945, US 5,993,855, US 6,045,830, US 6,087,324, US 6,113,943, US 6,197,350, US 6,248,363, US 6,264,970, US 6,267,981, US 6,376,461, US 6,419,961, US 6,589,548, US 6,613,358, US 6,699,500, and US 6,740,634; each patent is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients, for example, using hydroxypropyl methylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide desired release profiles in different proportions. Suitable controlled release formulations known to those skilled in the art (including those described in the present invention) can be easily selected for use with the active ingredients provided by the present invention.

[0258] All controlled release drug products share a common goal of improving drug therapy to be superior to non-controlled release drugs. In one embodiment, the use of an optimally designed controlled release formulation in medicine is characterized by using the least amount of drug substance to cure or control the condition in the shortest time. In certain embodiments, the advantages of controlled release formulations include extended drug activity, reduced dosing frequency, and increased subject compliance. In addition, controlled release formulations can be used to affect the onset time or other properties, such as the blood concentration of the drug, thereby affecting the occurrence of side effects (e.g., adverse reactions).

[0259] Most controlled release formulations are designed to release a certain amount of the drug (active ingredient) first, to rapidly produce the desired therapeutic effect, and then to gradually and continuously release other amounts of the drug to maintain this therapeutic or prophylactic effect level over a longer period of time. In order to maintain such a constant drug level in the body, the drug must be released from the dosage form at a certain rate to replace the amount of drug metabolized and excreted in the body. The controlled release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0260] In certain embodiments, the drug can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In one embodiment, a pump can 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, the controlled release system can be placed near the therapeutic target, i.e., thus only requiring a small fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)).

[0261] In some embodiments, the controlled release device is introduced near an inappropriate immune activation site or a tumor in a subject. Langer (Science 249:1527-1533 (1990)) discussed other controlled release systems in a review. The active ingredient may be dispersed in a solid internal matrix such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer classes, silicone rubber classes, polydimethylsiloxane classes, silicone carbonate copolymer classes, hydrophilic polymer classes (e.g., hydrogels of esters of acrylic acid and methacrylic acid, collagen, crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate), and the solid internal matrix is surrounded by an external polymer film, and the external polymer is, for example, polyethylene, polypropylene, ethylene / propylene copolymer classes, ethylene / ethyl acrylate copolymer classes, ethylene / vinyl acetate copolymer classes, silicone rubber classes, polydimethylsiloxane classes, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomers, butyl rubber, epichlorohydrin rubber classes, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyl glycol ether copolymers, and these external polymers are insoluble in body fluids. The active ingredient diffuses through the external polymer film in a release rate controlling step. The percentage of the active compound contained in such parenteral compositions highly depends on its specific properties and the needs of the subject. G. Targeted formulations

[0262] The compounds or their pharmaceutically acceptable salts provided by the present invention may also be formulated into delivery systems targeting specific tissues, receptors or other body parts of the subject to be treated, including liposome-based, resealed red blood cell-based and antibody-based delivery systems. Many such targeting methods are well known to those skilled in the art. The present invention contemplates all such targeting methods for the compositions of the present invention. For non-limiting examples of targeting methods, see, for example, U.S. Patent Nos. US 6,316,652, US 6,274,552, US 6,271,359, US 6,253,872, US 6,139,865, US 6,131,570, US 6,120,751, US 6,071,495, US 6,060,082, US 6,048,736, US 6,039,975, US 6,004,534, US 5,985,307, US5,972,366, US 5,900,252, US 5,840,674, US 5,759,542 and US 5,709,874.

[0263] In one embodiment, the antibody-based delivery system is an antibody-drug conjugate ("ADC"), e.g., as described in Hamilton G S, Biologicals, September 2015, 43(5):318-32; Kim E G and Kim K M, Biomol. Ther. (Seoul), November 2015, 23(6):493-509; and Peters C and Brown S, Biosci. Rep., Jun. 12, 2015, 35(4) pii:e00225, each of which is incorporated herein by reference.

[0264] In one embodiment, liposome suspensions, including tissue-targeted liposomes, e.g., tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These can all be prepared by methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. US 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV) can be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. A solution of the compound provided by the present invention in phosphate-buffered saline (PBS) lacking divalent cations is added to the flask, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, precipitated by centrifugation, and then resuspended in PBS. H. Articles

[0265] The compound or pharmaceutically acceptable salt thereof can be packaged into an article that contains a packaging material, the compound or its pharmaceutically acceptable salt provided by the present invention (for treating, preventing, or ameliorating one or more symptoms or progression of the diseases or disorders disclosed by the present invention), and a label that indicates that the compound or its pharmaceutically acceptable salt is for treating, preventing, or ameliorating one or more symptoms or progression of the diseases or disorders disclosed by the present invention.

[0266] The article provided by the present invention contains a packaging material. Packaging materials for packaging pharmaceutical products are well known to those skilled in the art. See, for example, U.S. Patent Nos. US 5,323,907, US 5,052,558, and US 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 the selected formulation and the intended mode of administration and treatment. The present invention contemplates various formulations of the compounds and compositions provided by the present invention.

[0267] In certain embodiments, the present invention also provides a kit that, when used by a healthcare provider, simplifies the process of administering an appropriate amount of the active ingredient to a subject. In certain embodiments, the kit provided by the present invention includes a container and a dosage form of the compound provided by the present invention, including a mixture of its single enantiomers or diastereomers; or its pharmaceutically acceptable salts, solvates or prodrugs.

[0268] In certain embodiments, the kit includes a container that contains a dosage form of the compound provided by the present invention, including a mixture of its single enantiomers or diastereomers; or its pharmaceutically acceptable salts, solvates or prodrugs, and the container further contains one or more other therapeutic agents described in the present invention.

[0269] The kit provided by the present invention may further include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless injectors, drip bags, patches, and inhalers. The kit provided by the present invention may further include a condom for administering the active ingredient.

[0270] The kit provided by the present invention may further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in solid form and must be reconstituted for parenteral administration, the kit may include a sealed container containing a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution 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 ethanol, 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. Dosage

[0271] The compounds and pharmaceutical compositions provided by the present invention can be administered according to certain therapeutically or prophylactically effective amounts, certain time intervals, certain dosage forms, and certain dosage regimens as described hereinafter.

[0272] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is about 0.005 to about 1,000 mg per day, about 0.01 to about 500 mg per day, about 0.01 to about 250 mg per day, about 0.01 to about 100 mg per day, about 0.1 to about 100 mg per day, about 0.5 to about 100 mg per day, about 1 to about 100 mg per day, about 0.01 to about 50 mg per day, about 0.1 to about 50 mg per day, about 0.5 to about 50 mg per day, about 1 to about 50 mg per day, about 0.02 to about 25 mg per day, about 0.05 to about 10 mg per day, about 0.05 to about 5 mg per day, about 0.1 to about 5 mg per day, or about 0.5 to about 5 mg per day.

[0273] In certain embodiments, a therapeutically or prophylactically effective amount is about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 150 mg per day.

[0274] In one embodiment, the recommended daily dose range of the compound or its derivative provided by the present invention for the conditions described in the present invention is about 0.5 mg to about 50 mg per day. In one embodiment, it is administered as a single dose once a day, or as divided doses throughout the day. In some embodiments, the dose range is about 1 mg to about 50 mg per day. In other embodiments, the dose range is about 0.5 mg to about 5 mg per day. Specific daily doses include 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg or 50 mg per day.

[0275] In certain embodiments, the recommended starting dose can be 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 50 mg per day. In another embodiment, the recommended starting dose can be 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg per day. The dose can be increased to 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg per day. In certain embodiments, the amount of the compound administered can be about 25 mg / day. In certain embodiments, the amount of the compound administered can be about 10 mg / day. In certain embodiments, the amount of the compound administered can be about 5 mg / day. In certain embodiments, the amount of the compound administered can be about 4 mg / day. In certain embodiments, the amount of the compound administered can be about 3 mg / day.

[0276] In some embodiments, a 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, from 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.

[0277] The dose administered can also be expressed in units other than mg / kg / day. For example, the dose administered parenterally can be expressed as mg / m 2 / day. One of ordinary skill in the art can readily know how to convert the dose from mg / kg / day to mg / m 2 / day based on the height or weight of the subject or both (see www.fda.gov / cder / cancer / animalframe.htm). For example, for a 65 kg person, a dose of 1 mg / kg / day is approximately equal to 38 mg / m 2 / day.

[0278] In some embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state in the range of 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, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM.

[0279] In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, in the range of from about 5 to about 100 nM, from about 5 to about 50 nM, from about 10 to about 100 nM, from about 10 to about 50 nM, or from about 50 to about 100 nM.

[0280] As used herein, the term "plasma concentration at steady state" is the concentration reached after administration of a compound or its derivative provided by the present invention for a period of time. Once steady state is reached, minor peaks and valleys appear in the curve of the plasma concentration of the compound over time.

[0281] In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, in the range of from about 0.001 to about 50 μM, from about 0.002 to about 200 μM, from about 0.005 to about 100 μM, from about 0.01 to about 50 μM, from about 1 to about 50 μM, from 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.

[0282] In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, in the range of from about 0.001 to about 500 μM, from about 0.002 to about 200 μM, from about 0.005 to about 100 μM, from about 0.01 to about 50 μM, from about 1 to about 50 μM, from 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.

[0283] In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, in the range of 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.

[0284] The methods provided by the present invention cover treating a patient, regardless of the age of the subject, although certain diseases or disorders are more common in certain age groups.

[0285] Depending on the disease to be treated and the condition of the subject, the compounds or their derivatives provided by the present invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implantation), inhalation, intranasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compounds or their derivatives provided by the present invention can be formulated alone or together with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles suitable for each route of administration into appropriate dosage units.

[0286] In one embodiment, the compounds or their derivatives provided by the present invention can be administered orally. In another embodiment, the compounds or their derivatives provided by the present invention can be administered parenterally. In yet another embodiment, the compounds or their derivatives provided by the present invention can be administered intravenously.

[0287] The compounds or their derivatives provided by the present invention can be administered in a single dose, such as a single bolus injection, or in the form of oral tablets or pills; or administered over time, such as by continuous infusion over time or by fractional bolus injections over time. If necessary, the compounds can be administered repeatedly, for example, until the condition of the subject stabilizes or regresses, or until the condition of the subject progresses or unacceptable toxicity occurs. For example, stable disease in solid tumors generally means that the perpendicular diameter of the measurable lesion has not increased by 25% or more compared to the previous measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205 - 216(2000). Whether the disease is stable is determined by methods known in the art, such as evaluating the patient's symptoms, physical examination, visualizing the tumor using X - ray, CAT, PET, or MRI scans, and other generally accepted evaluation methods.

[0288] The compounds or their derivatives provided by the present invention 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., administered on successive days or daily), or intermittent, for example, in a cyclic or periodic manner (i.e., including drug holidays of several days, weeks, or months). The terms "daily" or "every day" as used in the present invention are intended to mean that the therapeutic compound (e.g., the compound or its derivative provided by the present invention) is administered once or more times per day, for example, for a period of time. The terms "continuous" or "successive" are intended to mean that the therapeutic compound (e.g., the compound or its derivative provided by the present invention) is administered daily without interruption for at least 10 days to 52 weeks. The terms "intermittent" or "intermittently" as used in the present invention are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the compound or its derivative provided by the present invention is administering 1 to 6 days per week, cyclic or periodic administration (e.g., administering daily for 2 to 8 successive weeks, then taking a drug holiday for up to one week), or administering every other day. The terms "cyclic" or "periodic" as used in the present invention are intended to mean that the therapeutic compound (e.g., the compound or its derivative provided by the present invention) is administered daily or continuously, but with a rest period. In some such embodiments, the administration is once daily for 2 to 6 days, then taking a drug holiday for 5 to 7 days.

[0289] In some embodiments, the dosing frequency ranges from about daily dose to about monthly dose. In certain embodiments, the administration is once daily, twice daily, three times daily, four times daily, once every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound or its derivative provided by the present invention is administered once daily. In another embodiment, the compound or its derivative provided by the present invention is administered twice daily. In yet another embodiment, the compound or its derivative provided by the present invention is administered three times daily. In yet another embodiment, the compound or its derivative provided by the present invention is administered four times daily.

[0290] In certain embodiments, the compounds or their derivatives provided by the present invention are administered once daily for 1 day to 6 months, 1 week to 3 months, 1 week to 4 weeks, 1 week to 3 weeks, or 1 week to 2 weeks. In certain embodiments, the compounds or their derivatives provided by the present invention are administered once daily for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the compounds or their derivatives provided by the present invention are administered once daily for 4 days. In one embodiment, the compounds or their derivatives provided by the present invention are administered once daily for 5 days. In one embodiment, the compounds or their derivatives provided by the present invention are administered once daily for 6 days. In one embodiment, the compounds or their derivatives provided by the present invention are administered once daily for one week. In another embodiment, the compounds or their derivatives provided by the present invention are administered once daily for two weeks. In another embodiment, the compounds or their derivatives provided by the present invention are administered once daily for three weeks. In yet another embodiment, the compounds or their derivatives provided by the present invention are administered once daily for four weeks. VI. Methods of Treatment

[0291] The present invention provides a method for degrading CK1α of a cell by contacting the cell with a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for degrading CK1α of a subject by administering to the subject a compound or composition provided by the present invention.

[0292] In another embodiment, the present invention provides a method for inhibiting the activation of the Card11 / BCL10 / MALT1 (CBM) complex. It is known in the art that CK1α is required for the activation of the TCR- and BCR-regulated CBM complex (see, for example, 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 enables IL-2 induction, JNK signaling, and canonical NF-κB pathway signaling, and ultimately cell proliferation. Thus, CK1α degradation results in CBM complex inhibition and regulation of cell proliferation.

[0293] Accordingly, in one embodiment, the present invention provides a method for treating a subject suffering from a proliferative disease by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating a subject suffering from cancer by administering to the subject a compound or composition provided by the present invention.

[0294] 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.

[0295] In one embodiment, the cancer is 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.

[0296] In another embodiment, the cancer is a BTK inhibitor-resistant cancer. In one embodiment, the BTK inhibitor-resistant cancer is an ibrutinib-resistant cancer. In another embodiment, the ibrutinib-resistant cancer is ABC DLBCL.

[0297] 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 (SAR442168), fenebrutinib, vacabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068, or DTRMWXHA-12.

[0298] 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.

[0299] In another embodiment, the present invention provides a method for degrading CK1α and GSPT1 of a cell by contacting the cell with the compound or composition provided by the present invention. In another embodiment, the present invention provides a method for degrading CK1α and GSPT1 of a subject by administering the compound or composition provided by the present invention to the subject. As is known in the art, loss of CK1α activity stabilizes p53 and inhibits cell cycle progression. See, e.g., Huart et al., J. Biol. Chem. 2009, 284(47), 32384-32394. CK1α forms a complex with MDM2, which can regulate the stability of p53 and E2F-1 proteins. The CK1α-MDM2 complex promotes p53 degradation, thereby preventing the expression of p53 targets (e.g., p21, an inhibitor of cell cycle progression). GSPT1 degraders have shown efficacy against acute myeloid leukemia (AML) in clinical trials. Degradation of CK1α (providing elevated p53) and GSPT1 can improve the therapeutic window and safety.

[0300] It is also known in the art that GSPT1 is associated with various cancers, including AML, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, hepatocellular carcinoma, and gastric cancer. See, for example, WO 2022 / 066835, WO 2022 / 029138, WO 2021 / 069705, WO 2018 / 169777, WO 2019 / 173224, WO 2019 / 241271, WO2021 / 086830, WO 2022 / 007659, WO 2022 / 066835, and WO 2022 / 073469.

[0301] Accordingly, in another embodiment, the present invention provides a method for treating AML in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating solid tumors in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the solid tumor is breast cancer. In another embodiment, the present invention provides a method for treating glioma in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating thyroid cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating lung cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating colorectal cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating head and neck cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating gastric cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating liver cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating pancreatic cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating renal cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating urothelial cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating prostate cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating testicular cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating cervical cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating endometrial cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating ovarian cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating melanoma in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method for treating multiple myeloma in a subject by administering to the subject a compound or composition provided by the present invention.In another embodiment, the present invention provides a method of treating hepatocellular carcinoma in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the present invention provides a method of treating gastric cancer in a subject by administering to the subject a compound or composition provided by the present invention.

[0302] As described above, CK1α is required to activate the Card11 / BCL10 / MALT1 (CBM) complex. It is known in the art that inhibiting MALT1 can improve autoimmune pathogenesis. See, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320. CK1α degradation results in the inhibition of CBM activation and MALT1 signaling.

[0303] Accordingly, in another embodiment, the present invention provides a method of treating a subject suffering from an autoimmune disease by administering to the subject a compound or composition provided by the present invention. In one embodiment, the autoimmune disease 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.

[0304] It is known in the art that CK1α plays a role in promoting RAS - driven cancers, for example, by disrupting the stability of the 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. Oncol. 2016, 3(3), e1045117. Accordingly, in one embodiment, the present invention provides a method of treating a RAS - driven cancer in a subject by administering to the subject a compound or composition provided by the present invention. In another embodiment, the RAS - driven cancer is a RAS - mutant cancer. In another embodiment, the RAS - driven cancer is KRAS G12DDriver-driven cancers. In another embodiment, the RAS driver-driven cancer is lung cancer, head and neck cancer, pancreatic cancer, breast cancer, colorectal cancer, gastrointestinal cancer, melanoma, medullary cancer, bladder cancer, cervical cancer, ovarian cancer, or uterine cancer.

[0305] It is known in the art that inhibiting CK1α can prevent the acquired resistance of EGFR-mutant non-small cell lung cancer to erlotinib. See, e.g., Lantermann et al. Cancer Res. 2015, 75(22), 4937-4948. Thus, in one embodiment, the present invention provides a method for preventing the acquired resistance of EGFR-mutant non-small cell lung cancer in a subject to erlotinib by administering to the subject a compound or composition provided by the present invention. VII. Treatment in combination with a second active agent

[0306] The compounds or their derivatives provided by the present invention can also be combined or used in combination with other therapeutic agents for treating and / or preventing proliferative diseases, including cancer and autoimmune diseases.

[0307] In one embodiment, the present invention provides a method for treating, preventing, or controlling a proliferative disease, which comprises administering to a subject a compound or its derivative provided by the present invention; in combination with one or more second active agents.

[0308] As used in the present invention, the term "combination / co-administration" includes the use of more than one therapy (e.g., one or more prophylactic agents and / or therapeutic agents). Then, the use of the term "combination / co-administration" does not limit the order in which the therapies (e.g., prophylactic agents and / or therapeutic agents) are administered to a subject suffering from a disease or disorder. The first therapy (e.g., a prophylactic agent or therapeutic agent such as a compound provided by the present invention, a compound provided by the present invention such as a compound provided by the present invention, or its derivative) can be administered to the subject before (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), simultaneously with, or after (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 second therapy (e.g., a prophylactic agent or therapeutic agent). The present invention also contemplates triple therapy.

[0309] The compounds or their derivatives provided by the present invention, and one or more second active agents, can be administered to a subject simultaneously or sequentially via the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing before entering the bloodstream) and the disease or disorder being treated.

[0310] The route of administration of the compounds or their derivatives provided by the present invention is independent of the route of administration of the second therapy. In one embodiment, the compounds or their derivatives provided by the present invention are administered orally. In another embodiment, the compounds or their derivatives provided by the present invention are administered intravenously. Thus, according to these embodiments, the compounds or their derivatives provided by the present invention are administered orally or intravenously, while the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, by inhalation, vaginally, intravitreally, locally delivered through a catheter or stent, subcutaneously, intradermally, intraarticularly, intrathecally, or in a sustained release formulation. In one embodiment, both the compounds or their derivatives provided by the present invention and the second therapy are administered by the same route of administration, i.e., orally or by intravenous injection. In another embodiment, the compounds or their derivatives provided by the present invention are administered by one route of administration, e.g., by IV (intravenous injection), while the second drug is administered by another route of administration, e.g., orally.

[0311] In one embodiment, the second active agent is administered intravenously or subcutaneously, once or twice daily, in an amount of about 1 mg to about 1000 mg, about 5 mg to about 500 mg, about 10 mg to about 350 mg, or about 50 mg to about 200 mg. The specific dosage of the second active agent depends on the specific drug used, the type of disease being treated or controlled, the severity and stage of the disease, the amount of the compounds or their derivatives provided by the present invention, and any optional additional active agents simultaneously administered to the subject.

[0312] In the methods and compositions provided by the present invention, one or more second active ingredients or drugs can be used in combination with the compounds or their derivatives provided by the present invention. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

[0313] Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical macromolecular active agents are biomolecules, such as naturally occurring, synthetic, or recombinant proteins.

[0314] It is known in the art that targeting the CBM complex can prime regulatory T cells for immune checkpoint therapy. It is also known that MALT1 activity is crucial for regulatory T cell immunosuppression. Thus, in one embodiment, the second active agent is a checkpoint inhibitor, such as an anti-CTLA-4, 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 lymph node-involved melanoma; non-small cell lung cancer, including metastatic non-small cell lung cancer; renal cell carcinoma; Hodgkin lymphoma, including relapsed / refractory Hodgkin lymphoma; head and neck squamous cell carcinoma, including metastatic disease; urothelial carcinoma, including metastatic disease; colorectal cancer, including metastatic disease; or hepatocellular carcinoma.

[0315] In one embodiment, the compound or its derivative provided by the present invention in an amount ranging from about 0.1 mg to about 150 mg, about 1 mg to about 25 mg, or about 2 mg to about 10 mg can be administered orally daily alone or in combination or association with the second active agent before, during, or after using conventional therapies. VIII. Examples

[0316] The following examples are intended to illustrate certain embodiments provided by the present invention and are not intended to limit the scope of the present invention. Intermediate Example 1

[0317] Synthesis of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0318] Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0319] To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (20.0 g, 64.9 mmol, 1.00 equiv) in DMF (170 mL) was added 3-aminopiperidine-2,6-dione (11.8 g, 71.4 mmol, 1.10 equiv, HCl) and K2CO3 (26.9 g, 194 mmol, 3.00 equiv). The resulting mixture was heated at 70 °C for 16 h. To the resulting residue was added 500 mL of water, and the mixture was stirred at 25 °C for 0.5 h. The solid obtained was filtered and washed with 200 ml of ethyl acetate. The solid was dried under vacuum filtration to give the title compound (14.3 g, 43.6 mmol, 67.2% yield, HPLC (220 nm) purity 98.6%), as a white solid. 1 HNMR: (400 MHz, DMSO-d6) δ 10.49 - 11.15 (m, 8H), 7.89 (s, 1H), 7.66 - 7.73 (m, 2H), 5.10 (dd, J = 18.4, 8.4 Hz, 1H), 4.32 - 4.49 (m, 2H), 2.61 - 2.89 (m, 1H), 2.56 - 2.60 (m, 1H), 2.38 - 2.55 (m, 1H), 2.00 - 2.36 (m, 1H). (ESI + ) m / z: 322.7 (M + H) + , (C 13 H 11 BrN2O3).

[0320] Preparation of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione:

[0321] To a solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (10.0 g, 31.0 mmol, 1.00 equiv) in DMF (60.0 mL) in a sealed tube was added bis(pinacolato)diboron (BPD) (8.64 g, 34.0 mmol, 1.10 equiv), KOAc (9.11 g, 92.8 mmol, 3.00 equiv) and Pd(dppf)Cl2 (1.36 g, 1.86 mmol, 0.06 equiv). The reaction mixture was heated at 100 °C for 2 h under N2. To the reaction mixture was added 200 mL of water, and the mixture was stirred at 25 °C for 0.25 h. A solid precipitated out, was filtered and dried in vacuo to give the title compound (8.90 g, 23.5 mmol, 76.0% yield, HPLC (220 nm) purity 97.8%), as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.90 (s, 1H), 7.72 - 7.81 (m, 2H), 5.15 (dd, J = 18.4, 8.4 Hz, 1H), 4.33 - 4.49 (m, 2H), 2.88 - 2.91 (m, 1H), 2.62 - 2.86 (m, 1H), 2.35 - 2.38 (m, 1H), 2.01 - 2.33 (m, 1H), 1.32 (s, 12H). (ESI + ) m / z: 370.9 (M + H) + , (C 19 H 23 BN2O5). Example 1

[0322] Synthesis of 3-(5-(1-Methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0323] A. 3-(5-(1-Methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: At 25 °C, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (93.7 mg, 253 μmol, 1.20 equiv), 4-bromo-1-methyl-5-phenyl-1H-pyrazole (50.0 mg, 211 μmol, 1.00 equiv) and K3PO4 (89.5 mg, 422 μmol, 2.00 equiv) in dioxane (1.25 mL) and H2O (0.10 mL) was added (2-(2-aminophenyl)phenyl)-methylsulfonyloxy-palladium; dicyclohexyl-(2-(2,6-diisopropoxyphenyl)phenyl)phosphine (17.6 mg, 21.1 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 1 h. The mixture was filtered through celite and the cake was washed with ethyl acetate (2 x 20.0 mL). The filtrate was concentrated in vacuo at 40 °C to give a residue. The resulting mixture was purified by preparative HPLC (using Welch Xtimate (150 mm x 25 mm, 5 μm) and gradient of 13 - 43% acetonitrile / water (containing 0.05% HCl), flow rate 25 mL / min, elution for 8 min) to give the title compound (11.1 mg, 26.0 μmol, yield 12.3%) as a yellow solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.90 (s, 1H), 7.55 - 7.52 (m, 4H), 7.52 - 7.51 (m, 3H), 7.39 - 7.22 (m, 1H), 5.06 (dd, J = 5.2 Hz, J = 13.6 Hz, 1H), 4.34 (d, J = 17.6 Hz, 1H), 4.20 (d, J = 17.2 Hz, 1H), 3.74 (s, 3H), 2.90 - 2.89 (m, 1H), 2.59 - 2.55 (m, 1H), 2.38 - 2.33 (m, 1H), 1.98 - 1.95 (m, 1H). (ESI + ) m / z: 401.3 (M + H) + , (C 23 H 20 N4O3). Example 2

[0324] Synthesis of 3-(5-(1-Methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0325] A. 1-Methyl-5-phenyl-1H-imidazole: At 25 °C, benzaldehyde (4.08 g, 38.4 mmol, 3.89 mL, 1.00 equiv) and DIEA (9.93 g, 76.8 mmol, 13.4 mL, 2.00 equiv) were added to a solution of methylamine hydrochloride (5.19 g, 76.8 mmol, 2.00 equiv) in DMF (40.0 mL). The mixture was stirred at 25 °C for 2 h. Then, at 25 °C, K2CO3 (7.96 g, 57.63 mmol, 1.5 equiv) and 1-((isocyanomethyl)-sulfonyl)-4-methylbenzene (9.00 g, 46.1 mmol, 1.20 equiv) were added to the mixture. The mixture was stirred at 50 °C for 32 h. The mixture was poured into water (50.0 mL) and brine (50.0 mL), extracted with ethyl acetate (3 x 100 mL), the organic layer was collected, the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The resulting residue was purified by column chromatography (SiO2, ethyl acetate:petroleum ether = 10 / 1 to dichloromethane:methanol = 30 / 1) to give the title compound (2.20 g, 13.9 mmol, yield 36.1%, HPLC (220 nm) purity 99.7%) as a yellow solid. 11H NMR: (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.45 - 7.41 (m, 2H), 7.40 - 7.38 (m, 3H), 7.12 (s, 1H), 3.69 (s, 3H). (ESI + ) m / z: 158.8 (M + H) + , (C 10 H 10 N2).

[0326] B. 4 - Bromo - 1 - methyl - 5 - phenyl - 1H - imidazole: At 20 °C, NBS (624 mg, 3.51 mmol, 1.05 eq) was added to a solution of 1 - methyl - 5 - phenyl - 1H - imidazole (530 mg, 3.34 mmol, 99.7% purity, 1.00 eq) in ACN (20.0 mL). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure at 40 °C to give a residue. The resulting residue was purified by column chromatography (SiO2, ethyl acetate:petroleum ether = 8 / 1 to 1 / 5). Then the residue was dissolved in DCM (20.0 mL), washed with water (3 x 15.0 mL), the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the title compound (270 mg, 1.13 mmol, yield 33.8%, LCMS (220 nm) purity 99.5%) as a yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.49 - 7.40 (m, 5H), 3.60 (s, 3H).. (ESI + ) m / z: 237.0 (M + H) + , (C 10 H9BrN2).

[0327] C. 3-(5-(1-Methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (224 mg, 604 μmol, 1.20 equiv), 4-bromo-1-methyl-5-phenyl-1H-imidazole (120 mg, 504 μmol, 99.5% purity, 1.00 equiv), and K3PO4 (214 mg, 1.01 mmol, 2.00 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (42.1 mg, 50.4 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 1 h under N2. The mixture was filtered through Celite and the cake was washed with ethyl acetate (2 x 2.00 mL). The filtrate was concentrated in vacuo at 40 °C to give a residue. The resulting residue was purified by preparative HPLC (using Welch Ultimate C18 (150 mm x 25 mm 5 μm) with a gradient of 0 - 30% acetonitrile / water (containing 0.1% FA), flow rate of 25 mL / min, eluting for 10 min) to give the title compound (40.4 mg, 99.3 μmol, yield 19.7%, HPLC (220 nm) purity 98.4%) as an off-white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.52 - 7.44 (m, 4H), 7.42 - 7.40 (m, 3H), 5.06 (dd, J = 4.8 Hz, J = 13.2 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), 4.20 (d, J = 17.6 Hz, 1H), 3.74 (s, 3H), 2.90 - 2.86 (m, 1H), 2.60 - 2.59 (m, 1H), 2.37 - 2.33 (m, 1H), 1.98 - 1.96 (m, 1H). (ESI + ) m / z: 401.2 (M + H) + , (C 23 H 20 N4O3). Example 3

[0328] Synthesis of 3-(5-(1-Methyl-3-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0329] A. 3-(5-(1-Methyl-3-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 309 μmol, 1.00 equiv), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg, 402 μmol, 1.30 equiv) in DMF (1.00 mL) was added Pd(dppf)Cl2 (50.5 mg, 61.9 μmol, 0.20 equiv), K3PO4 (131 mg, 619 μmol, 2.00 equiv). The mixture was stirred at 90 °C for 12 h. The mixture was filtered and the filtrate was collected. The obtained filtrate was purified by preparative TLC (petroleum ether / ethyl acetate = 0 / 1, R f = 0.3) to give the title compound (50.4 mg, 125 μmol, yield 20.0%, HPLC (220 nm) purity 98.9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.40 - 7.32 (m, 6H), 5.13 - 5.08 (m, 1H), 4.43 - 4.38 (m, 2H), 3.93 (s, 1H), 2.94 - 2.87 (m, 2H), 2.60 - 2.54 (m, 1H), 2.45 - 2.38 (m, 1H). (ESI + ) m / z: 401.0 (M + H) + , (C 23 H 20 N4O3). Example 4

[0330] Synthesis of 3-(1-oxo-5-(4-phenylthiophen-3-yl)isoindolin-2-yl)piperidine-2,6-dione

[0331] Preparation of 3-(1-oxo-5-(4-phenylthiophen-3-yl)isoindolin-2-yl)piperidine-2,6-dione: 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (158 mg, 418 μmol, purity 97.8%, 1.00 equivalent), 3-bromo-4-phenylthiophene (100 mg, 418.18 μmol, 1.00 equivalent), and K3PO4 (176 mg, 836 μmol, 2.00 equivalents) were dissolved in dioxane (3.00 mL) and H2O (0.10 mL). Under N2, Ru-Phos-Pd-G3 (70.0 mg, 83.6 μmol, 0.20 equivalent) was added to the reaction mixture. The mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered, and the filtrate was collected. The obtained filtrate was purified by preparative HPLC (using Phenomenex luna C18 (150 mm x 25 mm 10 μm) and a gradient of 38 - 68% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 15 min), to give the title compound (73.9 mg, 179 μmol, yield 42.8%, HPLC (220 nm) purity 97.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.986 (s, 1H), 7.767 - 7.759 (d, J = 3.2 Hz, 1H), 7.70 - 7.692 (d, J = 3.2 Hz, 1H), 7.319 - 7.301 (m, 1H), 7.296 (s, 1H), 7.186 - 7.182 (m, 3H), 7.166 - 7.163 (m, 3H), 5.067 - 4.98 (m, 1H), 4.425 - 4.382 (m, 1H), 4.294 - 4.240 (m, 1H), 2.944 - 2.880 (m, 1H), 2.619 - 2.608 (m, 1H), 2.413 - 2.381 (m, 1H), 2.022 - 2.005 (m, 1H). (ESI + ) m / z: 403.0 (M + H) + , (C 23 H 18 N2O3S). Example 5

[0332] Synthesis of 3-(1-oxo-5-(3-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0333] A. 3-(1-Oxo-5-(3-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-3-phenyl-1H-pyrazole (100 mg, 448 μmol, 1.00 equiv), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (174 mg, 471 μmol, 1.05 equiv), (A-taphos)2PdCl2 (dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II), 63.5 mg, 90.0 μmol, 63.5 μL, 0.20 equiv) in dioxane (4.00 mL) and H2O (0.40 mL) was added K3PO4 (190 mg, 897 μmol, 2.00 equiv). The mixture was stirred at 100 °C for 12 h under N2. The mixture was filtered and the filtrate was collected. The resulting filtrate was purified by preparative HPLC (using Phenomenex luna C18 (150 mm x 25 mm 10 μm) and a gradient of 15 - 45% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 18 min) to give the title compound (5.91 mg, 15.2 μmol, yield 3.39%, HPLC (220 nm) purity 99.4%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 7.503 - 7.484 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.412 - 7.278 (m, 7H), 5.12 - 5.080 (m, 1H), 4.427 - 4.248 (m, 2H), 2.943 - 2.878 (m, 1H), 2.617–2.612 (m, 1H), 2.410–2.381 (m, 1H), 2.010–1.984 (m, 2H). (ESI + ) m / z: 387.0 (M+H) + , (C 22 H 18 N4O3). Example 6

[0334] Synthesis of 3-(1-Oxo-5-(1-phenyl-1H-pyrazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0335] A. 3-(1-Oxo-5-(1-phenyl-1H-pyrazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (50.0 mg, 154 μmol, 1.00 equiv), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54.3 mg, 201 μmol, 1.30 equiv) were dissolved in dioxane (1.00 mL) and H2O (0.05 mL), then (A-taphos)2PdCl2 (25.8 mg, 30.9 μmol, 0.20 equiv), K3PO4 (65.6 mg, 309 μmol, 2.00 equiv) were added under N2. The reaction mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by preparative HPLC (using Phenomenex Luna C18 (150 mm x 25 mm 10 μm) and gradient of 22 - 42% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 63 min) to give the title compound (15.0 mg, 38.5 μmol, yield 24.8%, HPLC (220 nm) purity 99.2%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.37 - 7.46 (m, 3H), 7.26 - 7.30 (m, 3H), 6.76 (d, J = 2.0 Hz, 1H), 5.11 (dd, J = 13.6 Hz, 5.2 Hz, 1H), 4.26 - 4.44 (m, 2H), 2.85 - 2.95 (m, 1H), 2.56 - 2.61 (m, 1H), 2.36 - 2.44 (m, 1H), 1.96 - 2.03 (m, 1H). (ESI + ) m / z: 387.2 (M + H) + , (C 22 H 18 N4O3). Example 7

[0336] Synthesis of 3-(1-oxo-5-(1-phenyl-1H-imidazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0337] A. 2-Iodo-1-phenyl-1H-imidazole: A solution of 1-phenylimidazole (1.90 g, 13.1 mmol, 1.00 equiv) in THF (95.0 mL) was cooled to -65 to -60 °C. n-BuLi (2.50 M, 7.04 mL, 1.33 equiv) was added dropwise at -65 to -60 °C under N2. Then the mixture was stirred at -60 °C for 1.5 h. At -65 to -60 °C, a solution of iodine (10.0 g, 39.5 mmol, 7.96 mL, 3.00 equiv) in THF (100 mL) was added to the mixture. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL), extracted with EtOAc (3 x 200 mL), and the organic layer was collected. The organic layer was washed with saturated aqueous Na2S2O3 (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1, TLC: petroleum ether / ethyl acetate = 5 / 1, R f = 0.50) to give the title compound (2.20 g, 8.15 mmol, yield 61.8%) as a yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 7.52 - 7.49 (m, 3H), 7.36 - 7.34 (m, 2H), 7.21 (s, 2H). (ESI + ) m / z: 271.1 (M + H) + , (C9H7IN2).

[0338] B. 3-(1-oxo-5-(1-phenyl-1H-imidazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 2-iodo-1-phenyl-imidazole (100 mg, 370 μmol, 1.00 equiv) and 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (137 mg, 370 μmol, 1.00 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) was added (A-taphos)2PdCl2 (61.9 mg, 74.0 μmol, 0.20 equiv) and K3PO4 (157 mg, 740 μmol, 2.00 equiv). The mixture was stirred at 100 °C for 1 h. The mixture was poured into H2O (20.0 mL), then extracted with EtOAc (3 x 20.0 mL), and the organic layer was collected. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 42.0%-72.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution time 13 min) to give the title compound (6.84 mg, 17.3 μmol, yield 4.68%, HPLC (220 nm) purity 97.8%), as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.60 (d, J = 6.0 Hz, 2H), 7.57 (d, J = 1.2 Hz, 1H), 7.52 - 7.44 (m, 3H), 7.35 - 7.31 (m, 3H), 7.25 (d, J = 1.2 Hz, 1H), 5.09 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.28 - 4.24 (m, 1H), 2.96 - 2.85 (m, 1H), 2.60 (br, 1H), 2.40 - 2.34 (m, 1H), 2.01 - 1.96 (m, 1H). (ESI + ) m / z: 387.1 (M + H) + , (C 22 H 18 N4O3). Example 8

[0339] Synthesis of 3-(5-(5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0340] A. 3-(5-(5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[5-(5-bromo-1-methyl-pyrazol-4-yl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (39.8 mg, 90.8 μmol, purity 91.9%, 1.00 eq) in dioxane (1.00 mL) was added 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (201 mg, 908 μmol, 10.0 eq), K2CO3 (50.2 mg, 363 μmol, 4.00 eq), and Pd(PPh3)4 (21.0 mg, 18.1 μmol, 0.200 eq). The reaction mixture was stirred at 100 °C under N2 for 4 h. After completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by preparative HPLC (using Welch Xtimate (C18 150x25 mm x 5 μm) with a gradient of 15 - 45% acetonitrile / water (containing 0.05% HCl), a flow rate of 25 mL / min, and elution for 15 min) to give the title compound (5.65 mg, 13.5 μmol, yield 14.8%, HPLC (220 nm) purity >99%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.90 (s, 1H), 7.60 - 7.55 (m, 1H), 7.49 - 7.43 (m, 2H), 7.40 - 7.33 (m, 3H), 7.25 - 7.20 (m, 1H), 5.08 (dd, J = 13.6, 5.2 Hz, 1H), 4.36 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 17.2 Hz, 1H), 3.72 (s, 3H), 2.95 - 2.84 (m, 1H), 2.63 - 2.59 (m, 1H), 2.43 - 2.31 (m, 1H), 2.01 - 1.94 (m, 1H). (ESI + ) m / z: 403.0 (M + H) + , (C 23 H 19 FN4O3). Example 9

[0341] Synthesis of 3-(1-oxo-5-(1-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0342] A. 3-(1-Oxo-5-(1-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (100 mg, 270 μmol, 1.00 equiv) and 4-bromo-1-phenyl-pyrazole (72.3 mg, 324 μmol, 1.20 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) were added K3PO4 (114 mg, 540 μmol, 2.00 equiv) and Ru-Phos-Pd-G3 (22.6 mg, 27.0 μmol, 0.10 equiv). The reaction mixture was stirred at 100 °C under N2 for 2 h. Then the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the crude product. The resulting crude product was purified by preparative TLC (SiO2, dichloromethane:methanol = 10:1, R f = 0.40) and preparative HPLC (using Welch Xtimate C18 150 mm x 25 mm x 5 μm) with a gradient of 21%-51% aqueous acetonitrile containing HCl (0.10 mol / L, 9 min) to give the title compound (15.2 mg, 39.1 μmol, yield 14.4%, HPLC (220 nm) purity 99.4%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.17 (s, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.92 - 7.89 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.4 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 5.15 - 5.10 (m, J = 5.2 Hz, 1H), 4.53 (d, J = 17.2 Hz, 1H), 4.39 (d, J = 17.2 Hz, 1H), 2.97 - 2.88 (m, 1H), 2.63 (d, J = 17.2 Hz, 1H), 2.46 - 2.42 (m, 1H), 2.04 - 2.00 (m, 1H). (ESI + ) m / z: 387.1 (M+H) + , (C 22 H 18 N4O3). Example 10

[0343] Synthesis of 3-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0344] A. 3-(5-(1-Methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, a microwave vial was charged with a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.24 mmol, 1.00 equiv), 1-methyl-4-(tributylstannyl)-1H-imidazole (597 mg, 1.61 mmol, 1.30 equiv) in DMF (4.00 mL). The mixture was degassed with N2 for 10 minutes, and Pd(dppf)Cl2·CH2Cl2 (202 mg, 247 μmol, 0.20 equiv) was added to the mixture. The reaction mixture was stirred in a microwave at 130 °C for 1.5 hours under N2. The mixture was filtered, and the liquid was collected and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1, R f = 0.30) to give the title compound (60.0 mg, 181 μmol, yield 7.30%, purity by LCMS (220 nm) 98.0%) as a brown solid. (ESI + ) m / z: 324.0 (M+H) + , (C 17 H 16 N4O3).

[0345] B. 3-(5-(5-Bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: At 0 °C, NBS (296 mg, 1.66 mmol, 1.10 equiv) was added to a solution of 3-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 1.51 mmol, 1.00 equiv) in MeOH (3.00 mL). The mixture was stirred at 25 °C for 3 hours. Then the reaction mixture was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f = 0.32) to give the title compound (40.0 mg, 98.9 μmol, yield 50.1%, purity by LCMS (220 nm) 99.7%) as a brown solid. (ESI + ) m / z: 403.2 (M+H) + , (C 17 H 15 BrN4O3).

[0346] C. 3-(5-(5-(4-Fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39.2 mg, 96.9 μmol, purity 99.7%, 1.00 equivalent), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 484 μmol, 5.00 equivalents) in dioxane (3.00 mL) and H2O (0.15 mL) was added K2CO3 (40.2 mg, 290 μmol, 3.00 equivalents) and Pd(dppf)Cl2·CH2Cl2 (15.8 mg, 19.4 μmol, 0.20 equivalent). The mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) and a gradient of 3.00% - 33.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 15 min) to obtain the title compound (1.28 mg, 2.93 μmol, yield 3.00%, HPLC (220 nm) purity 95.7%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.59 (s, 1H), 7.55 - 7.53 (m, 1H), 7.48 - 4.47 (m, 1H), 7.46 - 7.44 (m, 3H), 7.38 - 7.35 (m, 2H), 5.15 - 5.01 (m, 1H), 4.38 - 4.34 (m, 1H), 4.32 - 4.16 (m, 1H), 3.47 (s, 3H), 2.90 - 2.85 (m, 1H), 2.62 - 2.57 (m, 1H), 2.37 - 2.36 (m, 1H), 2.34 - 2.32 (m, 1H). (ESI + ) m / z: 419.3 (M + H) + , (C 23 H 19 FN4O3). Example 11

[0347] (Synthesis of 3-(5-(5-Methyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0348] A. 3-Iodo-5-methyl-4-phenyl-1H-pyrazole: To a solution of 5-methyl-4-phenyl-1H-pyrazole (100 mg, 632 μmol, 1.00 equiv) in THF (0.80 mL) and H2O (0.80 mL) were added NaI (189 mg, 1.26 mmol, 2.00 equiv), I2 (802 mg, 3.16 mmol, 637 μL, 5.00 equiv) and K2CO3 (174 mg, 1.26 mmol, 2.00 equiv). The mixture was stirred at 100 °C for 48 h. The combined mixture was quenched with Na2SO3 (10.0%, 35.0 mL). The mixture was extracted with ethyl acetate (3 × 15.0 mL), dried over Na2SO4, filtered, and the filtrate was collected and concentrated under reduced pressure to give a residue. Then the resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1, R f = 0.30) to afford the title compound (114 mg, 399 μmol, 63.2% yield, 99.6% purity by LCMS (220 nm)), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 13.1 (s, 1H), 7.44 - 7.43 (m, 2H), 7.42 - 7.40 (m, 3H), 2.29 - 2.24 (m, 3H). (ESI + ) m / z: 284.1 (M+H) + , (C 10 H9IN2).

[0349] B. 3-(5-(5-Methyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-iodo-5-methyl-4-phenyl-1H-pyrazole (80.0 mg, 281 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (114 mg, 309 μmol, 1.10 equiv) and K3PO4 (119 mg, 563 μmol, 2.00 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (47.1 mg, 56.3 μmol, 0.20 equiv). The mixture was stirred at 100 °C for 60 h under N2. Then the reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150x25 mm x 5 μm) and a gradient of 29.0%-49.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 58 min) to give the title compound (3.97 mg, 9.71 μmol, yield 3.45%, HPLC (220 nm) purity 97.9%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.36 (s, 1H), 7.70 (s, 2H), 7.44 - 7.39 (m, 3H), 7.37 - 7.35 (m, 1H), 7.31 - 7.27 (m, 2H), 5.13 - 5.06 (m, 1H), 4.28 - 4.24 (m, 1H), 4.23 - 4.20 (m, 1H), 2.93 - 2.63 (m, 1H), 2.61 - 2.60 (m, 1H), 2.39 - 2.32 (m, 1H), 2.22 (s, 3H), 2.00 - 1.97 (m, 1H), (ESI + ) m / z: 400.0 (M + H) + , (C 23 H 20 N4O3). Example 12

[0350] Synthesis of 3-(5-(2-Cyclopropyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0351] A. N-(2,2-Dimethoxyethyl)-N-methylcyclopropanecarboxamidine: To a solution of 2,2-dimethoxy-N-methylethan-1-amine (3.00 g, 25.2 mmol, 3.24 mL, 1.00 equiv) and cyclopropanecarbonitrile (2.11 g, 31.5 mmol, 2.32 mL, 1.25 equiv) was added CuCl (3.12 g, 31.5 mmol, 752 μL, 1.25 equiv). The mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound (5.00 g, crude) as a yellow oil. (ESI + ) m / z: 186 (C9H 18 N2O2).

[0352] B. 2-Cyclopropyl-1-methyl-1H-imidazole: To a solution of N-(2,2-dimethoxyethyl)-N-methylcyclopropanecarboxamidine (5.00 g, 26.9 mmol, 1.00 equiv) in MeOH (15.0 mL) was added concentrated HCl (12.0 M, 2.24 mL, 1.00 equiv). The mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (20.0 mL) at 20 °C for 30 min to give the title compound (2.00 g, 16.4 μmol, 60.9% yield) as a yellow oil. 1 1H NMR: (400 MHz, CDCl3) δ 7.27 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 15.6 Hz, 1H), 3.88 (s, 3H), 1.99 - 1.96 (m, 1H), 1.20 - 1.14 (m, 4H). (ESI + ) m / z: 123.1 (M+H) + , (C7H 10 N2).

[0353] C. 2-Cyclopropyl-1-methyl-5-phenyl-1H-imidazole: Under N2, to a solution of 2-cyclopropyl-1-methyl-1H-imidazole (1.00 g, 8.19 mmol, 1.00 equiv), PCy3 (229 mg, 819 μmol, 265 μL, 0.10 equiv), and NaOtBu (2.36 g, 24.5 mmol, 3.00 equiv) in o-xylene (40.0 mL) was added chlorobenzene (2.76 g, 24.5 mmol, 2.49 mL, 3.00 equiv) and Pd(OAc)2 (91.9 mg, 409 μmol, 0.05 equiv). The mixture was stirred at 130 °C under N2 for 17 h. Then the mixture was diluted with petroleum ether (100 mL), the organic layer was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1, R f = 0.20) to give the title compound (1.33 g, 6.35 mmol, yield 77.5%, LCMS (220 nm) purity 95.0%) as a yellow oil. (ESI + ) m / z: 199.0 (M+H) + , (C 13 H 14 N2).

[0354] D. 4-Bromo-2-cyclopropyl-1-methyl-5-phenyl-1H-imidazole: At 0 °C, to a solution of 2-cyclopropyl-1-methyl-5-phenyl-1H-imidazole (300 mg, 1.51 mmol, 1.00 equiv) in MeOH (3.00 mL) was added NBS (296 mg, 1.66 mmol, 1.10 equiv). The mixture was stirred at 25 °C for 3 h. Then the reaction mixture was concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f = 0.30) to give the title compound (380 mg, 1.05 mmol, yield 69.7%, LCMS (220 nm) purity 76.9%) as a yellow oil. (ESI + ) m / z: 277.0 (M+H) + , (C 13 H 13 BrN2).

[0355] E. 3-(5-(2-Cyclopropyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (701 mg, 1.89 mmol, 1.50 equiv), 4-bromo-2-cyclopropyl-1-methyl-5-phenyl-1H-imidazole (350 mg, 1.26 mmol, 1.00 equiv), and K3PO4 (536 mg, 2.53 mmol, 2.00 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) was added Ru-Phos-Pd-G3 (211 mg, 253 μmol, 0.20 equiv). The mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) with a gradient of 2.00% - 2.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 15 min) to give the title compound (33.1 mg, 72.2 μmol, 5.70% yield, HPLC (220 nm) purity 96.2%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.57 - 7.46 (m, 5H), 7.39 - 7.36 (m, 3H), 4.99 - 4.98 (m, 1H), 4.35 - 4.22 (m, 1H), 4.20 - 4.13 (m, 1H), 3.46 (s, 3H), 2.88 - 2.85 (m, 1H), 2.60 - 2.59 (m, 1H), 2.36 - 2.33 (m, 1H), 2.08 - 2.07 (m, 1H), 2.05 - 1.97 (m, 1H), 1.01 - 0.97 (m, 4H). (ESI + ) m / z: 441.0 (M + H) + , (C 26 H 24 N4O3). Example 13

[0356] Synthesis of 3-(1-oxo-5-(5-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0357] A. 4-Bromo-5-phenyl-1H-imidazole: To a solution of 5-phenyl-1H-imidazole (200 mg, 1.39 mmol, 1.00 equiv) in MeOH (3.00 mL) was added NBS (259 mg, 1.46 mmol, 1.05 equiv). The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, concentrated to give the title compound (98.0 mg, 431 μmol, 31.1% yield, 98.3% purity by LCMS (220 nm)), as a light yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 12.9 - 12.8 (m, 1H), 7.77 - 7.75 (m, 1H), 7.72 - 7.70 (m, 2H), 7.49 - 7.45 (m, 2H), 7.63 - 7.33 (m, 1H). (ESI + ) m / z: 224.7 (M + H) + , (C9H7BrN2).

[0358] B. 3-(1-Oxo-5-(5-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (165 mg, 448 μmol, 2.00 equiv) and 4-bromo-5-phenyl-1H-imidazole (50.0 mg, 224 μmol, 1.00 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) was added K3PO4 (142 mg, 672 μmol, 3.00 equiv) and Ru-Phos-Pd-G3 (18.7 mg, 22.4 μmol, 0.10 equiv). Then the mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 1.00% - 26.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 15 min) to give the title compound (21.8 mg, 54.9 μmol, 24.5% yield, 97.0% purity by HPLC (220 nm)), as a white solid. 11H NMR: (400 MHz, MeOD) δ 8.05 (s, 1H), 7.91 - 7.85 (m, 1H), 7.72 - 7.70 (m, 1H), 7.66 - 7.59 (m, 1H), 7.45 - 7.43 (m, 2H), 7.38 - 7.32 (m, 3H), 5.17 - 5.12 (m, 1H), 4.51 - 4.40 (m, 2H), 2.91 - 2.86 (m, 1H), 2.80 - 2.79 (m, 1H), 2.51 - 2.46 (m, 1H), 2.19 - 2.18 (m, 1H). (ESI + ) m / z: 387.1 (M + H) + , (C 22 H 18 N4O3). Example 14

[0359] Synthesis of 3-(5-(1,2 - dimethyl - 5 - phenyl - 1H - imidazol - 4 - yl)-1 - oxoisoindolin - 2 - yl)piperidine - 2,6 - dione

[0360] A. 1,2 - dimethyl - 5 - phenyl - 1H - imidazole: A solution of 1,2 - dimethylimidazole (100 mg, 1.04 mmol, 1.00 equiv), Pd(OAc)2 (11.6 mg, 52.0 μmol, 0.05 equiv), PCy3 (29.1 mg, 104 μmol, 33.7 μL, 0.10 equiv) and NaOBu - t (299 mg, 3.12 mmol, 3.00 equiv) in o - xylene (5.00 mL) and chlorobenzene (351 mg, 3.12 mmol, 316 μL, 3.00 equiv) was degassed and purged with N2 three times. Then the mixture was stirred at 130 °C for 12 h under a N2 atmosphere. After completion of the reaction, the reaction mixture was cooled to 25 °C and filtered. The filtrate was collected and dried in vacuo to give the title compound (170 mg, 977 μmol, yield 50.0%) as a white solid. (ESI + ) m / z: 172.1 (M + H) + , (C 11 H 12 N2).

[0361] B. 4-Bromo-1,2-dimethyl-5-phenyl-1H-imidazole: To a solution of 1,2-dimethyl-5-phenyl-imidazole (140 mg, 812 μmol, 1.00 equiv) in MeCN (8.00 mL) was added NBS (144 mg, 812 μmol, 1.00 equiv), and the mixture was stirred at 25 °C for 20 h. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (150 mg, 597 μmol, yield 73.4%) as a yellow oil. 1 H NMR: (400 MHz, DMSO-d6) δ 7.48 (t, J = 7.6 Hz, 2H), 7.44 - 7.39 (m, 3H), 3.43 (s, 3H), 2.33 (s, 3H). (ESI + ) m / z: 250.0 (M + H) + , (C 11 H 11 BrN2).

[0362] C. 3-(5-(1,2-Dimethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (0.20 g, 540 μmol, 1.00 equiv) and 4-bromo-1,2-dimethyl-5-phenyl-imidazole (108 mg, 432 μmol, 0.80 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) were added Ru-Phos-Pd-G3 (45.1 mg, 54.0 μmol, 0.10 equiv) and K3PO4 (229 mg, 1.08 mmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 1 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC using Welch Xtimate C18 (150 mm x 25 mm 10 μm) with a gradient of 3 - 33% acetonitrile / water (containing 0.05% FA) at a flow rate of 20 mL / min for 58 min to give the title compound (53.0 mg, 249 μmol, yield 25.0%, HPLC (220 nm) purity 97.8%) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.59 (s, 1H), 7.53 - 7.47 (m, 4H), 7.39 - 7.36 (m, 3H), 5.08 - 5.03 (m, 1H), 4.35 - 4.16 (m, 2H), 3.39 (s, 3H), 2.92 - 2.85 (m, 1H), 2.58 - 2.50 (m, 1H), 2.41 (s, 3H), 2.37 - 2.36 (m, 1H), 1.97 - 1.94 (m, 1H). (ESI + ) m / z: 415.2 (M + H) + , (C 24 H 22 N4O3). Example 15

[0363] Synthesis of 3-(1-oxo-5-(5-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0364] A. 3-(1-oxo-5-(5-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (248 mg, 670 μmol, 1.50 equiv), 4-bromo-5-phenyloxazole (100 mg, 446 μmol, 1.00 equiv) and K3PO4 (189 mg, 893 μmol, 2.00 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) was added Ru-Phos-Pd-G3 (74.7 mg, 893 μmol, 0.20 equiv). The mixture was stirred at 100 °C for 48 h under N2. Then the reaction mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (using column: WelchXtimate C18 (150 x 25 mm x 5 μm) and gradient of 24.0% - 54.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 15 min) to give the title compound (111 mg, 287 μmol, yield 64.0%, HPLC (220 nm) purity 99.7%), as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.60 - 8.58 (m, 2H), 7.95 - 7.83 (m, 1H), 7.60 - 7.58 (m, 1H), 7.58 - 7.54 (m, 1H), 7.51 - 7.50 (m, 2H), 7.55 - 7.45 (m, 2H), 5.15 - 5.10 (m, 1H), 4.37 - 4.35 (m, 1H), 4.34 - 4.33 (m, 1H), 2.95 - 2.87 (m, 1H), 2.62 - 2.58 (m, 1H), 2.41 - 2.37 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI + ) m / z: 387.1 (M + H) + , (C 22 H 17 N3O4). Example 16

[0365] Synthesis of 3-(2-(1-Methyl-5-phenyl-1H-imidazol-4-yl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione

[0366] A. 5-Bromo-3-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-2-carboxylic acid: To a solution of tert-butyl 5-bromo-3-(((2,6-dioxo-3-piperidinyl)amino)methyl)thiophene-2-carboxylate (2.00 g, 4.96 mmol, 1.00 equiv) in DCM (80.0 mL) was added TFA (28.2 g, 247 mmol, 18.3 mL, 50.0 equiv). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to afford the title compound (3.20 g, crude) as a black oil. (ESI + ) m / z: 348.9 (M + H) + , (C 11 H 11 BrN2O4S).

[0367] B. 3-(2-Bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione: To a solution of 5-bromo-3-[[(2,6-dioxopiperidin-3-yl)amino]methyl]thiophene-2-carboxylic acid (3.20 g, 9.22 mmol, 1.00 equiv) in DMF (120 mL) was added HATU (4.38 g, 11.5 mmol, 1.25 equiv) and DIEA (2.98 g, 23.0 mmol, 4.01 mL, 2.50 equiv). The reaction mixture was stirred at 25 °C for 3 h. The reaction solvent was removed in vacuo to give a residue, which was diluted with H2O (100 mL) and then extracted with DCM (2 x 150 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue. The obtained residue was triturated with ethyl acetate (10.0 mL) at 0 °C for 2 h to give the title compound (1.10 g, 3.32 mmol, 36.4% yield, HPLC (220 nm) purity 99.4%) as a white solid. (ESI + ) m / z: 328.9 (M + H) + , (C 11 H9BrN2O3S).

[0368] C. (5-(2,6-Dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)boronic acid: Under N2, to a solution of 3-(2-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (0.20 g, 607 μmol, 1.00 equiv) in dioxane (4.00 mL) was added BPD (308 mg, 1.22 mmol, 2.00 equiv), Pd(dppf)Cl2 (111 mg, 151 μmol, 0.25 equiv) and KOAc (119 mg, 1.22 mmol, 2.00 equiv). The reaction mixture was stirred at 90 °C for 16 h under N2. The reaction mixture was concentrated in vacuo to give the title compound (0.50 g, crude) as a white solid. (ESI + ) m / z: 295.0 (M + H) + , (C 11 H 11 BN2O5S).

[0369] D. 1-Methyl-5-phenyl-1H-imidazole: At 0 °C under N2, to a solution of 5-phenyl-1H-imidazole (2.50 g, 17.3 mmol, 1.00 equiv) in THF (50.0 mL) was added NaH (832 mg, 20.8 mmol, purity 60.0%, 1.20 equiv) (5 batches). The mixture was stirred at 0 °C under N2 for 30 minutes, then MeI (3.45 g, 24.3 mmol, 1.51 mL, 1.40 equiv) was added dropwise to the mixture. The reaction mixture was stirred at 25 °C under N2 for 2 hours. Under N2, the reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate (3 x 100 mL), washed with brine (50.0 mL), dried over Na2SO4, concentrated to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 0:1, petroleum ether:ethyl acetate = 0:1, R f = 0.50) to give the title compound (0.78 g, 4.93 mmol, yield 32.0%) as a yellow solid. (ESI + ) m / z: 159.0 (M+H) + , (C 10 H 10 N2).

[0370] E. 4-Bromo-1-methyl-5-phenyl-1H-imidazole: To a solution of 1-methyl-5-phenyl-imidazole (0.74 g, 4.68 mmol, 1.00 equiv) in ACN (7.00 mL) was added NBS (874 mg, 4.91 mmol, 1.05 equiv). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to obtain a residue. The obtained residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1; TLC, petroleum ether:ethyl acetate = 1:1, R f = 0.25) to give the title compound (0.73 g, 3.08 mmol, yield 65.0%) as a colorless oil. 1 1H NMR: (400 MHz, CDCl3) δ 7.50 - 7.21 (m, 6H), 3.58 (s, 3H). (ESI + ) m / z: 236.6 (M+H) + , (C 10 H9BrN2).

[0371] F.3-(2-(1-Methyl-5-phenyl-1H-imidazol-4-yl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[6-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[2,3-c]pyrrol-5-yl]piperidine-2,6-dione (0.20 g, 531 μmol, 1.00 equiv), 4-bromo-1-methyl-5-phenyl-imidazole (151 mg, 637 μmol, 1.20 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (88.9 mg, 106 μmol, 0.20 equiv), K3PO4 (225 mg, 1.06 mmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Welch Xtimate C18 (150 mm x 25 mm 10 μm) with a gradient of 40 - 70% acetonitrile / water (containing 0.05% FA), flow rate of 25 mL / min, elution for 58 min) to give the title compound (16.9 mg, 41.2 μmol, yield 14.0%, HPLC (220 nm) purity 99.1%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.83 (s, 1H), 7.59 - 7.55 (m, 3H), 7.51 - 7.49 (m, 2H), 6.74 (s, 1H), 4.96 - 4.91 (m, 1H), 4.23 - 4.10 (m, 2H), 3.46 (s, 3H), 2.89 - 2.53 (m, 1H), 2.33 - 2.26 (m, 2H), 1.97 - 1.95 (m, 1H). (ESI + ) m / z: 407.1 (M + H) + , (C 21 H 18 N4O3S). Example 17

[0372] Synthesis of 3-(5-(1,5-dimethyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0373] A. 3-Iodo-1,5-dimethyl-4-phenyl-1H-pyrazole: To a solution of 3-iodo-5-methyl-4-phenyl-1H-pyrazole (300 mg, 1.06 mmol, 1.00 equiv) in DMF (3.00 mL) was added K2CO3 (292 mg, 2.11 mmol, 2.00 equiv), and the mixture was stirred at 0 °C under N2 for 30 min. Then CH3I (180 mg, 1.27 mmol, 78.9 μL, 1.20 equiv) was added to the reaction mixture. The reaction mixture was stirred at 25 °C under N2 for 3 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (3 x 15.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, R f = 0.30) to give the title compound (100 mg, 328 μmol, yield 31.1%, purity by LCMS (220 nm) 97.8%) as a white solid. (ESI + ) m / z: 299.3 (M+H) + , (C 11 H 11 IN2).

[0374] B. 3-(5-(1,5-Dimethyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (102 mg, 276 μmol, 1.20 equiv) and 3-iodo-1,5-dimethyl-4-phenyl-1H-pyrazole (70.0 mg, 229 μmol, 1.00 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) were added K3PO4 (146 mg, 688 μmol, 3.00 equiv) and Ru-Phos-Pd-G3 (19.2 mg, 22.9 μmol, 0.10 equiv). The mixture was stirred at 100 °C under N2 for 10 h. The mixture was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) with a gradient of 25.0%-55.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution time 13 min) to give the title compound (9.40 mg, 22.7 μmol, yield 9.00%, purity by HPLC (220 nm) 98.7%) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H), 7.58 - 7.56 (m, 2H), 7.41 - 7.36 (m, 3H), 7.33 - 7.31 (m, 1H), 7.18 - 7.16 (m, 2H), 5.10 - 5.06 (m, 1H), 4.39 - 4.35 (m, 1H), 4.25 - 4.21 (m, 1H), 3.85 (s, 3H), 2.94 - 2.86 (m, 1H), 2.72 - 2.61 (m, 1H), 2.43 - 2.34 (m, 1H), 2.26 - 2.22 (m, 3H), 2.05 - 1.95 (m, 1H). (ESI + ) m / z: 414.9 (M + H) + , (C 24 H 22 N4O3). Example 18

[0375] Synthesis of 3-(5-(1,3-dimethyl-4-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0376] A. 5-Iodo-1,3-dimethyl-4-phenyl-1H-pyrazole: To a solution of 3-iodo-5-methyl-4-phenyl-1H-pyrazole (300 mg, 1.06 mmol, 1.00 equiv) in DMF (3.00 mL) was added K2CO3 (292 mg, 2.11 mmol, 2.00 equiv), and the mixture was stirred at 0 °C under N2 for 30 minutes. Then CH3I (180 mg, 1.27 mmol, 78.9 μL, 1.20 equiv) was added to the reaction mixture. The reaction mixture was stirred at 25 °C under N2 for 3 hours. The reaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (3 x 15.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, R f = 0.40) to give the title compound (80.0 mg, 258 μmol, yield 24.4%, LCMS (220 nm) purity 96.1%) as a white solid. (ESI + ) m / z: 299.3 (M + H) + , (C 11 H 11 IN2).

[0377] B. 3-(5-(1,3-Dimethyl-4-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (104 mg, 282 μmol, 1.20 equiv) and 5-iodo-1,3-dimethyl-4-phenyl-1H-pyrazole (73.0 mg, 235 μmol, 1.00 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) were added K3PO4 (150 mg, 704 μmol, 3.00 equiv) and Ru-Phos-Pd-G3 (19.6 mg, 23.5 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h under N2. It was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) with a gradient of 24.0%-54.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 13 min) to give the title compound (1.14 mg, 2.75 μmol, yield 1.00%, HPLC (220 nm) purity 97.1%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.07 - 10.9 (m, 1H), 7.73 - 7.71 (m, 1H), 7.58 (s, 1H), 7.46 - 7.40 (m, 1H), 7.35 - 7.33 (m, 2H), 7.27 - 7.18 (m, 1H), 7.09 - 7.07 (m, 2H), 5.14 - 5.10 (m, 1H), 4.48 - 4.44 (m, 1H), 4.35 - 4.31 (m, 1H), 3.70 (s, 3H), 2.93 - 2.88 (m, 1H), 2.62 - 2.61 (m, 1H), 2.41 - 2.38 (m, 1H), 2.21 (s, 3H), 2.06 - 1.96 (m, 1H). (ESI + ) m / z: 415.0 (M + H) + , (C 24 H 22 N4O3). Example 19

[0378] Synthesis of 3-(5-(2-Methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0379] A. N-(2-oxo-2-phenylethyl)acetamide: To a solution of 2-amino-1-phenylethanone (10.0 g, 58.2 mmol, 1.00 equiv., HCl) in THF (300 mL) was added ethyl acetoacetate (16.1 g, 158 mmol, 14.8 mL, 2.71 equiv.) and TEA (11.7 g, 116 mmol, 16.2 mL, 2.00 equiv.). The mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the title compound (10.0 g, crude) as a brown oil. 1 1H NMR: (400 MHz, DMSO-d6) δ 8.27 (t, J = 5.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 4.59 (d, J = 5.6 Hz, 2H), 1.91 (s, 3H). (ESI + ) m / z: 177.0 (M+H) + , (C 10 H 11 NO2).

[0380] B. 2-Methyl-5-phenyloxazole: Compound N-phenylacetoacetamide (10.0 g, 56.0 mmol, 1.00 equiv.) was added to H2SO4 (10.0 mL), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to 25 °C and poured into ice water (50.0 mL). The solution was neutralized with 28% aqueous ammonia and extracted with ethyl acetate (3 x 20.0 mL). The organic layer was concentrated under reduced pressure to give the title compound (0.30 g, crude) as a yellow solid. (ESI + ) m / z: 160.0 (M+H) + , (C 10 H9NO).

[0381] C. 4-Bromo-2-methyl-5-phenyloxazole: At 0 °C, NBS (1.40 g, 8.17 mmol, 1.30 equiv.) was added to a solution of 2-methyl-5-phenyloxazole (0.30 g, 1.90 mmol, 1.00 equiv.) in ACN (10.0 mL). The reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1; TLC, petroleum ether:ethyl acetate = 3:1, R f = 0.50) to give the title compound (0.30 g, 1.28 mmol, 66.0% yield) as a yellow solid. 11H NMR: (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 3.6 Hz, 2H), 7.37 - 7.27 (m, 1H), 2.54 (s, 3H). (ESI + ) m / z: 237.9 (M + H) + , (C 10 H8BrNO).

[0382] D. 3-(5-(2-Methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (0.20 g, 540 μmol, 1.00 equiv) and 4-bromo-2-methyl-5-phenyloxazole (154 mg, 648 μmol, 1.20 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) were added Ru-Phos-Pd-G3 (90.3 mg, 108 μmol, 0.20 equiv), K3PO4 (229 mg, 1.08 mmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC using Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 27 - 57% acetonitrile / water (containing 0.05% FA) at a flow rate of 20 mL / min for 58 min, to afford the title compound (75.3 mg, 170 μmol, 30.0% yield, 90.7% purity by HPLC (220 nm)), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.80 (s, 1H), 7.76 - 7.72 (m, 2H), 7.56 - 7.54 (m, 2H), 7.46 - 7.44 (m, 3H), 5.14 - 5.09 (m, 1H), 4.49 - 4.31 (m, 2H), 2.94 - 2.88 (m, 1H), 2.56 - 2.54 (m, 1H), 2.53 (s, 3H), 2.41 - 2.38 (m, 1H), 2.36 - 2.01 (m, 1H). (ESI + ) m / z: 402.1 (M + H) + , (C 23 H 19 N3O4). Example 20

[0383] Synthesis of 3-(7-(1-Methyl-5-phenyl-1H-imidazol-4-yl)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione

[0384] A. 3-(7-(1-Methyl-5-phenyl-1H-imidazol-4-yl)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione: Under N2, Ru-Phos-Pd-G3 (26.9 mg, 32.2 μmol, 0.10 eq) was added to a solution of 3-(3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-2-yl)piperidine-2,6-dione (crude, 120 mg, 322 μmol, 1.00 eq), 4-bromo-1-methyl-5-phenyl-1H-imidazole (91.7 mg, 386 μmol, 1.20 eq), and K3PO4 (136 mg, 644 μmol, 2.00 eq) in dioxane (2.00 mL) and H2O (0.10 mL). The reaction mixture was stirred at 100 °C for 2 h under N2. Then the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the crude product. The obtained crude product was purified by reverse-phase HPLC (under 0.1% HCl condition) to give the title compound (12.8 mg, 31.8 μmol, yield 7.69%, HPLC (220 nm) purity >99%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H), 8.98 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.64 - 7.59 (m, 3H), 7.57 - 7.52 (m, 2H), 7.21 (s, 1H), 6.47 (d, J = 7.2 Hz, 1H), 5.35 (dd, J = 12.8, 5.2 Hz, 1H), 3.59 (s, 3H), 2.94 - 2.84 (m, 1H), 2.65 - 2.58 (m, 1H), 2.49 - 2.43 (m, 1H), 2.18 - 2.10 (m, 1H). (ESI + ) m / z: 403.2 (M + H) + , (C 21 H 18 N6O3). Example 21

[0385] Synthesis of 3-(5-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0386] A. 3-(5-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (0.10 g, 270 μmol, 1.00 equiv), 5-bromo-1-methyl-4-phenyl-imidazole (76.5 mg, 324 μmol, 1.20 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) were added Ru-Phos-Pd-G3 (22.5 mg, 17.0 μmol, 0.10 equiv) and K3PO4 (114 mg, 540 μmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Welch Xtimate C18 (150 mm x 25 mm 10 μm) with a gradient of 1 - 31% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, eluting for 58 min) to give the title compound (65.0 mg, 81.0 μmol, 60.0% yield, HPLC (220 nm) purity 100%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.83 - 7.81 (m, 2H), 7.67 (s, 1H), 7.31 - 7.29 (m, 2H), 7.50 - 7.48 (m, 1H), 7.39 - 7.37 (m, 2H), 5.17 - 5.12 (m, 1H), 4.53 - 4.36 (m, 2H), 3.50 (s, 3H), 2.93 - 2.87 (m, 1H), 2.65 - 2.62 (m, 1H), 2.42 - 2.39 (m, 1H), 2.05 - 2.02 (m, 1H). (ESI + ) m / z: 401.2 (M + H) + , (C 23 H 20 N4O3). Example 22

[0387] Synthesis of 3-(5-(1-Isobutyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0388] A. 1-Isobutyl-5-phenyl-1H-imidazole: At -5 °C, TEA (3.35 g, 33.1 mmol, 4.61 mL, 5.00 equiv) was added to a solution of (E)-N-(2-phenyl-1-tosylethylenyl)formamide (2.00 g, 6.63 mmol, 1.00 equiv) in DME (20.0 mL). Then POCl3 (0.81 g, 5.30 mmol, 492 μL, 0.80 equiv) was added dropwise at -5 °C. 2-Methylpropan-1-amine (1.03 g, 14.1 mmol, 1.40 mL, 2.00 equiv) was added to the mixture. Then the mixture was stirred at 25 °C for 5 h. The mixture was poured into water (100 mL) at 0 °C and extracted with DCM (3 x 80.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1, TLC: dichloromethane:methanol = 10:1, R f = 0.2) to give the title compound (400 mg, 2.00 mmol, yield 30.1%) as a brown oil. (ESI + ) m / z: 201.0 (M+H) + , (C 13 H 16 N2).

[0389] B. 4-Bromo-1-isobutyl-5-phenyl-1H-imidazole: At 0 °C, NBS (249 mg, 1.40 mmol, 0.70 equiv) was slowly added to a solution of 1-isobutyl-5-phenyl-1H-imidazole (400 mg, 2.00 mmol, 1.00 equiv) in ACN (20.0 mL). Then the mixture was stirred at 25 °C for 2 h. Then the mixture was poured into H2O (20.0 mL) and extracted with DCM (3 x 15.0 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 15.0 mL), dried over Na2SO4, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (DCM:MeOH = 10:1, R f = 0.55) to give the title compound (500 mg, 1.69 mmol, yield 84.3%, LCMS (220 nm) purity 94.1%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.52 - 7.40 (m, 5H), 3.79 - 3.77 (m, 2H), 1.63 - 1.53 (m, 1H), 0.64 - 0.61 (m, 6H). (ESI + ) m / z: 279.0 (M+H)+ ,(C 13 H 15 BrN2).

[0390] C. 3-(5-(1-Isobutyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-1-isobutyl-5-phenyl-1H-imidazole (300 mg, 1.07 mmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (517 mg, 1.40 mmol, 1.30 equiv) and K3PO4 (456 mg, 2.15 mmol, 2.00 equiv) in dioxane (6.00 mL) and H2O (0.30 mL) was added Ru-Phos-Pd-G3 (89.9 mg, 107 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 4 h under N2. The mixture was poured into H2O (20.0 mL) and extracted with DCM (3 x 15.0 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 15.0 mL), dried over Na2SO4, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using column: Welch Xtimate C18 (150 x 25 mm x 5 μm) and gradient of 11.0%-41.0% acetonitrile / water (containing 0.05% FA), flow rate of 25 mL / min, eluting for 15 min) to give the title compound (125 mg, 279 μmol, yield 25.9%, HPLC (220 nm) purity 98.7%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.89 (s, 1H), 7.59 - 7.53 (m, 1H), 7.52 - 7.46 (m, 5H), 7.43 - 7.39 (m, 2H), 5.08 - 5.04 (m, 1H), 4.36 - 4.31 (m, 2H), 3.70 - 3.66 (m, 2H), 2.92 - 2.86 (m, 1H), 2.54 - 2.52 (m, 1H), 2.37 - 2.34 (m, 1H), 1.98 - 1.96 (m, 1H), 1.66 - 1.63 (m, 6H). (ESI + ) m / z: 443.0 (M + H) + ,(C 26 H 26 N4). Example 23

[0391] Synthesis of 3-(1-oxo-5-(5-phenylthiazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0392] A. 4-Bromo-5-phenylthiazole: At 25 °C and under N2, NBS (607 mg, 3.41 mmol, 1.10 eq) was added to a solution of 5-phenylthiazole (0.50 g, 3.10 mmol, 1.00 eq) in ACN (5.00 mL). The mixture was stirred at 50 °C for 1 h. The reaction mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, and concentrated to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1, TLC: petroleum ether:ethyl acetate = 3:1, R f = 0.30) to afford the title compound (563 mg, 2.34 mmol, 75.6% yield, purity by LCMS (220 nm) 100%) as a light yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.66 - 7.64 (m, 2H), 7.46 - 7.44 (m, 3H). (ESI + ) m / z: 241.8 (M+H) + , (C9H6BrNS).

[0393] B. 3-(1-Oxo-5-(5-phenylthiazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (185 mg, 499 μmol, 1.20 equiv) and 4-bromo-5-phenylthiazole (100 mg, 416 μmol, 1.00 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) were added Ru-Phos-Pd-G3 (34.8 mg, 41.6 μmol, 0.10 equiv) and K3PO4 (176.8 mg, 832 μmol, 2.00 equiv). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 7 μm) with a gradient of 26.0%-56.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 20 min) to give the title compound (102.1 mg, 205 mmol, yield 60.1%, HPLC (220 nm) purity 98.9%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.24 (s, 1H), 7.73 - 7.72 (m, 1H), 7.65 - 7.63 (m, 1H), 7.52 - 7.46 (m, 1H), 7.43 - 7.37 (m, 5H), 5.12 - 5.08 (m, 1H), 4.44 - 4.26 (m, 2H), 2.93 - 2.87 (m, 1H), 2.61 - 2.56 (m, 1H), 2.40 - 2.36 (m, 1H), 2.02 - 2.00 (m, 1H). (ESI + ) m / z: 404.0 (M + H) + , (C 22 H 17 N3O3S). Example 24

[0394] (R)-3-(5-(5-(4-Fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione synthesis

[0395] (S)-tert-Butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate: At 0 °C, to a suspension of (4S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester (14.5 g, 60.6 mmol, 1.00 equiv, HCl) in MeCN (231 mL) was added DIEA (28.0 g, 2171 mmol, 37.7 mL, 3.57 equiv). After stirring for 15 minutes, methyl 4-bromo-2-(bromomethyl)benzoate (22.0 g, 71.4 mmol, 1.18 equiv) was added to the above mixture in several portions over 15 minutes. The reaction mixture was stirred at 0 °C for 30 minutes, then warmed to 25 °C and maintained for 3 hours. The reaction mixture was warmed to 60 °C and maintained for 12 hours. The mixture was cooled to 25 °C. 50 mL of water was added, and the mixture was stirred at 25 °C for 30 minutes. The resulting solid was filtered and washed with 20 mL of EtOAc. The solid was dried by vacuum filtration to obtain the title compound (18.0 g, 45.3 mmol, yield 74.8%), as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.69 - 7.67 (m, 2H), 7.57 - 7.67 (m, 1H), 7.19 (s, 1H), 4.74 - 4.71 (m, 1H), 4.71 - 4.44 (m, 2H), 2.19 - 2.14 (m, 3H), 2.00 - 1.97 (m, 1H), 1.33 (s, 9H). (ESI + ) m / z: 396.1 (M + H) + , (C 17 H 21 BrNO4).

[0396] B. (S)-tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate: To a solution of (S)-tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (10.0 g, 25.2 mmol, 1.00 equiv), BPD (7.67 g, 30.2 mmol, 1.20 equiv) in dioxane (100 mL) was added AcOK (7.41 g, 75.52 mmol, 3.00 equiv), Pd(dppf)Cl2 (1.01 g, 1.38 mmol, 0.05 equiv). The mixture was stirred at 60 °C under N2 for 2 h. The reaction mixture was diluted with EtOAc (50.0 mL), filtered through a Celite plug and washed with additional EtOAc (30.0 mL). The filtrate was dried in vacuo to give the title compound (8.74 g, 14.5 mmol, 57% yield, purity by LCMS (220 nm) 73.8%) as an off-white solid. (ESI + ) m / z: 445.1 (M+H) + , (C 22 H 33 BN2O6).

[0397] C. (S)-tert-Butyl 5-amino-4-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: At 25 °C, under N2, to a solution of (S)-tert-Butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (117 mg, 264 μmol, 1.10 equiv) and 4-iodo-1-methyl-1H-imidazole (50.0 mg, 240 μmol, 1.00 equiv) in dioxane (1.00 mL) and H2O (0.10 mL) were added K3PO4 (153 mg, 721 μmol, 3.00 equiv) and cataCXium A Pd G3 (n-Butyldi(1-adamantyl)phosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, 17.5 mg, 24.0 μmol, 0.1 equiv). The mixture was stirred at 80 °C under N2 for 10 h. The mixture was concentrated under reduced pressure to give a residue. The residue was poured into H2O (5.0 mL) and extracted with DCM (3x10 mL), and the organic layers were collected. The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo at 40 °C to give a residue. The resulting residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f= 0.20) Purification gave the title compound (40.0 mg, 72.8 μmol, yield 32.0%, purity by LCMS (220 nm) 85.0%), as a brown solid. (ESI + ) m / z: 399.1 (M + H) + , (C 21 H 26 N4O4).

[0398] D. (S)-tert-Butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: At 0 °C, NBS (12.8 mg, 72.0 μmol, 1.00 equiv) was added to a solution of (S)-tert-butyl 5-amino-4-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (40.0 mg, 72.1 μmol, 1.00 equiv) in MeCN (1.00 mL). The mixture was then stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f = 0.25) to give the title compound (15.0 mg, 30.9 μmol, yield 53.0%, purity by LCMS (220 nm) 98.6%), as a brown solid. 1 1H NMR (400 MHz, DMSO-d6): δ 8.11 - 8.08 (m, 1H), 8.05 - 8.00 (m, 2H), 7.75 - 7.23 (m, 1H), 7.56 (s, 1H), 7.19 (s, 1H), 4.76 - 4.72 (m, 1H), 4.61 - 4.48 (m, 2H), 3.66 (s, 3H), 2.19 - 2.14 (m, 3H), 2.00 - 1.97 (m, 1H), 1.33 (s, 9H). (ESI + ) m / z: 476.1 (M + H) + , (C 21 H 25 BrN4O4).

[0399] E.(S)-tert-Butyl 5-amino-4-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: Under N2, to a solution of (S)-tert-butyl 5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (15.0 mg, 30.9 μmol, 1.00 equiv), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.67 mg, 61.9 μmol, 2.00 equiv) and K2CO3 (8.56 mg, 61.9 μmol, 2.00 equiv) in dioxane (1.00 mL) was added Pd(dppf)Cl2 (7.16 mg, 6.20 μmol, 0.20 equiv). The reaction mixture was then stirred at 100 °C for 2 h under N2. The mixture was poured into H2O (6.0 mL), extracted with DCM (3 x 10.0 mL), and the organic layer was collected. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo at 40 °C to give a residue. The resulting residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f = 0.15) to give the title compound (10.0 mg, 19.8 μmol, 60.0% yield, 97.5% purity by LCMS (220 nm)) as a white solid. (ESI + ) m / z: 493.3 (M+H) + , (C 27 H 29 FN4O4).

[0400] F.(R)-3-(5-(5-(4-Fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of tert-butyl (S)-5-amino-4-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (10.0 mg, 19.8 μmol, 1.00 equiv) in MeCN (1.00 mL) was added TsOH (17.0 mg, 98.9 μmol, 5.00 equiv). The mixture was stirred at 80 °C for 4 h. The mixture was poured into H2O (10.0 mL) and extracted with DCM (3 x 10.0 mL). The combined organic layers were washed with brine (2 x 15.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC using Phenomenex luna C18 (150 x 25 mm x 5 μm) with a gradient of 4 - 34% acetonitrile / water (containing 0.05% FA) at a flow rate of 25 mL / min for 15 min, to afford the title compound (2.57 mg, 5.96 μmol, yield 29.4%, HPLC (220 nm) purity 97.1%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.9 - 10.8 (m, 1H), 7.85 (s, 1H), 7.59 - 7.55 (m, 1H), 7.53 - 7.52 (m, 1H), 7.48 - 7.47 (m, 1H), 7.46 - 7.45 (m, 3H), 7.44 - 7.41 (m, 2H), 5.09 - 5.04 (m, 1H), 4.30 - 4.25 (m, 1H), 4.20 - 4.15 (m, 1H), 3.47 (s, 3H), 2.95 - 2.86 (m, 1H), 2.55 - 2.54 (m, 1H), 2.37 - 2.34 (m, 1H), 2.32 - 1.90 (m, 1H). (ESI + ) m / z: 418.1 (M + H) + , (C 23 H 19 FN4O3). Example 25

[0401] Synthesis of 3-(5-(1-Methyl-2-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0402] A. 4,5-Dibromo-2-phenyl-1H-imidazole: At 0 °C, NBS (24.6 g, 138 mmol, 2.00 equivalents) was added to a solution of 2-phenyl-1H-imidazole (10.0 g, 69.3 mmol, 1.00 equivalent) in DMF (100 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. H2O (100 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated aqueous Na2SO3 (2 x 100 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to give the title compound (6.00 g, crude), as a yellow solid. (ESI + ) m / z: 300.8 (M + H) + , (C9H6Br2N2).

[0403] B. 4-Bromo-2-phenyl-1H-imidazole: Under N2, Na2S2O3 (10.4 g, 66.2 mmol, 4.00 equivalents) was added to a solution of 4,5-dibromo-2-phenyl-1H-imidazole (5.00 g, 16.5 mmol, 1.00 equivalent) in EtOH (50.0 mL) and H2O (50.0 mL). The reaction mixture was stirred at 110 °C for 96 h under N2. The mixture was cooled to 25 °C and the solvent was removed under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 5:1; TLC, petroleum ether:ethyl acetate = 3:1, R f = 0.40) to give the title compound (1.10 g, 4.88 mmol, yield 25.0%, HPLC (220 nm) purity 98.9%), as a yellow solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.45 - 7.41 (m, 2H), 7.40 - 7.38 (m, 1H), 4.37 - 4.35 (m, 1H). (ESI + ) m / z: 223.0 (M + H) + , (C9H7BrN2).

[0404] C. 4-Bromo-1-methyl-2-phenyl-1H-imidazole: At 0 °C under N2, to a solution of 4-bromo-2-phenyl-1H-imidazole (0.50 g, 2.24 mmol, 1.00 equiv) in THF (10.0 mL) was added NaH (117 mg, 2.91 mmol, purity 60.0%, 1.30 equiv) (5 batches). The mixture was stirred at 0 °C under N2 for 30 min, then CH3I (636 mg, 4.48 mmol, 279 μL, 2.00 equiv) was added dropwise to the mixture. The reaction mixture was stirred at 25 °C under N2 for 2 h. Under N2, the reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate (3 × 100 mL), washed with brine (50.0 mL), dried over Na2SO4, concentrated to give a residue. The crude product was purified by preparative TLC (dichloromethane:methanol = 100:1, R f = 0.60) to give the title compound (200 mg, 844 μmol, yield 37.6%). (ESI + ) m / z: 236.9 (M+H) + , (C 10 H9BrN2).

[0405] D. 3-(5-(1-Methyl-2-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (131 mg, 354 μmol, 1.20 equiv) and 4-bromo-1-methyl-2-phenyl-imidazole (70.0 mg, 295 μmol, 1.00 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) was added K3PO4 (125 mg, 590 μmol, 2.00 equiv) and Ru-Phos-Pd-G3 (49.3 mg, 59.0 μmol, 0.20 equiv). The reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 3-33% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 58 min) to give the title compound (17.8 mg, 42.1 μmol, yield 14.2%, HPLC (220 nm) purity 94.7%) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.02 (s, 1H), 7.79 - 7.77 (m, 1H), 7.72 - 7.69 (m, 3H), 7.54 - 7.48 (m, 4H), 5.13 - 5.09 (m, 1H), 4.51 - 4.33 (m, 2H), 3.80 (s, 3H), 2.91 - 2.88 (m, 1H), 2.63 - 2.62 (m, 1H), 2.43 - 2.40 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI + ) m / z: 401.1 (M + H) + , (C 23 H 20 N4O3). Example 26

[0406] Synthesis of 3-(5-(1-Ethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0407] A. (E)-N-(2-Phenyl-1-tosylvinyl)formamide: A solution of t-BuOK (6.32 g, 56.3 mmol, 1.10 eq) in THF (80.0 mL) was cooled to -40 °C. At -40 °C, a solution of 2-tosylacetonitrile (10.0 g, 51.2 mmol, 1.00 eq) in THF (20.0 mL) was added dropwise. The mixture was stirred at -40 °C for 0.5 h. At -40 °C, a solution of benzaldehyde (5.71 g, 53.8 mmol, 5.44 mL, 1.05 eq) in THF (20.0 mL) was added dropwise. Then the mixture was stirred at -40 °C for 0.5 h. The mixture was poured into ice water (100 mL), neutralized with 1 N HCl solution (pH = 7), and then extracted with DCM (3 x 100 mL). Then the organic layer was dried over Na2SO4, filtered, and concentrated to give a residue. The obtained residue was triturated with MTBE (2 x 20.0 mL) at 25 °C to give the title compound (12.0 g, 39.7 mmol, yield 77.6%, purity by LCMS (220 nm) 99.8%) as a yellow solid. (ESI + ) m / z: 302.6 (M + H) + , (C 16 H 15 NO3S).

[0408] B. 1-Ethyl-5-phenyl-1H-imidazole: At -5 °C, TEA (3.35 g, 33.1 mmol, 4.61 mL, 5.00 equiv) was added to a solution of (E)-N-(2-phenyl-1-tosylvinyl)formamide (2.00 g, 6.63 mmol, 1.00 equiv) in DME (20.0 mL). Then POCl3 (0.81 g, 5.30 mmol, 492 μL, 0.80 equiv) was added dropwise at -5 °C. Then the reaction mixture was stirred at 0 °C for 1 h. Then ethylamine (636 mg, 14.1 mmol, 923 μL, 2.00 equiv) was added to the mixture. Then the mixture was stirred at 25 °C for 4 h. The mixture was poured into water (100 mL) at 0 °C and extracted with DCM (3 x 80.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1, TLC: dichloromethane:methanol = 10:1, R f = 0.2) to give the title compound (400 mg, 2.29 mmol, yield 35.0%, purity by LCMS (220 nm) 98.5%) as a brown oil. (ESI + ) m / z: 173.0 (M+H) + , (C 11 H 12 N2).

[0409] C. 4-Bromo-1-ethyl-5-phenyl-1H-imidazole: At 25 °C under N2, NBS (319 mg, 1.79 mmol, 0.80 equiv) was added to a solution of 1-ethyl-5-phenyl-1H-imidazole (386 mg, 2.24 mmol, 1.00 equiv) in MeCN (15.0 mL). The mixture was stirred at 25 °C under N2 for 1 h. The reaction mixture was poured into H2O (10.0 mL) and extracted with dichloromethane (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f = 0.30) to give the title compound (250 mg, 995 μmol, yield 44.4%) as a brown oil. 1 1H NMR: (400 MHz, DMSO-d6) δ 7.84 - 7.82 (m, 1H), 7.51 - 7.42 (m, 5H), 3.97 - 3.91 (m, 2H), 1.14 - 1.10 (m, 3H). (ESI + ) m / z: 251.1 (M+H) + , (C 11 H11 BrN2).

[0410] D. 3-(5-(1-Ethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, at 25 °C, to a solution of 4-bromo-1-ethyl-5-phenyl-1H-imidazole (200 mg, 796 μmol, 1.00 equiv) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (383 mg, 1.04 mmol, 1.30 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) were added Ru-Phos-Pd-G3 (99.9 mg, 119 μmol, 0.15 equiv) and K3PO4 (507 mg, 2.39 mmol, 3.00 equiv). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 5.00%-35.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, eluting for 13 min) to give the title compound (10.5 mg, 24.9 μmol, yield 3.14%, HPLC (220 nm) purity 98.6%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.96 - 7.86 (m, 1H), 7.61 - 7.49 (m, 5H), 7.42 - 7.40 (m, 3H), 5.10 - 5.02 (m, 1H), 4.29 - 4.14 (m, 2H), 3.91 - 3.78 (m, 2H), 2.90 - 2.86 (m, 1H), 2.60 - 2.58 (m, 1H), 2.34 - 2.32 (m, 1H), 1.97 - 1.96 (m, 1H), 1.17 - 1.13 (m, 3H). (ESI + ) m / z: 415.1 (M + H) + , (C 24 H 22 N4O3). Example 27

[0411] Synthesis of 3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0412] A. 4-Bromo-1-(difluoromethyl)-5-phenyl-1H-pyrazole: 4-Bromo-5-phenyl-1H-pyrazole (1.00 g, 4.48 mmol, 1.00 equiv) and 18-crown-6 (646 mg, 1.79 mmol, 0.40 equiv) were dissolved in ACN (25.0 mL). The reagents were stirred until a colorless solution was formed, and then sodium (2-chloro-2,2-difluoro-acetyl)oxy (1.37 g, 8.97 mmol, 2.00 equiv) was added to the reaction mixture. The reaction mixture was heated to 80 °C and maintained for 48 h. The reaction mixture was filtered through celite and washed with EtOAc (3 x 10.0 mL). The combined organic layers were concentrated under reduced pressure to give the title compound (0.40 g, 1.26 mmol, yield 28.0%) as a white solid. (ESI + ) m / z: 272.9 (M+H) + , (C 10 H7BrF2N2).

[0413] B. 3-(5-(1-(Difluoromethyl)-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (418 mg, 1.13 mmol, 1.20 equiv) and 4-bromo-1-(difluoromethyl)-5-phenyl-pyrazole (300 mg, 941 μmol, 1.00 equiv) in dioxane (3.00 mL) and H2O (0.15 mL) were added Ru-Phos-Pd-G3 (157 mg, 188 μmol, 0.20 equiv) and K3PO4 (399 mg, 1.88 mmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC using WelchXtimate C18 (150 mm x 25 mm 10 μm) with a gradient of 29 - 59% acetonitrile / water (containing 0.05% FA) at a flow rate of 20 mL / min for 58 min, to give the title compound (122 mg, 278 μmol, yield 29.6%, HPLC (220 nm) purity 99.7%) as a yellow solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.60 (s, 1H), 7.90 - 7.68 (m, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.40 - 7.38 (m, 6H), 5.13 - 5.08 (m, 1H), 4.45 - 4.27 (m, 2H), 2.94 - 2.89 (m, 1H), 2.61 - 2.50 (m, 1H), 2.42 - 2.37 (m, 1H), 2.02 - 2.00 (m, 1H). (ESI + ) m / z: 437.2 (M + H) + , (C 23 H 18 F2N4O3). Example 28

[0414] Synthesis of 3-(5-(1-Methyl-2-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0415] A. 3-(5-(1-Methyl-2-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (168 mg, 455 μmol, 1.20 equiv) and 5-bromo-1-methyl-2-phenyl-imidazole (90.0 mg, 379 μmol, 1.00 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (63.5 mg, 75.9 μmol, 0.20 equiv) and K3PO4 (161 mg, 759 μmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 1 - 31% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 58 min) to give the title compound (21.2 mg, 52.4 μmol, yield 13.8%, HPLC (220 nm) purity 99.0%), as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.83 - 7.82 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.71 - 7.69 (m, 3H), 5.19 - 5.14 (m, 1H), 4.60 - 4.43 (m, 2H), 3.77 (s, 3H), 2.98 - 2.90 (m, 1H), 2.64 - 2.50 (m, 1H), 2.47 - 2.43 (m, 1H), 2.05 - 2.04 (m, 1H). (ESI + ) m / z: 401.2 (M + H) + , (C 23 H 20 N4O3). Example 29

[0416] Synthesis of 3-(5-(3-Methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0417] A. 3-(5-(3-Methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2 at 25 °C, to a solution of 4-iodo-3-methyl-5-phenylisoxazole (100 mg, 350 μmol, 1.00 equiv) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (168 mg, 456 μmol, 1.30 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) was added K3PO4 (223 mg, 1.05 mmol, 3.00 equiv) and Ru-Phos-Pd-G3 (58.6 mg, 70.1 μmol, 0.20 equiv). The mixture was stirred at 100 °C under N2 for 4 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) with a gradient of 26.0% - 56.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 13 min) to give the title compound (17.7 mg, 43.1 μmol, yield 12.3%, HPLC (220 nm) purity 97.5%), as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.66 - 7.51 (m, 1H), 7.49 - 7.47 (m, 1H), 7.45 - 7.43 (m, 6H), 5.39 - 5.09 (m, 1H), 4.55 - 4.43 (m, 2H), 2.96 - 2.89 (m, 1H), 2.62 - 2.58 (m, 1H), 2.43 - 2.39 (m, 1H), 2.21 (s, 3H), 2.05 - 2.03 (m, 1H). (ESI + ) m / z: 402.0 (M + H) + , (C 23 H 19 N3O4). Example 30

[0418] Synthesis of 3-(5-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0419] A. 4-Iodo-3-methyl-5-phenyl-1H-pyrazole: To a solution of I2 (1.28 g, 5.06 mmol, 1.02 mL, 1.00 equiv) and (diacetoxyiodo)benzene (1.63 g, 5.06 mmol, 1.00 equiv) in DCM (15.0 mL) was added 3-methyl-5-phenyl-1H-pyrazole (800 mg, 5.06 mmol, 1.00 equiv). The reaction mixture was then stirred at 25 °C for 1 h. The reaction mixture was poured into water (50.0 mL) and extracted with DCM (3 x 40.0 mL). The combined organic layers were washed with saturated aqueous Na2SO3, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 7 μm) and a gradient of 34.0% - 64.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 15 min) to give the title compound (548 mg, 1.93 mmol, yield 38.2%, LCMS (220 nm) purity 100%) as a light yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 9.08 - 8.92 (m, 1H), 7.72 - 7.70 (m, 2H), 7.45 - 7.27 (m, 3H), 2.21 (s, 3H). (ESI + ) m / z: 283.9 (M + H) + , (C 10 H9IN2).

[0420] B. 3-(5-(3-Methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, to a solution of 4-iodo-3-methyl-5-phenyl-1H-pyrazole (100 mg, 351 μmol, 1.00 equivalent) and 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (390 mg, 1.06 mmol, 3.00 equivalents) in dioxane (4.00 mL) and H2O (0.20 mL) was added K3PO4 (224 mg, 1.06 mmol, 3.00 equivalents) and Ru-Phos-Pd-G3 (29.4 mg, 35.2 μmol, 0.10 equivalent). The mixture was stirred at 100 °C for 3 hours under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) with a gradient of 14.0%-44.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 13 minutes) to give the title compound (33.2 mg, 82.4 μmol, yield 23.4%, HPLC (220 nm) purity 99.5%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 13.0 - 12.9 (m, 1H), 10.9 (s, 1H), 7.68 - 7.66 (m, 1H), 7.43 - 7.24 (m, 7H), 5.13 - 5.09 (m, 1H), 4.46 - 4.28 (m, 2H), 2.92 - 2.90 (m, 1H), 2.62 - 2.61 (m, 1H), 2.40 - 2.36 (m, 1H), 2.25 - 2.19 (m, 3H), 2.09 - 2.02 (m, 1H). (ESI + ) m / z: 400.1 (M + H) + , (C 23 H 20 N4O3). Example 31

[0421] Synthesis of 3-(1-oxo-5-(4-phenylisothiazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0422] A. 5-Bromo-4-iodoisothiazole: At 25 °C and under N2, NIS (1.37 g, 6.10 mmol, 1.00 equiv) was added to a solution of 5-bromoisothiazole (1.00 g, 6.10 mmol, 1.00 equiv) in TFA (10.0 mL). The mixture was stirred at 80 °C for 12 h under N2. The reaction mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 10:1, R f = 0.30) to give the title compound (1.42 g, 4.90 mmol, 80.3% yield, 97.9% purity by LCMS (220 nm)), as a pale yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 8.29 (s, 1H). (ESI + ) m / z: 291.7 (M + H) + , (C3HBrINS).

[0423] B. 5-Bromo-4-phenylisothiazole: At 25 °C and under N2, Pd(PPh3)Cl2 (72.6 mg, 103 μmol, 0.10 equiv) and NaHCO3 (330 mg, 3.93 mmol, 153 μL, 3.80 equiv) were added to a solution of 5-bromo-4-iodoisothiazole (300 mg, 1.03 mmol, 1.00 equiv) and phenylboronic acid (113 mg, 931 μmol, 0.90 equiv) in dioxane (6.00 mL) and H2O (0.30 mL). The mixture was stirred at 60 °C for 24 h under N2. The reaction mixture was poured into H2O (10.0 mL) and extracted with dichloromethane (3 x 10.0 mL). The combined organic layers were washed with brine (3 × 10.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f = 0.70) to give the title compound (70.0 mg, 291 μmol, 28.1% yield), as a pale yellow oil. (ESI + ) m / z: 238.9 (M + H) + , (C9H6BrNS).

[0424] C. 3-(1-Oxo-5-(4-phenylisothiazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2 at 25 °C, to a solution of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (501 mg, 1.35 mmol, 2.50 equiv) and 5-bromo-4-phenylisothiazole (130 mg, 541 μmol, 1.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) was added K3PO4 (344 mg, 1.62 mmol, 3.00 equiv) and Ru-Phos-Pd-G3 (45.3 mg, 54.1 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 28.0%-58.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 13 min) to give the title compound (30.0 mg, 73.4 μmol, yield 13.5%, HPLC (220 nm) purity 98.7%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H), 8.78 (s, 1H), 7.75 - 7.73 (m, 1H), 7.76 (s, 1H), 7.42 - 7.35 (m, 6H), 5.14 - 5.09 (m, 1H), 4.51 - 4.31 (m, 2H), 2.89 - 2.83 (m, 1H), 2.64 - 2.60 (m, 1H), 2.38 - 2.32 (m, 1H), 2.03 - 1.99 (m, 1H). (ESI + ) m / z: 403.9 (M + H) + , (C 22 H 17 N3O3S). Example 32

[0425] Synthesis of 3-(1-oxo-5-(1-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0426] A. 4-Bromo-1-phenyl-1H-imidazole: At 0 °C under N2, NBS (790 mg, 4.44 mmol, 0.80 eq) was added to a solution of 1-phenyl-1H-imidazole (800 mg, 5.55 mmol, 1.00 eq) in ACN (8.00 mL). The mixture was stirred at 25 °C under N2 for 2 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with ethyl acetate (3 x 15.0 mL). The combined organic layers were washed with brine (3 x 15.0 mL), dried over Na2SO4, filtered, and concentrated. The mixture was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 0:1, TLC: petroleum ether:ethyl acetate = 5:1, R f = 0.3) to give the title compound (330 mg, 1.48 mmol, 26.6% yield) as a yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.52 - 7.49 (m, 3H), 7.43 - 7.36 (m, 3H). (ESI + ) m / z: 224.9 (M+H) + , (C9H7BrN2).

[0427] B. 3-(1-Oxo-5-(1-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, Ru-Phos-Pd-G3 (37.5 mg, 44.8 μmol, 0.10 eq) was added to a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (414 mg, 1.12 mmol, 2.50 eq), 4-bromo-1-phenyl-1H-imidazole (100 mg, 448 μmol, 1.00 eq), and K3PO4 (285 mg, 1.34 mmol, 3.00 eq) in dioxane (5.00 mL) and H2O (0.25 mL). The mixture was stirred at 100 °C under N2 for 4 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) with a gradient of 1.00% - 31.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 15 min) to give the title compound (51.0 mg, 127 μmol, 28.4% yield, HPLC (220 nm) purity 96.6%) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.61 - 7.56 (m, 3H), 7.49 - 7.47 (m, 3H), 7.34 - 7.25 (m, 4H), 5.11 - 5.06 (m, 1H), 4.42 - 4.23 (m, 2H), 2.92 - 2.86 (m, 1H), 2.60 (s, 1H), 2.38 - 2.32 (m, 1H), 2.01 - 1.97 (m, 1H). (ESI + ) m / z: 386.1 (M + H) + , (C 22 H 18 N4O3). Example 33

[0428] Synthesis of 3-(1-oxo-5-(5-phenyl-1H-pyrazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0429] A. 3-(5-Nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of methyl 2-(bromomethyl)-4-nitrobenzoate (1.00 g, 3.65 mmol, 1.00 equiv) and 3-aminopiperidine-2,6-dione (660 mg, 4.01 mmol, 1.10 equiv, HCl) in DMF (10.0 mL) was added K2CO3 (1.51 g, 10.9 mmol, 3.00 equiv). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated to give a residue. To the resulting residue was added water (10.0 mL), and the mixture was stirred at 25 °C for 30 min. The resulting solid was filtered, washed with EtOAc (2 × 10.0 mL), and concentrated under reduced pressure to give the title compound (0.80 g, 2.77 mmol, yield 75.0%, HPLC (220 nm) purity 100%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.52 (s, 1H), 8.37 - 8.34 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 5.18 - 5.13 (m, 1H), 4.63 - 4.46 (m, 2H), 2.91 - 2.88 (m, 1H), 2.63 - 2.62 (m, 1H), 2.59 - 2.41 (m, 1H), 2.06 - 2.04 (m, 1H). (ESI + ) m / z: 290.0 (M + H) + , (C 13 H 11 N3O5).

[0430] B. 3-(5-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, Pd / C (0.30 g, 10% purity) was added to a solution of 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.80 g, 2.77 mmol, 1.00 equiv) in THF (8.00 mL) and MeOH (8.00 mL). The reaction mixture was stirred at 25 °C under H2 (15 psi) for 12 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (0.20 g, 771 μmol, 27.8% yield) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.62 (t, J = 1.0 Hz, 2H), 5.79 (s, 2H), 5.02 - 4.97 (m, 1H), 4.26 - 4.08 (m, 2H), 2.90 - 2.59 (m, 1H), 2.58 - 2.54 (m, 1H), 2.50 - 2.31 (m, 1H), 1.95 - 1.93 (m, 1H). (ESI + ) m / z: 260.1 (M+H) + , (C 13 H 13 N3O3).

[0431] C. 3-(5-Hydrazino-1-oxoisoindolin-2-yl)piperidine-2,6-dione: At 0 °C, a solution of NaNO2 (13.3 mg, 192 μmol, 1.00 equiv) in H2O (0.50 mL) was added to a solution of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50.0 mg, 192 μmol, 1.00 equiv) in concentrated HCl (1.00 mL). After 0.5 h, a solution of SnCl2·2H2O (87.0 mg, 385 μmol, 2.00 equiv) in concentrated HCl (1.00 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the title compound (0.19 g, crude) as a yellow solid. (ESI + ) m / z: 275.1 (M+H) + , (C 13 H 14 N4O3).

[0432] D. 3-(1-Oxo-5-(5-phenyl-1H-pyrazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione: A solution of 3-(5-hydrazino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (151 mg, 553 μmol, 1.20 equiv) and 3-phenylprop-2-ynal (60.0 mg, 461 μmol, 56.2 μL, 1.00 equiv) in ACN (1.00 mL) was stirred at 25 °C for 1 h. Then Cu(OAc)2 (8.37 mg, 46.1 μmol, 0.10 equiv) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC using Welch Xtimate C18 (150 mm x 25 mm 5 μm) with a gradient of 20 - 50% acetonitrile / water (containing 0.05% FA), a flow rate of 20 mL / min, and elution for 63 min to afford the title compound (13.4 mg, 32.6 μmol, yield 7.00%, HPLC (220 nm) purity 94.0%), as a yellow solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.83 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.39 - 7.37 (m, 3H), 7.29 - 7.26 (m, 3H), 6.72 (s, 1H), 5.13 - 5.08 (m, 1H), 4.48 - 4.30 (m, 2H), 2.94 - 2.84 (m, 1H), 2.65 - 2.60 (m, 1H), 2.43 - 2.36 (m, 1H), 2.04 - 1.99 (m, 1H). (ESI + ) m / z: 387.2 (M+H) + , (C 22 H 18 N4O3). Example 34

[0433] Synthesis of 3-(1-Oxo-5-(1-phenyl-1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione

[0434] A. 3-(1-Oxo-5-(1-phenyl-1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 370 μmol, 1.00 equiv), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (179 mg, 555 μmol, 1.50 equiv) and K3PO4 (235 mg, 1.11 mmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (30.9 mg, 37.0 μmol, 0.100 equiv). The mixture was stirred at 70 °C for 2 h under N2. The mixture was filtered, the liquid was collected, and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using column: Welch Xtimate C18 (150 x 25 mm x 5 μm) and gradient of 30.0%-60.0% acetonitrile / water (containing 0.05% TFA), flow rate of 25 mL / min, elution for 15 min) to give the title compound (15.7 mg, 39.5 μmol, yield 11.0%, HPLC (220 nm) purity of 97.2%), as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.68 - 8.67 (m, 1H), 8.20 - 8.16 (m, 1H), 8.15 - 8.14 (m, 1H), 8.14 - 8.13 (m, 2H), 8.00 - 7.98 (m, 1H), 7.86 - 7.84 (m, 1H), 7.41 - 7.40 (m, 1H), 7.37 - 7.23 (m, 1H), 7.22 (s, 1H), 5.20 - 5.14 (m, 1H), 4.48 - 4.46 (m, 1H), 4.45 - 4.42 (m, 1H), 2.94 - 2.92 (m, 1H), 2.58 - 2.54 (m, 1H), 2.49 - 2.48 (m, 1H), 2.11 - 2.06 (m, 1H). (ESI + ) m / z: 386.4 (M + H) + , (C 22 H 18 N4O3). Example 35

[0435] Synthesis of 3-(5-(1-Methyl-3-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0436] A. 3-(5-(1-Methyl-3-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 5-bromo-1-methyl-3-phenyl-1H-pyrazole (100 mg, 421 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (312 mg, 843 μmol, 2.00 equiv) and K3PO4 (268 mg, 1.27 mmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (35.3 mg, 42.2 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h. The mixture was filtered, the liquid was collected and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC using a column: Welch Xtimate C18 (150 x 25 mm x 5 μm) and a gradient of 27%-57.0% acetonitrile / water (containing 0.05% TFA) at a flow rate of 25 mL / min for 15 min, to give the title compound (14.4 mg, 34.4 μmol, 8.40% yield, 95.6% purity (HPLC at 220 nm)), as an off-white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.88 - 7.84 (m, 4H), 7.76 - 7.74 (m, 1H), 7.44 - 7.40 (m, 2H), 7.33 - 7.30 (m, 1H), 7.00 (s, 1H), 5.18 - 5.13 (m, 1H), 4.57 - 4.53 (m, 1H), 4.45 - 4.40 (m, 1H), 3.99 - 3.95 (m, 3H), 2.98 - 2.92 (m, 1H), 2.56 - 2.53 (m, 1H), 2.46 - 2.42 (m, 1H), 2.07 - 2.04 (m, 1H). (ESI + ) m / z: 400.4 (M+H) + , (C 23 H 20 N4O3). Example 36

[0437] Synthesis of 3-(5-(1-Methyl-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0438] A. 3-(5-(1-Methyl-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, Ru-Phos-Pd-G3 (52.9 mg, 63.2 μmol, 0.15 equiv) was added to a solution of 3-bromo-1-methyl-5-phenyl-1H-pyrazole (100 mg, 421 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (546 mg, 1.48 mmol, 3.50 equiv) and K3PO4 (268 mg, 1.27 mmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL). The mixture was stirred at 100 °C under N2 for 7 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) with a gradient of 26.0%-56.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 13 min) to give the title compound (51.3 mg, 125 μmol, yield 29.6%, HPLC (220 nm) purity 97.6%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.77 - 8.00 (m, 2H), 7.77 - 7.75 (m, 1H), 7.60 - 7.48 (m, 5H), 7.02 (s, 1H), 5.15 - 5.10 (m, 1H), 4.52 - 4.36 (m, 2H), 3.93 (s, 3H), 2.95 - 2.89 (m, 1H), 2.63 - 2.62 (m, 1H), 2.44 - 2.39 (m, 1H), 2.06 - 1.96 (m, 1H). (ESI + ) m / z: 400.9 (M+H) + , (C 23 H 20 N4O3). Example 37

[0439] Synthesis of 3-(1-oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0440] A. 3-(1-Oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: At 25 °C under N2, to a solution of 4-bromo-2-phenyloxazole (100 mg, 446 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (495 mg, 1.34 mmol, 3.00 equiv) and K3PO4 (284 mg, 1.34 mmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (37.3 mg, 44.6 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 5 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 30.0%-60.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 13 min) to give the title compound (50.4 mg, 133 μmol, yield 29.9%, HPLC (220 nm) purity 99.1%) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.89 - 8.88 (m, 1H), 8.12 - 8.02 (m, 4H), 7.83 - 7.81 (m, 1H), 7.59 - 7.58 (m, 3H), 5.16 - 5.11 (m, 1H), 4.57 - 4.39 (m, 2H), 2.96 - 2.88 (m, 1H), 2.67 - 2.66 (m, 1H), 2.33 - 2.32 (m, 1H), 2.03 - 2.01 (m, 1H). (ESI + ) m / z: 388.1 (M + H) + , (C 22 H 17 N3O4). Example 38

[0441] Synthesis of 3-(1-oxo-5-(3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0442] A. 3-(1-Oxo-5-(3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-(4-bromo-1H-pyrazol-3-yl)pyridine (100 mg, 446 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (330 mg, 892 μmol, 2.00 equiv) and K3PO4 (284 mg, 1.34 mmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) was added cataCXium A Pd G3 (65.0 mg, 89.2 μmol, 0.20 equiv). The mixture was stirred at 100 °C under N2 for 18 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 0.00%-24.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, eluting for 15 min) to give the title compound (13.8 mg, 34.1 μmol, yield 7.63%, HPLC (220 nm) purity 95.7%), as an off-white solid. 1 1H NMR: (400 MHz, DMSO) δ 13.5 - 13.4 (m, 1H), 11.0 (s, 1H), 8.67 - 8.53 (m, 2H), 8.15 - 8.10 (m, 1H), 7.71 - 7.69 (m, 1H), 7.53 (s, 1H), 7.40 - 7.39 (m, 3H), 5.13 - 5.09 (m, 1H), 4.46 - 4.29 (m, 2H), 2.49 - 2.87 (m, 1H), 2.66 - 2.62 (m, 1H), 2.41 - 2.37 (m, 1H), 2.02 - 2.01 (m, 1H). (ESI + ) m / z: 387.9 (M + H) + , (C 21 H 17 N5O3). Example 39

[0443] Synthesis of 3-(1-oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0444] A. 4-Bromo-5-phenylisoxazole: 5-Phenylisoxazole (150 mg, 1.03 mmol, 1.00 equivalent) and NBS (183 mg, 1.03 mmol, 1.00 equivalent) were dissolved in acetic acid (2.00 mL). The mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into H2O (10.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f = 0.80) to give the title compound (130 mg, 393 μmol, 79.5% yield, 88.0% purity by LCMS (220 nm)) as a pale yellow oil. 1 1H NMR: (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.06 - 8.03 (m, 2H), 7.53 - 7.27 (m, 3H). (ESI + ) m / z: 223.7 (M + H) + , (C9H6BrNO).

[0445] B. 3-(1-Oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-5-phenylisoxazole (175 mg, 781 μmol, 1.00 equivalent), 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 equivalents), and K3PO4 (497 mg, 2.34 mmol, 3.00 equivalents) in dioxane (6.00 mL) and H2O (0.30 mL) was added Ru-Phos-Pd-G3 (65.3 mg, 78.1 μmol, 0.10 equivalent). The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) and a gradient of 28.0% - 48.0% acetonitrile / water (containing 0.05% FA), flow rate 25 mL / min, elution for 10 min) to give the title compound (22.5 mg, 57.2 μmol, 7.34% yield, 98.5% purity by HPLC (220 nm)) as an off-white solid. 11H NMR: (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H), 9.01 - 8.98 (m, 1H), 7.78 - 7.70 (m, 1H), 7.60 - 7.59 (m, 1H), 7.53 - 7.50 (m, 2H), 7.45 - 7.31 (m, 4H), 5.15 - 5.10 (m, 1H), 4.51 - 4.32 (m, 2H), 2.95 - 2.88 (m, 1H), 2.69 - 2.62 (m, 1H), 2.43 - 2.38 (m, 1H), 2.03 - 2.00 (m, 1H). (ESI + ) m / z: 387.9 (M + H) + , (C 22 H 17 N3O4). Example 40

[0446] Synthesis of 3-(5-(1-Methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0447] A. 2-Bromo-1-methyl-5-phenyl-1H-imidazole: To a solution of phenylboronic acid (213 mg, 1.75 mmol, 1.40 equiv), 2,5-dibromo-1-methyl-1H-imidazole (300 mg, 1.25 mmol, 1.00 equiv) and K3PO4 (796 mg, 3.75 mmol, 3.00 equiv) in THF (10.0 mL) was added Pd(OAc)2 (28.0 mg, 125 μmol, 0.10 equiv). The mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate (3 x 15.0 mL). The combined organic layers were washed with brine (3 × 15.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f = 0.30) to give the title compound (75.0 mg, 309 μmol, yield 24.7%, LCMS (220 nm) purity 97.7%) as a pale yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 7.46 - 7.27 (m, 5H), 7.05 (s, 1H), 3.63 - 3.56 (m, 3H). (ESI + ) m / z: 236.8 (M + H) + , (C 10 H9BrN2).

[0448] B. 3-(5-(1-Methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 2-bromo-1-methyl-5-phenyl-1H-imidazole (65.0 mg, 274 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (253 mg, 685 μmol, 2.50 equiv) and K3PO4 (174 mg, 822 μmol, 3.00 equiv) in dioxane (4.00 mL) and H2O (0.20 mL) was added Ru-Phos-Pd-G3 (22.9 mg, 27.4 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) with a gradient of 0.00%-30.0% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 10 min) to give the title compound (7.85 mg, 18.6 μmol, yield 6.79%, HPLC (220 nm) purity 95.0%) as an off-white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.13 - 8.12 (m, 1H), 7.97 - 7.84 (m, 2H), 7.57 - 7.56 (m, 2H), 7.53 - 7.50 (m, 2H), 7.44 - 7.42 (m, 1H), 7.23 (s, 1H), 5.18 - 5.13 (m, 1H), 4.58 - 4.41 (m, 2H), 3.73 (s, 3H), 2.96 - 2.93 (m, 1H), 2.64 - 2.59 (m, 1H), 2.44 - 2.41 (m, 1H), 2.05 - 2.02 (m, 1H). (ESI + ) m / z: 401.1 (M + H) + , (C 23 H 20 N4O3). Example 41

[0449] Synthesis of 3-(5-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0450] A. 1-Methyl-4-phenyl-1H-imidazole: At 20 °C, MeI (3.94 g, 27.7 mmol, 1.73 mL, 2.00 eq) was added to a solution of 4-phenyl-1H-imidazole (2.00 g, 13.8 mmol, 1.00 eq) and Cs2CO3 (6.78 g, 20.8 mmol, 1.50 eq) in DMF (30.0 mL). The mixture was stirred at 25 °C under N2 for 8 h. The mixture was poured into H2O (70.0 mL) and extracted with ethyl acetate (3 x 40.0 mL). The organic layer was washed with saturated aqueous NaCl solution (3 x 30.0 mL), dried over Na2SO4, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (dichloromethane:methanol = 10:1, R f = 0.30) to give the title compound (270 mg, 1.69 mmol, yield 12.3%, purity by LCMS (220 nm) 99.1%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6): δ 7.73 - 7.71 (m, 2H), 7.61 - 7.59 (m, 1H), 7.58 - 7.52 (m, 1H), 7.35 - 7.31 (m, 2H), 7.19 - 7.15 (m, 1H), 3.67 (s, 3H). (ESI + ) m / z: 159.0 (M + H) + , (C 10 H 10 N2).

[0451] B. 2-Iodo-1-methyl-4-phenyl-1H-imidazole: At -70 °C under a N2 atmosphere, n-BuLi (2.50 M, 758 μL, 2.00 eq) was added to a solution of 1-methyl-4-phenyl-1H-imidazole (150 mg, 948 μmol, 1.00 eq) in THF (1.00 mL). The mixture was stirred at -70 °C for 1 h. Then a solution of I2 (481 mg, 1.90 mmol, 382 μL, 2.00 eq) in THF (3.00 mL) was added via syringe, keeping the reaction temperature below -50 °C. Then the reaction temperature was raised to 0 °C and stirred under a N2 atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (30.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with Na2SO3 (10.0%, 3 x 30.0 mL), dried over Na2SO4, filtered, the liquid was collected, and the filtrate was concentrated under reduced pressure to give the title compound (188 mg, 633 μmol, yield 66.7%, purity by LCMS (220 nm) 95.7%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.68 - 7.66 (m, 2H), 7.36 - 7.32 (m, 2H), 7.21 - 7.17 (m, 1H), 3.60 (s, 3H). (ESI + ) m / z: 284.8 (M + H) + , (C 10 H9IN2).

[0452] C. 3-(5-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 2-iodo-1-methyl-4-phenyl-1H-imidazole (150 mg, 528 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (489 mg, 1.32 mmol, 2.50 equiv) and K3PO4 (336 mg, 1.58 mmol, 3.00 equiv) in dioxane (2.50 mL) and H2O (0.12 mL) was added Ru-Phos-Pd-G3 (44.2 mg, 52.8 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 3 h under N2. Then the reaction mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give a residue, and the obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) and a gradient of 4 - 34% acetonitrile / water (containing 0.5% TFA), flow rate 25 mL / min, eluting for 15 min) to give the title compound (37.4 mg, 91.9 μmol, yield 17.4%, HPLC (220 nm) purity 98.4%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 8.08 - 7.99 (m, 2H), 7.98 - 7.94 (m, 2H), 7.84 - 7.82 (m, 2H), 7.50 - 7.46 (m, 2H), 7.38 - 7.36 (m, 1H), 5.20 - 5.15 (m, 1H), 4.61 - 4.55 (m, 1H), 4.49 - 4.44 (m, 1H), 3.88 (s, 3H), 2.97 - 2.89 (m, 1H), 2.61 - 2.60 (m, 1H), 2.44 - 2.43 (m, 1H), 2.07 - 2.04 (m, 1H). (ESI + ) m / z: 401.0 (M + H) + , (C 23 H 20N4O3). Example 42

[0453] Synthesis of 3-(1-oxo-5-(4-phenyloxazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0454] A. 4-Phenyloxazole: A mixture of 2-bromo-1-phenylethanone (10.0 g, 50.2 mmol, 1.00 equiv) and HCOONH4 (11.0 g, 175 mmol, 3.50 equiv) in HCOOH (50.0 mL) was stirred at 100 °C for 5 h. After completion of the reaction, the reaction mixture was diluted with 100 mL of water and then basified to pH = 9 with saturated Na2CO3 solution. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 100:1 to 5:1, R f = 0.60 (petroleum ether:EtOAc = 5:1)) to give the title compound (2.00 g, 12.9 mmol, yield 25.7%, purity by LCMS (220 nm) 93.7%) as a yellow oil. (ESI + ) m / z: 146.3 (M+H) + , (C9H7NO).

[0455] B. 2-Bromo-4-phenyloxazole: At -78 °C under N2, n-BuLi (2.50 M, 568 μL, 1.10 equiv) was added dropwise to a solution of 4-phenyloxazole (200 mg, 1.29 mmol, 1.00 equiv) in THF (2.00 mL). The reaction mixture was stirred for an additional 0.5 h and then 1,2-dibromo-1,1,2,2-tetrafluoroethane (352 mg, 1.36 mmol, 1.05 equiv) was added dropwise at -78 °C. Then the reaction mixture was stirred at 25 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with 10.0 mL of saturated NH4Cl solution at 0 °C under N2. Then the mixture was extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by preparative TLC (SiO2, petroleum ether:EtOAc = 5:1, R f = 0.80) to give the title compound (150 mg, 669 μmol, yield 51.8%, purity by LCMS (220 nm) 100%) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.76 - 7.72 (m, 2H), 7.47 - 7.42 (m, 2H), 7.39 - 7.34 (m, 1H). (ESI + ) m / z: 223.8 (M + H) + , (C9H6BrNO).

[0456] C. 3-(1-Oxo-5-(4-phenyloxazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-bromo-4-phenyloxazole (120 mg, 535 μmol, 1.00 equiv) and 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (396 mg, 1.07 mmol, 2.00 equiv) in dioxane (6.00 mL) and H2O (0.30 mL) was added Ru-Phos-Pd-G3 (44.7 mg, 53.5 μmol, 0.10 equiv) and K3PO4 (341 mg, 1.61 mmol, 3.00 equiv). The mixture was stirred at 100 °C under N2 for 2 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and gradient of 32 - 62% acetonitrile / water (containing 0.5% FA), flow rate of 25 mL / min, elution for 8 min) to give the title compound (16.2 mg, 41.8 μmol, yield 7.81%, HPLC (220 nm) purity 100%) as a gray solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.82 (s, 1H), 8.31 (s, 1H), 8.21 (dd, J = 7.6, 0.8 Hz, 1H), 7.93 - 7.88 (m, 3H), 7.51 - 7.46 (m, 2H), 7.41 - 7.35 (m, 1H), 5.16 (dd, J = 13.2, 5.2 Hz, 1H), 4.52 (dd, J = 48.8, 17.6 Hz, 2H), 2.97 - 2.88 (m, 1H), 2.64 - 2.60 (m, 1H), 2.45 - 2.38 (m, 1H), 2.09 - 2.01 (m, 1H). (ESI + ) m / z: 388.0 (M + H) + , (C 22 H 17 N3O4). Example 43

[0457] Synthesis of 3-(1-oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0458] A. (2,2-Dibromocyclopropyl)benzene: At 40 °C under N2, TEBA (349 mg, 1.54 mmol, 0.032 equiv) and KOH (4.04 g, 72.0 mmol, 1.50 equiv) were added to a solution of styrene (5.00 g, 48.0 mmol, 1.00 equiv) in DCM (25.0 mL). At 40 °C under N2, CHBr3 (15.5 g, 61.4 mmol, 5.38 mL, 1.28 equiv) was added to the mixture over 2 h. The mixture was stirred at 25 °C under N2 for 20 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by column chromatography (SiO2, ethyl acetate:petroleum ether = 0:1, R f = 0.50 (ethyl acetate:petroleum ether = 0:1)) to give the title compound (5.00 g, 18.1 mmol, yield 37.7%) as a yellow oil. 1 1H NMR: (400 MHz, DMSO-d6) δ 7.38 - 7.32 (m, 3H), 7.26 (d, J = 6.4 Hz, 2H), 2.96 (t, J = 8.8 Hz, 1H), 2.13 (t, J = 7.6 Hz, 1H), 2.01 (t, J = 8.0 Hz, 1H). (ESI + ) m / z: 274.9 (M + H) + , (C9H8Br2).

[0459] B. 5-Bromo-3-phenylisoxazole: At 25 °C under N2, a solution of (2,2-dibromocyclopropyl)benzene (5.00 g, 18.1 mmol, 1.00 equiv) in anhydrous ACN (10.0 mL) was added dropwise to a solution of nitridooxonium tetrafluoroborate (2.54 g, 21.7 mmol, 1.20 equiv) in anhydrous ACN (15.0 mL). Then the reaction mixture was stirred at 25 °C for 5 h. After completion of the reaction, the reaction mixture was quenched with 30.0 mL of water and then extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a crude product. The obtained crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 10:1, R fPurified with petroleum ether:ethyl acetate = 10:1 (0.20), the title compound (500 mg, 1.94 mmol, yield 12.3%, purity by LCMS (220 nm) 86.9%) was obtained as a yellow oil. 1 H NMR: (400 MHz, DMSO-d6) δ 7.88 - 7.84 (m, 2H), 7.56 - 7.51 (m, 3H), 7.39 (s, 1H). (ESI + ) m / z: 223.9 (M + H) + , (C9H6BrNO).

[0460] C. 3-(1-Oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 5-bromo-3-phenyl-isoxazole (100 mg, 446 μmol, 1.00 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) were added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (330 mg, 892 μmol, 2.00 equiv), K3PO4 (189 mg, 892 μmol, 2.00 equiv) and Ru-Phos-Pd-G3 (37.3 mg, 44.6 μmol, 0.10 equiv). The reaction mixture was stirred at 80 °C for 2 h under N2. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 5 - 35% acetonitrile / water (containing 0.5% TFA), flow rate 25 mL / min, elution for 10 min), and the title compound (19.8 mg, 50.5 μmol, yield 11.3%, purity by HPLC (220 nm) 98.8%) was obtained as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.96 - 7.91 (m, 3H), 7.80 (s, 1H), 7.61 - 7.54 (m, 3H), 5.16 (dd, J = 13.2, 4.8 Hz, 1H), 4.53 (dd, J = 52.4, 17.6 Hz, 2H), 2.98 - 2.88 (m, 1H), 2.67 (s, 1H), 2.33 (s, 1H), 2.07 (s, 1H). (ESI + ) m / z: 388.1 (M + H) + , (C 22 H17 N3O4). Example 44

[0461] Synthesis of 3-(5-(2-Cyclopropyl-1-methyl-5-(pyridin-3-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0462] A. 3-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: Under N2, 3-bromopyridine (2.33 g, 14.7 mmol, 1.42 mL, 3.00 equivalents) and Pd(OAc)2 (221 mg, 982 μmol, 0.20 equivalents) were added to a solution of 2-cyclopropyl-1-methyl-imidazole (600 mg, 4.91 mmol, 1.00 equivalent), PCy3 (138 mg, 491 μmol, 159 μL, 0.10 equivalent), and NaOtBu (1.42 g, 14.7 mmol, 3.00 equivalents) in o-xylene (30.0 mL). The mixture was stirred at 130 °C for 12 h under N2. Then the mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (using Welch Ultimate XB-SiOH (250x50x10 μm) with a gradient of 15 - 45% EtOH + MeOH / water, a flow rate of 25 mL / min, and elution for 25 min) to give the title compound (360 mg, 1.79 mmol, yield 39.6%, purity by LCMS (220 nm) 99.1%) as a yellow oil. 1 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.55 - 8.53 (m, 1H), 7.89 - 7.86 (m, 1H), 7.48 - 7.45 (m, 1H), 6.95 (s, 1H), 3.66 (s, 3H), 2.06 - 1.99 (m, 1H), 0.948 - 0.942 (m, 2H), 0.87 - 0.85 (m, 2H). (ESI + ) m / z: 200.0 (M + H) + , (C 12 H 13 N3).

[0463] B. 3-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: At 0 °C, NBS (354 mg, 1.99 mmol, 1.10 equiv) was added to a solution of 3-(2-cyclopropyl-3-methyl-imidazol-4-yl)pyridine (360 mg, 1.81 mmol, 1.00 equiv) in ACN (4.50 mL). The mixture was then stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (30.0 mL) and extracted with DCM (3 x 20.0 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 15.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 0 / 1, R f = 0.25) to afford the title compound (450 mg, 1.61 mmol, 89.0% yield, 99.4% purity by LCMS (220 nm)), as a yellow oil. 1 1H NMR (400 MHz, DMSO-d6): δ 8.64 - 8.61 (m, 2H), 7.90 - 7.87 (m, 1H), 7.55 - 7.52 (m, 1H), 3.58 (s, 3H), 2.10 - 2.04 (m, 1H), 0.98 - 0.95 (m, 2H), 0.89 - 0.88 (m, 2H). (ESI + ) m / z: 278.0 (M + H) + , (C 12 H 12 BrN3).

[0464] C. 3-(5-(2-Cyclopropyl-1-methyl-5-(pyridin-3-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 3-(4-bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine (300 mg, 1.08 mmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (799 mg, 2.16 mmol, 2.00 equiv) and K3PO4 (458 mg, 2.16 mmol, 2.00 equiv) in dioxane (6.00 mL) and H2O (0.30 mL) was added Ru-Phos-Pd-G3, K3PO4 (180 mg, 216 μmol, 0.20 equiv). The mixture was stirred at 100 °C for 2.5 h under N2. Then the mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) with a gradient of 0 - 21% acetonitrile / water (containing 0.05% FA), a flow rate of 25 mL / min, and elution for 15 min) to give the title compound (113 mg, 255 μmol, yield 23.6%, HPLC (220 nm) purity 100%), as a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 8.68 - 8.67 (m, 1H), 8.57 - 8.56 (m, 1H), 7.87 - 7.85 (m, 1H), 7.56 - 7.53 (m, 3H), 7.35 - 7.33 (m, 1H), 5.09 - 5.04 (m, 1H), 4.37 - 4.32 (m, 1H), 4.25 - 4.18 (m, 1H), 3.49 (s, 3H), 2.90 - 2.89 (m, 1H), 2.86 - 2.56 (m, 1H), 2.36 - 2.32 (m, 1H), 2.11 - 2.08 (m, 1H), 1.97 - 1.96 (m, 1H), 1.02 - 0.98 (m, 4H). (ESI + ) m / z: 442.0 (M + H) + , (C 25 H 23 N5O3). Example 45

[0465] Synthesis of 3-(5-(2-Cyclopropyl-1-methyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0466] A. 4-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: Under N2, to a solution of 2-cyclopropyl-1-methyl-imidazole (600 mg, 4.91 mmol, 1.00 equivalent), PCy3 (138 mg, 491 μmol, 159 μL, 0.10 equivalent) and NaOtBu (1.42 g, 14.7 mmol, 3.00 equivalents) in o-xylene (30.0 mL) was added 4-bromopyridine (2.33 g, 14.7 mmol, 3.00 equivalents) and Pd(OAc)2 (221 mg, 982 μmol, 0.20 equivalent). The mixture was stirred at 130 °C under N2 for 12 h. The mixture was filtered, the liquid was collected, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, DCM:MeOH = 10:1, R f = 0.35) to give the title compound (856 mg, 3.83 mmol, yield 78.0%, purity by LCMS (220 nm) 89.2%) as a yellow oil. 1 1H NMR (400 MHz, DMSO-d6): δ 8.58 - 8.56 (m, 2H), 7.47 - 7.46 (m, 2H), 7.11 (s, 1H), 3.74 (s, 3H), 2.07 - 2.02 (m, 1H), 0.95 - 0.93 (m, 2H), 0.86 - 0.84 (m, 2H). (ESI + ) m / z: 200.0 (M+H) + , (C 12 H 13 N3).

[0467] B. 4-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: 4-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine (300 mg, 1.43 mmol, 1.00 equivalent) was dissolved in MeOH (3.0 mL), and then NBS (255 mg, 1.43 mmol, 1.00 equivalent) was added to the reaction mixture. The mixture was stirred at 25 °C for 8 h. The reaction mixture was poured into H2O (30.0 mL) and extracted with DCM (3 x 20.0 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 15.0 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a residue. Then the obtained residue was purified by preparative TLC (petroleum ether / ethyl acetate = 0 / 1, R f = 0.25) to give the title compound (450 mg, 1.61 mmol, yield 72.8%, purity by LCMS (220 nm) 99.4%) as a yellow oil. 11H NMR (400 MHz, DMSO-d6): δ 8.64 - 8.61 (m, 2H), 7.90 - 7.87 (m, 1H), 7.55 - 7.52 (m, 1H), 3.58 (s, 3H), 2.10 - 2.04 (m, 1H), 0.97 - 0.95 (m, 2H), 0.89 - 0.88 (m, 2H). (ESI + ) m / z: 278.0 (M + H) + , (C 12 H 12 BrN3).

[0468] C. 3-(5-(2-Cyclopropyl-1-methyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-(4-bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine (270 mg, 970 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (719 mg, 1.94 mmol, 2.00 equiv) and K3PO4 (412 mg, 1.94 mmol, 2.00 equiv) in dioxane (5.40 mL) and H2O (0.27 mL) was added Ru-Phos-Pd-G3 (162 mg, 194 μmol, 0.20 equiv). The mixture was stirred at 100 °C for 2 h under N2. Then the mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) and gradient of 0 - 21% acetonitrile / water (containing 0.05% FA), flow rate of 25 mL / min, elution for 15 min) to give the title compound (242 mg, 548 μmol, yield 56.5%, 100% purity (HPLC 220 nm)), as a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 8.68 - 8.64 (m, 2H), 7.57 - 7.44 (m, 2H), 7.41 - 7.35 (m, 3H), 5.09 - 5.04 (m, 1H), 4.38 - 4.17 (m, 2H), 3.54 (s, 3H), 2.90 - 2.60 (m, 1H), 2.37 - 2.36 (m, 1H), 2.12 - 2.10 (m, 1H), 2.33 - 2.32 (m, 1H), 2.08 - 1.97 (m, 1H), 1.06 - 0.98 (m, 4H). (ESI +)m / z: 442.0 (M+H) + , (C 25 H 23 N5O3). Example 46

[0469] Synthesis of 3-(5-(2-Cyclopropyl-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0470] A. 4-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-pyrazole: Under N2, to a solution of 2-cyclopropyl-1-methyl-imidazole (0.30 g, 2.46 mmol, 1.00 equiv) and 4-bromo-1-methyl-pyrazole (1.19 g, 7.37 mmol, 3.00 equiv) in o-xylene (15.0 mL) were added PCy3 (68.8 mg, 245 μmol, 79.6 μL, 0.10 equiv), Pd(OAc)2 (27.5 mg, 122 μmol, 0.05 equiv) and tBuONa (707 mg, 7.37 mmol, 3.00 equiv). The reaction mixture was stirred at 130 °C for 12 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 to 20:1; TLC, dichloromethane:methanol = 20:1, R f = 0.60) to afford the title compound (0.40 g, 1.98 mmol, 80.5% yield) as a colorless oil. (ESI + )m / z: 203.1 (M+H) + , (C 11 H 14 N4).

[0471] B. 4-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-pyrazole: At 0 °C, to a solution of 2-cyclopropyl-1-methyl-5-(1-methylpyrazol-4-yl)imidazole (0.30 g, 1.48 mmol, 1.00 equiv) in ACN (2.00 mL) was added a solution of NBS (158 mg, 889 μmol, 0.60 equiv) in ACN (1.00 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 20:1, R f= 0.40) Purification gave the title compound (120 mg, 426 μmol, yield 28.7%) as a yellow oil. (ESI + ) m / z: 281.0 (M+H) + , (C 11 H 13 BrN4).

[0472] C. 3-(5-(2-Cyclopropyl-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-2-cyclopropyl-1-methyl-5-(1-methylpyrazol-4-yl)imidazole (120 mg, 426 μmol, 1.00 equiv) and 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (189 mg, 512 μmol, 1.20 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) was added K3PO4 (181 mg, 853 μmol, 2.00 equiv) and Ru-Phos-Pd-G3 (35.7 mg, 42.6 μmol, 0.10 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex Luna (200 mm x 40 mm x 10 μm) with a gradient of 1 - 25% acetonitrile / water (containing 0.05% TFA), flow rate 25 mL / min, elution for 10 min) to give the title compound (40.3 mg, 86.4 μmol, yield 20.2%, HPLC (220 nm) purity 95.3%) as an off-white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.03 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 5.14 - 5.09 (m, 1H), 4.47 - 4.30 (m, 2H), 3.90 (s, 3H), 3.66 (s, 3H), 2.96 - 2.88 (m, 1H), 2.62 - 2.50 (m, 1H), 2.41 - 2.32 (m, 2H), 2.05 - 2.02 (m, 1H), 1.32 - 1.22 (m, 4H). (ESI + ) m / z: 445.0 (M+H) + , (C 24 H 24 N6O3). Example 47

[0473] Synthesis of 3-(5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0474] A. 3-(5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-3-cyclopropyl-1H-pyrazole (100 mg, 534 μmol, 1.00 equiv) in dioxane (5.00 mL) and H2O (0.20 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (395 mg, 1.07 mmol, 2.00 equiv), Ru-Phos-Pd-G3 (151 mg, 213 μmol, 151 μL, 0.40 equiv) and K3PO4 (340 mg, 1.60 mmol, 3.00 equiv). The mixture was stirred at 100 °C for 2 h under N2. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The obtained residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f = 0:1, R f = 0.40) and preparative HPLC (using Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and gradient of 10 - 40% acetonitrile / water (containing 0.1% TFA), flow rate 25 mL / min, elution for 15 min) to give the title compound (12.6 mg, 35.3 μmol, yield 3.36%, HPLC (220 nm) purity 98.3%), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.37 (t, J = 8.4 Hz, 2H), 5.12 (dd, J = 9.2, 4.8 Hz, 1H), 4.41 (dd, J = 53.2, 16.8 Hz, 2H), 2.98 - 2.92 (m, 1H), 2.62 (s, 1H), 2.44 - 2.39 (m, 1H), 2.06 - 2.00 (m, 2H), 0.96 (d, J = 6.8 Hz, 2H), 0.82 (s, 2H). (ESI + ) m / z: 351.1 (M + H) + , (C 19 H 18N4O3). Example 48

[0475] Synthesis of 3-(5-(1-Cyclohexyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0476] A. tert-Butyl 5-amino-4-(5-(1-cyclohexyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg, 1.01 mmol, 1.00 equiv) and 1-cyclohexyl-1H-imidazole (212 mg, 1.41 mmol, 1.40 equiv) in dioxane (16.0 mL) were added CuI (384 mg, 2.01 mmol, 2.00 equiv), PPh3 (26.4 mg, 101 μmol, 0.10 equiv), and DBU (307 mg, 2.01 mmol, 304 μL, 2.00 equiv). Then, under N2, Pd(OAc)2 (56.5 mg, 252 μmol, 0.25 equiv) was added to the mixture. The mixture was then stirred at 140 °C for 18 h. The reaction mixture was concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100 / 1 to 15 / 1, TLC: dichloromethane:methanol = 10 / 1, R f = 0.40) to afford the title compound (220 mg, 380 μmol, 37.7% yield, purity by LCMS (220 nm) 80.6%) as a yellow solid. (ESI + ) m / z: 467.1 (M+H) + , (C 26 H 34 N4O4).

[0477] B. 3-(5-(1-Cyclohexyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Dissolve tert-butyl 5-amino-4-(5-(1-cyclohexyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (220 mg, 380 μmol, 1.00 eq) and TsOH (131 mg, 760 μmol, 2.00 eq) in ACN (5.00 mL). Then the mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) with a gradient of 10.0%-40.0% acetonitrile / water (containing 0.50% TFA), a flow rate of 25 mL / min, and elution for 15 min) to give the title compound (47.6 mg, 121 μmol, yield 22.7%, HPLC (220 nm) purity 100%), as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.14 (s, 1H), 8.12 - 8.00 (m, 2H), 7.91 - 7.83 (m, 2H), 5.21 - 5.16 (m, 1H), 4.63 - 4.46 (m, 2H), 4.18 - 4.12 (m, 1H), 2.94 - 2.92 (m, 1H), 2.69 - 2.65 (m, 1H), 2.43 - 2.40 (m, 1H), 2.04 - 1.99 (m, 3H), 1.84 - 1.77 (m, 4H), 1.68 - 1.66 (m, 1H), 1.33 - 1.19 (m, 3H). (ESI + ) m / z: 393.2 (M + H) + , (C 22 H 24 N4O3). Example 49

[0478] Synthesis of 3-(5-(2-Cyclohexyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0479] A. N-(2,2-Dimethoxyethyl)-N-methylcyclohexanecarboxamidine: 2,2-Dimethoxy-N-methyl-ethylamine (3.00 g, 25.1 mmol, 3.24 mL, 1.00 equiv) was charged into a round-bottom flask, and then cyclohexanecarbonitrile (3.44 g, 31.4 mmol, 3.74 mL, 1.25 equiv) and CuCl (3.12 g, 31.4 mmol, 1.25 equiv) were added. The reaction mixture was stirred at 85 °C for 12 h to give the title compound (3.00 g, crude), as a brown oil. (ESI + ) m / z: 229.1 (M+H) + , (C 12 H 24 N2O2).

[0480] B. 2-Cyclohexyl-1-methyl-1H-imidazole: Concentrated HCl (3.00 mL, 2.74 equiv) was added to a solution of N-(2,2-dimethoxyethyl)-N-methyl-cyclohexanecarboxamidine (3.00 g, 13.1 mmol, 1.00 equiv) in MeOH (15.0 mL). The reaction mixture was concentrated in vacuo to give a residue. At 0 °C, 50% aqueous NaOH solution (5.00 g) was added to the reaction mixture, and then TMBE (30.0 mL) was added. The mixture was stirred at 20 °C for 5 min. The reaction mixture was filtered to give a solid, and the obtained solid was washed with TMBE (2 x 15.0 mL) and dried in vacuo. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 to 20:1, R f = 0.20) to give the title compound (120 mg, 730 μmol, yield 5.56%), as a yellow oil. 1 1H NMR: (400 MHz, CDCl3) δ 6.92 (s, 1H), 6.74 (s, 1H), 3.58 (s, 3H), 2.65 - 2.60 (m, 1H), 1.89 - 1.85 (m, 3H), 1.74 - 1.70 (m, 1H), 1.66 - 1.63 (m, 2H), 1.37 - 1.32 (m, 4H). (ESI + ) m / z: 165.1 (M+H) + , (C 10 H 16 N2).

[0481] C. 2-Cyclohexyl-1-methyl-5-phenyl-1H-imidazole: Under N2, Pd(OAc)2 (16.4 mg, 73.0 μmol, 0.10 equiv), tris(2-furyl)phosphine (P(oxole)3) (33.9 mg, 146 μmol, 0.20 equiv), and K2CO3 (201 mg, 1.46 mmol, 2.00 equiv) were added to a solution of 2-cyclohexyl-1-methyl-imidazole (120 mg, 730 μmol, 1.00 equiv) and bromobenzene (344 mg, 2.19 mmol, 230 μL, 3.00 equiv) in DMF (1.00 mL). The reaction mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 20:1, R f = 0.25) to afford the title compound (55.0 mg, 228 μmol, 31.3% yield) as a yellow solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 7.47 - 7.42 (m, 4H), 7.38 - 7.34 (m, 1H), 6.89 (s, 1H), 3.55 (s, 3H), 2.80 - 2.74 (m, 1H), 1.88 - 1.81 (m, 2H), 1.80 - 1.78 (m, 2H), 1.65 - 1.60 (m, 1H), 1.55 - 1.51 (m, 2H), 1.50 - 1.41 (m, 2H), 1.38 - 1.26 (m, 1H). (ESI + ) m / z: 201.1 (M+H) + , (C 16 H 20 N2).

[0482] D. 4-Bromo-2-cyclohexyl-1-methyl-5-phenyl-1H-imidazole: A solution of NBS (42.7 mg, 240 μmol, 1.05 equiv) in ACN (1.00 mL) was added to a reaction mixture of 2-cyclohexyl-1-methyl-5-phenyl-imidazole (55.0 mg, 228 μmol, 1.00 equiv) in ACN (1.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (5.00 mL), extracted with EtOAc (3 x 5.00 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The resulting residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 20:1; TLC, dichloromethane:methanol = 20:1, R f = 0.50) to afford the title compound (52.0 mg, 162 μmol, 71.1% yield) as a colorless oil. 11H NMR: (400 MHz, DMSO-d6) δ 7.51 - 7.47 (m, 2H), 7.44 - 7.41 (m, 3H), 3.46 (s, 3H), 2.82 - 2.75 (m, 1H), 1.87 - 1.67 (m, 5H), 1.51 - 1.47 (m, 2H), 1.38 - 1.36 (m, 2H), 1.35 - 1.24 (m, 1H). (ESI + ) m / z: 319.0 (M + H) + , (C 16 H 19 BrN2).

[0483] E. 3-(5-(2-Cyclohexyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-2-cyclohexyl-1-methyl-5-phenyl-imidazole (50.0 mg, 156 μmol, 1.00 equiv), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (86.9 mg, 234 μmol, 1.50 equiv) in dioxane (1.00 mL) and H2O (0.05 mL) was added Ru-Phos-Pd-G3 (13.1 mg, 15.6 μmol, 0.10 equiv), K3PO4 (66.4 mg, 313 μmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 10 - 40% acetonitrile / water (TFA), flow rate of 25 mL / min, elution for 10 min) to give the title compound (30.3 mg, 62.7 μmol, yield 40.0%, HPLC (220 nm) purity 100%), as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.68 (s, 1H), 7.58 - 7.55 (m, 4H), 7.50 - 7.45 (m, 2H), 7.44 - 7.41 (m, 1H), 5.11 - 5.07 (m, 1H), 4.41 - 4.24 (m, 2H), 3.57 (s, 3H), 2.90 - 2.60 (m, 1H), 2.59 - 2.50 (m, 1H), 2.43 - 2.38 (m, 2H), 2.03 - 2.00 (m, 3H), 1.98 - 1.87 (m, 2H), 1.87 - 1.72 (m, 3H), 1.72 - 1.47 (m, 2H), 1.45 - 1.30 (m, 1H). (ESI + ) m / z: 483.2 (M + H) + , (C 29 H 30 N4O3). Example 50

[0484] Synthesis of 3-(5-(1-Methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0485] A. N-(2,2-Dimethoxyethyl)-N-methylcyclohexanecarboxamidine: 2,2-Dimethoxy-N-methylethan-1-amine (3.00 g, 25.1 mmol, 3.24 mL, 1.00 equiv) was charged into a round-bottom flask, and then tetrahydro-2H-pyran-4-carbonitrile (3.50 g, 31.4 mmol, 1.25 equiv) and CuCl (3.12 g, 31.4 mmol, 1.25 equiv) were added. The reaction mixture was stirred at 85 °C for 12 h to give the title compound (3.00 g, crude), as a brown oil. (ESI + ) m / z: 229.1 (M + H) + , (C 11 H 22 N2O3).

[0486] B. 1-Methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of N-(2,2-dimethoxyethyl)-N-methylcyclohexanecarboxamidine (3.00 g, 13.1 mmol, 1.00 equiv) in MeOH (15.0 mL) was added concentrated HCl (3.00 mL, 2.74 equiv). The reaction mixture was concentrated in vacuo to give a residue. At 0 °C, 50% aqueous NaOH solution (5.00 g) was added to the reaction mixture, followed by TMBE (30.0 mL), and the mixture was stirred at 20 °C for 5 minutes. The reaction mixture was filtered to give a solid, and the resulting solid was washed with TMBE (2 x 15.0 mL) and dried in vacuo. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 to 20:1; TLC, dichloromethane:methanol = 20:1, R f = 0.25) to give the title compound (400 mg, 2.41 mmol, 18.4% yield) as a yellow oil. 1 1H NMR: (400 MHz, CDCl3) δ 6.95 (s, 1H), 6.78 (s, 1H), 4.10 - 4.07 (m, 2H), 3.62 (s, 3H), 3.56 - 2.50 (m, 2H), 2.90 - 2.86 (m, 1H), 2.09 - 2.02 (m, 2H), 1.80 - 1.77 (m, 2H). (ESI + ) m / z: 167.1 (M+H) + , (C9H 14 N2O).

[0487] C. 1-Methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: Under N2, to a solution of 1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (400 mg, 2.41 mmol, 1.00 equiv) and bromobenzene (1.13 g, 7.22 mmol, 3.00 equiv) in DMF (4.00 mL) were added Pd(OAc)2 (54.3 mg, 240 μmol, 0.10 equiv), tris(2-furyl)phosphine (P(oxole)3) (111 mg, 481 μmol, 0.20 equiv) and K2CO3 (665 mg, 4.81 mmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 12 hours under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 to 80:1; TLC, dichloromethane:methanol = 20:1, R f = 0.40) to give the title compound (200 mg, 825 μmol, 34.3% yield) as a yellow solid. 11H NMR: (400 MHz, DMSO-d6) δ 7.48 - 7.42 (m, 4H), 6.91 (s, 1H), 3.96 - 3.92 (m, 2H), 3.58 (s, 3H), 3.51 - 3.45 (m, 2H), 3.07 - 3.04 (m, 1H), 1.81 - 1.76 (m, 4H). (ESI + ) m / z: 243.6 (M + H) + , (C 15 H 18 N2O).

[0488] D. 4-Bromo-1-methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: At 0 °C, a solution of NBS (115 mg, 649 μmol, 1.05 equiv) in ACN (1.00 mL) was added to a reaction mixture of 1-methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (150 mg, 619 μmol, 1.00 equiv) in ACN (1.00 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (5.00 mL), extracted with EtOAc (3 x 5.00 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The resulting residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 20:1; TLC, dichloromethane:methanol = 20:1, R f = 0.50) to afford the title compound (150 mg, 466 μmol, 75.4% yield) as a colorless oil. 1 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) + , (C 15 H 17 BrN2O).

[0489] E. 3-(5-(1-Methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-1-methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (150 mg, 466 μmol, 1.00 equiv), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (259 mg, 700 μmol, 1.50 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (39.1 mg, 46.6 μmol, 0.10 equiv), K3PO4 (198 mg, 933 μmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The obtained residue was purified by preparative HPLC (using Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and gradient of 10 - 40% acetonitrile / water (TFA), flow rate of 25 mL / min, elution for 10 min) to give the title compound (88.2 mg, 182 μmol, yield 39.0%, HPLC (220 nm) purity 100%) as a white solid. 1 1H NMR: (400 MHz, MeOD) δ 7.79 (d, J = 8.0 Hz, 1H), 7.59 - 7.56 (m, 4H), 7.54 - 7.52 (m, 1H), 7.46 - 7.44 (m, 2H), 5.17 - 5.12 (m, 1H), 4.45 - 4.43 (m, 2H), 4.14 - 4.11 (m, 2H), 3.72 (s, 3H), 3.69 - 3.63 (m, 3H), 2.86 - 2.78 (m, 2H), 2.14 - 2.10 (m, 1H), 2.08 - 2.00 (m, 5H). (ESI + ) m / z: 485.2 (M + H) + , (C 28 H 28 N4O4). Example 51

[0490] Synthesis of 3-(5-(2-Ethyl-5-phenyl-2H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0491] A. 4-Iodo-5-phenyl-2H-1,2,3-triazole: At 0 °C, NIS (1.21 g, 5.37 mmol, 1.30 equiv) was added to a solution of 4-phenyl-2H-1,2,3-triazole (600 mg, 4.13 mmol, 1.00 equiv) in MeCN (20.0 mL). The mixture was stirred at 50 °C for 72 h. The reaction mixture was poured into H2O (25.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (3 x 20.0 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, dichloromethane:methanol = 15:1, TLC: dichloromethane:methanol = 15:1, R f = 0.40) to afford the title compound (500 mg, 1.82 mmol, 44.0% yield, 98.7% purity by LCMS (220 nm)) as a pale yellow solid. (ESI + ) m / z: 271.7 (M+H) + , (C8H6IN3).

[0492] B. 2-Ethyl-4-iodo-5-phenyl-2H-1,2,3-triazole: 4-Iodo-5-phenyl-2H-1,2,3-triazole (440 mg, 1.62 mmol, 1.00 equiv), K2CO3 (112 mg, 811 μmol, 0.50 equiv), and bromoethane (194 mg, 1.79 mmol, 133 μL, 1.10 equiv) were dissolved in DMF (10.0 mL). The mixture was stirred at 25 °C for 30 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (3 x 20.0 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f = 0.70) to afford the title compound (280 mg, 928 μmol, 57.2% yield, 99.2% purity by LCMS (220 nm)) as a yellow solid. (ESI + ) m / z: 299.8 (M+H) + , (C 10 H 10 IN3).

[0493] C. 3-(5-(2-Ethyl-5-phenyl-2H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 2-ethyl-4-iodo-5-phenyl-2H-1,2,3-triazole (200 mg, 660 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (495 mg, 1.34 mmol, 2.00 equiv) and K3PO4 (425 mg, 2.01 mmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL) was added Ru-Phos-Pd-G3 (55.9 mg, 66.8 μmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 30.0%-60.0% acetonitrile / water (containing 0.50% TFA), flow rate 25 mL / min, elution for 15 min) to give the title compound (106 mg, 255 μmol, yield 38.1%, HPLC (220 nm) purity 100%), as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H), 7.76 - 7.73 (m, 2H), 7.61 - 7.56 (m, 1H), 7.45 - 7.37 (m, 5H), 5.14 - 5.10 (m, 1H), 4.61 - 4.51 (m, 2H), 4.49 - 4.29 (m, 2H), 2.91 - 2.80 (m, 1H), 2.63 - 2.58 (m, 1H), 2.41 - 2.37 (m, 1H), 2.09 - 1.97 (m, 1H), 1.60 - 1.53 (m, 3H). (ESI + ) m / z: 416.0 (M + H) + , (C 23 H 21 N5O3). Example 52

[0494] Synthesis of 3-(5-(1-Methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0495] A. 1-Methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 4-phenyl-2H-1,2,3-triazole (50 mg, 344 μmol, 1.00 equiv) in DCE (1.50 mL) was added TFAA (180 mg, 861 μmol, 119 μL, 2.50 equiv). The mixture was then stirred at 50 °C for 15 h. Then MeNH2 (69.7 mg, 1.03 mmol, 3.00 equiv) was added to the mixture. The mixture was then stirred in MW at 140 °C for 3 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f = 0.50) to give the title compound (86.0 mg, 356 μmol, 25.8% yield, 93.8% purity by LCMS (220 nm)), as a yellow solid. (ESI + ) m / z: 227.0 (M+H) + , (C 11 H9F3N2).

[0496] B. 4-Bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole: At 0 °C, NBS (95.2 mg, 534 μmol, 1.10 equiv) was added to a solution of 1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (110 mg, 486 μmol, 1.00 equiv) in ACN (3.00 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f = 0.60) to give the title compound (86.0 mg, 356 μmol, 70.1% yield, 93.8% purity by LCMS (220 nm)), as a light yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 7.56 - 7.51 (m, 3H), 7.49 - 7.39 (m, 2H), 3.71 - 3.66 (m, 3H). (ESI + ) m / z: 303.9 (M+H) + , (C 11 H8BrF3N2).

[0497] C. 3-(5-(1-Methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, Ru-Phos-Pd-G3 (24.6 mg, 29.5 μmol, 0.10 equiv) was added to a solution of 4-bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (90.0 mg, 294 μmol, 1.00 equiv), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (218 mg, 589 μmol, 2.00 equiv) and K3PO4 (187 mg, 884 μmol, 3.00 equiv) in dioxane (5.00 mL) and H2O (0.25 mL). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) and a gradient of 34.0%-64.0% acetonitrile / water (containing 0.50% TFA), flow rate 25 mL / min, elution for 10 min) to give the title compound (59.3 mg, 126 μmol, 42.7% yield, 98.4% purity (HPLC 220 nm)) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H), 7.63 - 7.50 (m, 7H), 7.48 - 7.40 (m, 1H), 5.11 - 5.05 (m, 1H), 4.43 - 4.21 (m, 2H), 3.56 (s 3H), 2.95 - 2.84 (m, 1H), 2.60 - 2.53 (m, 1H), 2.38 - 2.33 (m, 1H), 1.99 - 1.91 (m, 1H). (ESI + ) m / z: 468.1 (M + H) + , (C 24 H 19 F3N4O3). Example 53

[0498] Synthesis of 3-(1-oxo-5-(5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0499] A. 5-Phenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 4-phenyl-2H-1,2,3-triazole (250 mg, 1.72 mmol, 1.00 equiv) in DCE (7.50 mL) was added TFAA (904 mg, 4.31 mmol, 598 μL, 2.50 equiv). The mixture was then stirred at 50 °C for 15 h. Then AcONH4 (663 mg, 8.61 mmol, 5.00 equiv) was added to the mixture. The mixture was then stirred at 140 °C under MW for 2 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f = 0.50) to give the title compound (287 mg, 1.34 mmol, yield 38.8%, purity by LCMS (220 nm) 99.0%) as a light yellow solid. (ESI + ) m / z: 212.9 (M+H) + , (C 10 H7F3N2).

[0500] B. 4-Bromo-5-phenyl-2-(trifluoromethyl)-1H-imidazole: At 0 °C, NBS (323 mg, 1.31 mmol, 1.00 equiv) was added to a solution of 5-phenyl-2-(trifluoromethyl)-1H-imidazole (280 mg, 1.31 mmol, 1.00 equiv) in ACN (5.00 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f = 0.50) to give the title compound (314 mg, 1.07 mmol, yield 82.4%, purity by LCMS (220 nm) 99.6%) as a light yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ 9.98 - 9.89 (m, 1H), 7.68 - 7.64 (m, 2H), 7.52 - 7.43 (m, 3H). (ESI + ) m / z: 292.7 (M+H) + , (C 10 H6BrF3N2).

[0501] C. 3-(1-Oxo-5-(5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, Ru-Phos-Pd-G3 (214 mg, 256 μmol, 0.50 equivalent) was added to a solution of 4-bromo-5-phenyl-2-(trifluoromethyl)-1H-imidazole (150 mg, 513 μmol, 1.00 equivalent), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (380 mg, 1.03 mmol, 2.00 equivalents), and K3PO4 (326 mg, 1.54 mmol, 3.00 equivalents) in dioxane (5.00 mL) and H2O (0.25 mL). The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 x 25 mm x 5 μm) with a gradient of 24.0%-54.0% acetonitrile / water (containing 0.50% TFA) at a flow rate of 25 mL / min for 10 min) to afford the title compound (111 mg, 244 μmol, 47.5% yield, HPLC (220 nm) purity 100%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 11.1–10.9 (m, 1H), 7.80 - 7.67 (m, 2H), 7.56 - 7.33 (m, 6H), 5.11 - 5.03 (m, 1H), 4.49 - 4.28 (m, 2H), 2.94 - 2.87 (m, 1H), 2.61 - 2.57 (m, 1H), 2.38 - 2.32 (m, 1H), 2.11 - 1.91 (m, 1H). (ESI + ) m / z: 455.2 (M + H) + , (C 23 H 17 F3N4O3). Example 54

[0502] Synthesis of 3-(1-oxo-5-(2-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0503] A. 3-(1-Oxo-5-(2-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: Under N2, to a solution of 4-bromo-2-phenyl-1H-imidazole (150 mg, 672 μmol, 1.00 equiv), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (497 mg, 1.34 mmol, 2.00 equiv) in dioxane (2.00 mL) and H2O (0.10 mL) was added Ru-Phos-Pd-G3 (112 mg, 134 μmol, 0.20 equiv), K3PO4 (285 mg, 1.34 mmol, 2.00 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Welch Xtimate C18 (150 mm x 25 mm x 10 μm) with a gradient of 6 - 36% acetonitrile / water (containing 0.05% TFA), flow rate of 25 mL / min, eluting for 10 min) to give the title compound (46.3 mg, 118 μmol, 17.5% yield, 98.5% purity by HPLC (220 nm)), as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 8.06 - 8.03 (m, 3H), 7.83 - 7.81 (m, 1H), 7.60 - 7.54 (m, 3H), 5.16 - 5.12 (m, 1H), 4.56 - 4.38 (m, 2H), 2.96 - 2.90 (m, 1H), 2.64 - 2.59 (m, 1H), 2.46 - 2.43 (m, 1H), 2.04 - 2.02 (m, 1H). (ESI + ) m / z: 386.9 (M + H) + , (C 22 H 18 N4O3). Examples 55 - 116

[0504] The compounds shown in Examples 55 - 116 were prepared according to Scheme 1 below:

[0505] Step 1 Suzuki coupling

[0506] Condition 1: Under N2 protection, K3PO4 (1.5 M H2O solution, 450 μmol, 3.00 equivalents) and Pd-118 (15.0 μmol, 0.10 equivalent) were added to a vial containing a solution of A001 (150 μmol, 1.00 equivalent) and Bi (180 μmol, 1.20 equivalents) in dioxane (1.20 mL). The mixture was stirred at 65 °C for 16 hours. 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 obtain the crude intermediate for the next step.

[0507] Condition 2: Under N2 protection, K3PO4 (1.5 M H2O solution, 450 μmol, 3.00 equivalents) and Pd-118 (15.0 μmol, 0.10 equivalent) were added to a vial containing a solution of A001 (150 μmol, 1.00 equivalent) and Bi (180 μmol, 1.20 equivalents) in dioxane (1.20 mL). The mixture was stirred in a microwave at 120 °C for 2 hours. 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 obtain the crude intermediate for the next step.

[0508] Step 2 Ring Closure

[0509] Condition: TsOH (1.50 mmol, 10.0 equivalents) was added to a vial containing a solution of A001Bi_1 (~150 μmol, 1.00 equivalent) in CH3CN (1.50 mL). The mixture was stirred at 80 °C for 2 hours. The residue was concentrated under reduced pressure and purified by preparative HPLC to obtain the final product.

[0510] The following compounds were synthesized according to the above method: Example 117

[0511] Synthesis of 3-(5-(2-cyclopropyl-1-methyl-5-(pyrimidin-5-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0512] 5-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyrimidine: Under N2, to a solution of 2-cyclopropyl-1-methyl-imidazole (0.30 g, 2.46 mmol, 1.00 eq) and 5-bromopyrimidine (1.17 g, 7.37 mmol, 3.00 eq) in DMF (2.00 mL) were added Pd(OAc)2 (55.1 mg, 245 μmol, 0.10 eq), tris(2-furyl)phosphine (P(oxole)3) (114 mg, 491 μmol, 0.20 eq) and K2CO3 (678 mg, 4.91 mmol, 2.00 eq). The reaction mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f = 0.25) to give the title compound (0.40 g, 2.00 mmol, yield 81.3%) as a yellow solid. 1 1H NMR: (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.94 (s, 2H), 7.09 (s, 1H), 3.71 (s, 3H), 2.09 - 2.03 (m, 1H), 0.97 - 0.94 (m, 2H), 0.87 - 0.86 (m, 2H). (ESI + ) m / z: 201.1 (M + H) + , (C 11 H 12 N4).

[0513] B. 5-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyrimidine: At 0 °C, a solution of NBS (426 mg, 2.40 mmol, 1.20 eq) in ACN (2.00 mL) was added to a solution of 5-(2-cyclopropyl-3-methyl-imidazol-4-yl)pyrimidine (0.40 g, 2.00 mmol, 1.00 eq) in ACN (2.00 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (10.0 mL), extracted with EtOAc (3 x 10.0 mL), dried over Na2SO4, concentrated in vacuo to give a residue. The resulting residue was purified by preparative TLC (SiO2, methanol:dichloromethane = 20:1; TLC, methanol:dichloromethane = 20:1, R f = 0.40) to afford the title compound (245 mg, 877 μmol, 43.9% yield) as a yellow solid. (ESI + ) m / z: 279.0 (M+H) + , (C 11 H 11 BrN4).

[0514] C. 3-(5-(2-Cyclopropyl-1-methyl-5-(pyrimidin-5-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Under N2, Ru-Phos-Pd-G3 (119 mg, 143 μmol, 0.20 eq) and K3PO4 (304 mg, 1.43 mmol, 2.00 eq) were added to a solution of 5-(5-bromo-2-cyclopropyl-3-methyl-imidazol-4-yl)pyrimidine (200 mg, 716 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 (397 mg, 1.07 mmol, 1.50 eq) in dioxane (2.00 mL) and H2O (0.10 mL). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified by preparative HPLC (using Phenomenex luna C18 (150 mm x 25 mm x 10 μm) with a gradient of 4 - 34% acetonitrile / water (TFA), flow rate of 25 mL / min, eluting for 10 min) to afford the title compound (22.2 mg, 49.5 μmol, 6.92% yield, HPLC (220 nm) purity 98.6%) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.32 (s, 1H), 8.89 (s, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.10 - 5.06 (m, 1H), 4.41 - 4.23 (m, 2H), 3.63 (s, 3H), 2.93 - 2.86 (m, 1H), 2.60 - 2.50 (m, 1H), 2.38 - 2.32 (m, 2H), 2.05 - 1.98 (m, 1H), 1.40 - 1.00 (m, 4H). (ESI + ) m / z: 443.2 (M + H) + , (C 24 H 22 N6O3). Example 118

[0515] Synthesis of 3-(1-oxo-5-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0516] A. 2-(4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridine: At 25 °C, DHP (1.40 g, 16.6 mmol, 1.52 mL, 9.30 equiv) was added portionwise slowly to a solution of 2-(4-bromo-1H-pyrazol-3-yl)pyridine (400 mg, 1.79 mmol, 1.00 equiv), TFA (81.4 mg, 714 μmol, 53.1 μL, 0.40 equiv) in toluene (2.00 mL) and ACN (2.00 mL). The mixture was stirred at 100 °C for 8 h. The mixture was poured into H2O (20.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with saturated aqueous sodium chloride (3 × 20.0 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl a...

Claims

1. A compound represented by Formula I or II: or a pharmaceutically acceptable derivative thereof, wherein: Ar is an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic group composed of 5-7 atoms, or heterocyclic alkenyl group composed of 5-7 atoms; 5-7 cycloalkyl, C 5-7 cycloalkenyl, heterocyclic group composed of 5-7 atoms, or heterocyclic alkenyl group composed of 5-7 atoms; E is a group moiety that binds to an E3 ubiquitin ligase; X 1 -X 2 each independently is N or C; and X 3 -X 5 each independently is CR, N, NR, S or O; where each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic group; or two R groups at adjacent positions on the ring together form an alkylene group; or R and Ar at adjacent positions on the 5-atom ring together form a fused ring; provided that: i) In formula II, when X 1 is C, X 2 , X 4 and X 5 are N respectively, and X 3 is CH, or when X 1 and X 2 are C respectively, X 3 is NMe, X 4 is N, and X 5 is CH, then E is not an isatin moiety; ii) In formula II, when X 1 and X 2 are each C, X 3 is CH, X 4 is N, and X 5 is NMe, then Ar is not 5-fluoro-2-pyridyl; iii) In formula II, when X 1 is N, X 2 is C, X 3 and X 4 are each CH, and X 5 is N, or when X 1 and X 3 are each N, X 2 is C, and X 4 and X 5 are each CH, then Ar is not phenyl; iv) In formula II, the ring containing X 1 -X 5 is not 1,2,3-triazole-1,4-diyl; v) Ar is not tetrahydropyran-2-yl; and vi) the compound is not: 3-[1,3-dihydro-1-oxo-5-(5-phenyl-4-oxazolyl)-2H-isoindol-2-yl]-2,6-piperidinedione, 3-[1,3-dihydro-1-oxo-5-(2-phenyl-4-oxazolyl)-2H-isoindol-2-yl]-2,6-piperidinedione, or 3-[1,3-dihydro-1-oxo-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-2H-isoindol-2-yl]-2,6-piperidinedione.

2. The compound according to claim 1, wherein, X 1 is C, and X 2 is N.

3. The compound according to claim 1, wherein, X 1 is N, and X 2 is C.

4. The compound according to claim 1, wherein, The compound has the following structure:

5. The compound according to claim 1, which has a structure represented by one of the following formulas:

6. The compound according to claim 1, which has the following structure:

7. The compound according to claim 1 or 6, which has the following structure:

8. The compound according to claim 1, 6 or 7, which has the following structure:

9. The compound according to claim 1 or any one of claims 6 - 8, which has the following structure:

10. The compound according to claim 1 or 6, which has the following structure:

11. The compound according to claim 1, 6 or 10, which has the following structure:

12. The compound according to claim 1, 6, 10 or 11, which has the following structure:

13. The compound according to claim 1 or 6, which has the following structure:

14. The compound according to claim 1, 6 or 13, which has the following structure:

15. The compound according to claim 1 or 6, which has the following structure:

16. The compound according to claim 1, which has the following structure:

17. The compound according to claim 1, which has the following structure:

18. The compound according to claim 1, which has the following structure:

19. The compound according to any one of claims 1-18, wherein, Each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic group; or two R groups at adjacent positions on the ring together form an alkylene group.

20. The compound according to any one of claims 1-18, wherein, Each R is independently H, alkyl, alkenyl, or alkynyl.

21. The compound according to any one of claims 1-18, wherein, Each R is independently H, alkyl, cycloalkyl, heterocyclic group, or aryl; or two R groups at adjacent positions on the ring together form a lower alkylene group.

22. The compound according to any one of claims 1-18, wherein, Each R is independently H or alkyl; or two R groups at adjacent positions on the ring together form a lower alkylene group.

23. The compound according to any one of claims 1-18, wherein, Each R is independently H, alkyl, or haloalkyl.

24. The compound according to any one of claims 1-18, wherein, Each R is independently H, methyl, ethyl, isopropyl, difluoromethyl, fluoromethyl, trifluoromethyl, 2,2-difluoro-1-ethyl, 2,2,2-trifluoro-1-ethyl, difluoropropyl, cyclopropyl, trideuteriomethyl, ethyl, 2-hydroxy-2-methylpropyl, cyclohexyl, 1,3-dioxanyl, 4-pyranyl, or phenyl; or two R groups at adjacent positions on the ring together form propylene.

25. The compound according to any one of claims 1-18, wherein, Each R is independently H, methyl, difluoromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoro-1-ethyl, cyclopropyl, trideuteriomethyl, ethyl, 2-hydroxy-2-methylpropyl, cyclohexyl, 4-pyranyl, or phenyl; or two R groups at adjacent positions on the ring together form propylene.

26. The compound according to any one of claims 1-18, wherein, Each R is independently H, methyl, difluoromethyl, or 2,2,2-trifluoro-1-ethyl.

27. The compound according to any one of claims 1-18, wherein, Each R is independently H or methyl.

28. The compound according to any one of claims 1-18, wherein, Each R is H.

29. The compound according to any one of claims 1-18, wherein, Each R is methyl.

30. The compound according to any one of claims 1-29, wherein, E is a group moiety that binds to cereblon.

31. The compound according to any one of claims 1-30, wherein, E contains a group moiety derived from imide, amide, thioamide, or thioimide.

32. The compound according to any one of claims 1-31, wherein, E contains a phthalimido group, or an analogue or derivative thereof.

33. The compound according to any one of claims 1-32, wherein, E contains a phthalimido-glutarimide group, or an analogue or derivative thereof.

34. The compound according to any one of claims 1-33, wherein, E contains a thalidomide, lenalidomide, or pomalidomide group moiety, or an analogue or derivative thereof.

35. A compound according to any one of claims 1 - 34, wherein, E has a structure shown by one of the following formulas: Wherein: A is a cyclic amide or cyclic imide, or a derivative thereof; R 1 and R 2 each independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl; Y 1 and Y 2 one of which is S and the other is CR 3 wherein R 3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and Z 1 -Z 4 each independently is N or CR 4 wherein each R 4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl, respectively.

36. The compound according to any one of claims 1-34, wherein, E has a structure shown by the following formula: Wherein: A is a cyclic amide or cyclic imide, or a derivative thereof; and Z 2 and Z 3 each independently is N or CR 4 where each R 4 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl.

37. A compound according to any one of claims 1-36, wherein, A is a cyclic imide having the following structure: Wherein: R 5 is H or alkyl; R 6 and R 7 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic group; and m is an integer from 1 to 4.

38. A compound according to any one of claims 1-37, wherein, R 5 is H or a lower alkyl group.

39. A compound according to any one of claims 1 - 38, wherein, R 5 is H or methyl.

40. A compound according to any one of claims 1-39, wherein, R 5 is H.

41. A compound according to any one of claims 1 - 39, wherein, R 5 is methyl.

42. The compound according to any one of claims 1-41, wherein, R 6 and R 7 each independently is H or alkyl.

43. The compound according to any one of claims 1-42, wherein, R 6 and R 7 each independently is H or methyl.

44. A compound according to any one of claims 1 - 43, wherein, R 6 and R 7 are each H.

45. A compound according to any one of claims 1-44, wherein, m is 1, 2, or 3.

46. The compound according to any one of claims 1-45, wherein, m is 2 or 3.

47. A compound according to any one of claims 1-46, wherein, m is 2.

48. A compound according to any one of claims 1-46, wherein, m is 3.

49. A compound according to any one of claims 1 - 47, wherein, A has the following structure:

50. A compound according to any one of claims 1 - 47 and 49, wherein, A has the following structure:

51. A compound according to any one of claims 1 - 47, 49 and 50, wherein, A has one of the following structures:

52. The compound according to any one of claims 1 - 51, wherein, R 1 and R 2 each independently is H, alkyl, alkenyl, or alkynyl.

53. A compound according to any one of claims 1-52, wherein, R 1 and R 2 each independently is H or alkyl.

54. A compound according to any one of claims 1 - 53, wherein, R 1 and R 2 are each independently H or methyl.

55. A compound according to any one of claims 1-54, wherein, R 1 and R 2 are each H.

56. A compound according to any one of claims 1-55, wherein, R 3 is H, alkyl, alkenyl, or alkynyl.

57. A compound according to any one of claims 1-56, wherein, R 3 is H or an alkyl group.

58. A compound according to any one of claims 1-57, wherein, R 3 is H or methyl.

59. A compound according to any one of claims 1 - 58, wherein, R 3 is H.

60. The compound according to any one of claims 1-59, wherein, R 4 is H, an alkyl group, an alkenyl group, or an alkynyl group.

61. The compound according to any one of claims 1 - 60, wherein, R 4 is H or an alkyl group.

62. The compound according to any one of claims 1-61, wherein, R 4 is H or methyl.

63. The compound according to any one of claims 1 - 62, wherein, R 4 is H.

64. The compound according to any one of claims 33 - 63, wherein, Y 1 is S, and Y 2 is CR 3 。 65. A compound according to any one of claims 33 - 64, wherein, Y 1 is S, and Y 2 is CH.

66. A compound according to any one of claims 33 - 63, wherein, Y 1 is CR 3 and Y 2 is S.

67. A compound according to any one of claims 33 - 63 and 66, wherein, Y 1 is CH, and Y 2 is S.

68. A compound according to any one of claims 33 - 63, wherein, Z 1 is N, and Z 2 -Z 4 are respectively CR 4 .

69. A compound according to any one of claims 33 - 63 and 68, wherein, Z 1 is N, and Z 2 -Z 4 are CH respectively.

70. A compound according to any one of claims 33 - 63, wherein, Z 2 is N, and Z 1 、Z 3 and Z 4 are respectively CR 4 。 71. A compound according to any one of claims 33 - 63 and 70, wherein, Z 2 is N, and Z 1 and Z 3 and Z 4 are each CH.

72. A compound according to any one of claims 33 - 63, wherein, Z 3 is N, and Z 1 , Z 2 and Z 4 are respectively CR 4 .

73. A compound according to any one of claims 33 - 63 and 72, wherein, Z 3 is N, and Z 1 、Z 2 and Z 4 are CH respectively.

74. A compound according to any one of claims 33 - 63, wherein, Z 4 is N, and Z 1 -Z 3 are respectively CR 4 .

75. A compound according to any one of claims 33 - 63 and 74, wherein, Z 4 is N, and Z 1 -Z 3 are CH respectively.

76. The compound according to any one of claims 1-75, wherein, E is selected from:

77. A compound according to any one of claims 1-76, wherein, E has the following structure:

78. A compound according to any one of claims 1-77, wherein, E is selected from:

79. A compound according to any one of claims 1-78, wherein, Ar is an optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, optionally substituted pyridopyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted benzofuranyl, optionally substituted imidazopyridyl, optionally substituted benzopyrazolyl, optionally substituted pyrrolopyridyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted thienopyridyl, optionally substituted dihydrobenzofuranyl, optionally substituted benzopyridazinyl, optionally substituted benzopyranyl, optionally substituted benzothienyl, optionally substituted triazolopyrimidinyl, optionally substituted piperidinyl, optionally substituted cyclohexenyl, optionally substituted tetrahydropyridyl, optionally substituted tetrahydrofuranyl, optionally substituted dihydrofuranyl, optionally substituted morpholinyl, optionally substituted tetrahydroisoquinolinyl, optionally substituted azabicycloheptyl, optionally substituted isoquinolinyl, optionally substituted cycloheptenyl, optionally substituted indenyl, optionally substituted dihydronaphthyl, optionally substituted 8-azabicyclooctyl, optionally substituted adamantyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl. group, optionally substituted azabicycloheptyl, optionally substituted isoquinolinyl, optionally substituted cycloheptenyl, optionally substituted indenyl, optionally substituted dihydronaphthyl, optionally substituted 8-azabicyclooctyl, optionally substituted adamantyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl.

80. A compound according to any one of claims 1-78, wherein, Ar is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted pyridino-pyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted dihydrobenzofuranyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl.

81. A compound according to any one of claims 1 - 78, wherein, Ar is phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, pyridopyrazolyl, isoxazolyl, indolyl, isoindolyl, thienyl, dihydrobenzofuranyl, dihydroindenyl, cyclopropyl, or cyclohexyl, and each group of Ar is optionally substituted with one or more substituents, and the one or more substituents are each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 , wherein: R 8 is an alkyl group, OR 13 , or NR 14 R 15 ; R 9 is H, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, or COR 16 ; R 10 and R 11 each independently is H, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, or COR 17 ; R 12 is alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, OR 18 , or NR 14 R 15 ; Each R 13 , R 14 and R 15 is independently H, alkyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl; R 16 is alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, OR 13 , or NR 14 R 15 ; R 17 is alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, OR 13 , or NR 14 R 15 ; R 18 is alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; and n is 0, 1, or 2.

82. The compound according to any one of claims 1-81, wherein, Ar is substituted with 1 to 5, or 1 to 3, or 1 or 2 substituents.

83. A compound according to any one of claims 1 - 81, wherein, Ar is unsubstituted.

84. A compound according to any one of claims 1 - 81, wherein, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

85. A compound according to any one of claims 1 - 81, wherein, Ar is phenyl, said phenyl optionally substituted by one or more substituents, said one or more substituents each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

86. The compound according to any one of claims 1-81, wherein, Ar is phenyl, which is optionally substituted by one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 , OR 9 , NR 10 R 11 and S(O)2R 12 .

87. A compound according to any one of claims 1 - 81, wherein, Ar is phenyl, which is optionally substituted by one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridinyl-oxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl and SO2-(1-pyrrolidinyl).

88. The compound according to any one of claims 1-81, wherein, Ar is phenyl, which is optionally substituted by one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridinyl-oxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl and SO2-(1-pyrrolidinyl).

89. A compound according to any one of claims 1 - 81, wherein, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

90. A compound according to any one of claims 1 - 81, wherein, Ar is phenyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2 and NMe2.

91. A compound according to any one of claims 1 - 81, wherein, Ar is unsubstituted phenyl, unsubstituted 4-biphenylyl, or unsubstituted 1-naphthyl.

92. A compound according to any one of claims 1 - 81, wherein, Ar is unsubstituted phenyl.

93. A compound according to any one of claims 1 - 81, wherein, Ar is a thienyl group, and the thienyl group is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

94. A compound according to any one of claims 1 - 81, wherein, Ar is a thienyl group, said thienyl group being optionally substituted by one or more substituents, said one or more substituents each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclic alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

95. A compound according to any one of claims 1 - 81, wherein, Ar is a thienyl group, the thienyl group is optionally substituted with one or more substituents, and the one or more substituents are each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclic alkyl, CONR 14 R 15 , OR 9 , NR 10 R 11 and S(O)2R 12 .

96. A compound according to any one of claims 1 - 81, wherein, Ar is thienyl, which is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-methoxybenzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl and SO2-(1-pyrrolidinyl).

97. A compound according to any one of claims 1 - 81, wherein, Ar is a thienyl group, and the thienyl group is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, and SO2-(1-pyrrolidinyl).

98. The compound according to any one of claims 1 - 81, wherein, Ar is a thienyl group, and the thienyl group is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2, and NMe2.

99. A compound according to any one of claims 1 - 81, wherein, Ar is an unsubstituted thienyl group.

100. A compound according to any one of claims 1-81, wherein, Ar is a pyrazolyl group, said pyrazolyl group being optionally substituted with one or more substituents, said one or more substituents being each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

101. A compound according to any one of claims 1 - 81, wherein, Ar is a pyrazolyl group, the pyrazolyl group being optionally substituted with one or more substituents, each of the one or more substituents being independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclic alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

102. A compound according to any one of claims 1 - 81, wherein, Ar is a pyrazolyl group, said pyrazolyl group being optionally substituted by one or more substituents, said one or more substituents being each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic group, heteroaryl, heterocyclic alkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 。 103. A compound according to any one of claims 1 - 81, wherein, Ar is a pyrazolyl group, and the pyrazolyl group is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-methoxybenzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

104. A compound according to any one of claims 1 - 81, wherein, Ar is a pyrazolyl group, said pyrazolyl group being optionally substituted with one or more substituents, said one or more substituents each independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me and SO2-(1-pyrrolidinyl).

105. A compound according to any one of claims 1 - 81, wherein, Ar is a pyrazolyl group, said pyrazolyl group being optionally substituted with one or more substituents, said one or more substituents each independently selected from chlorine, fluorine, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridyl, hydroxy, methoxy, CONH2, CONHMe, CONMe2, NH2 and NMe2.

106. The compound according to any one of claims 1 - 81, wherein, Ar is an unsubstituted pyrazolyl group.

107. The compound according to claim 1, which has the following structure: wherein R 5 is H or an alkyl group.

108. The compound according to claim 1, which has the following structure: wherein R 5 is H or an alkyl group.

109. The compound according to claim 1 or 106, which has the following structure: wherein R 5 is H or an alkyl group.

110. The compound according to claim 1 or 106, which has the following structure: wherein R 5 is H or alkyl.

111. The compound according to claim 1 has the following structure: wherein R 5 is H or an alkyl group.

112. The compound according to claim 1 has the following structure: wherein R 5 is H or an alkyl group.

113. The compound according to claim 1 or 112, which has the following structure:

114. The compound according to any one of claims 1, 112 and 113, which has the following structure:

115. The compound according to claim 1 or 106, which has the following structure:

116. A compound according to any one of claims 1, 106, and 115, having the following structure:

117. A compound according to any one of claims 1, 106, 114 and 115, having the following structure:

118. The compound according to claim 1 or 106, which has the following structure: The compound according to any one of claims 1, 106, and 118, which has the following structure: The compound according to any one of claims 1, 106, 118 and 119, which has the following structure:

121. The compound according to claim 1 or 106, which has the following structure:

122. A compound according to any one of claims 1, 106 and 121, having the following structure: The compound according to any one of claims 1, 106, 121 and 122, which has the following structure:

124. A compound according to any one of claims 1, 106, and 121 - 123, which has the following structure:

125. The compound according to claim 1 or 106, which has the following structure:

126. A compound according to any one of claims 1, 106, and 125, having the following structure: The compound according to any one of claims 1, 106, 125 and 126, having the following structure: A compound according to any one of claims 1, 106, and 125 - 127, having the following structure:

129. The compound according to claim 1, which has the following structure:

130. The compound according to claim 1, which has the following structure:

131. The compound according to claim 1, which has the following structure:

132. The compound according to claim 1, which has the following structure:

133. A compound according to any one of claims 106 - 132, wherein, Ar is phenyl, which is optionally substituted by one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

134. A compound according to any one of claims 106-132, wherein, Ar is phenyl, said phenyl optionally being substituted by one or more substituents, said one or more substituents each independently selected from halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, CONR 14 R 15 、OR 9 、NR 10 R 11 and S(O)2R 12 。 135. A compound according to any one of claims 106-132, wherein, Ar is phenyl, and the phenyl is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

136. A compound according to any one of claims 106 - 132, wherein, Ar is a thienyl group, and the thienyl group is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

137. A compound according to any one of claims 106 - 132, wherein, Ar is thienyl, and the thienyl is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, hydroxy, methoxy, benzyloxy, 3-methoxybenzyloxy, 3-pyridyloxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

138. A compound according to any one of claims 106 - 132, wherein, Ar is a pyrazolyl group, said pyrazolyl group being optionally substituted with one or more substituents, said one or more substituents each independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylalkyl, heterocyclic group alkyl, COR 8 , OR 9 , NR 10 R 11 and S(O) n R 12 .

139. A compound according to any one of claims 106 - 132, wherein, Ar is a pyrazolyl group, and the pyrazolyl group is optionally substituted with one or more substituents, and each of the one or more substituents is independently selected from chlorine, fluorine, cyano, methyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, phenoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-piperidinyl, 1-pyrrolidinylmethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-tert-butoxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-methoxybenzyloxy, 3-pyridinyl-oxy, 3-(4-morpholinyl)propoxy, CONH2, CONHMe, CONMe2, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH2, NMe2, NHCOPh, SO2Me, SO2NH-cyclohexyl, and SO2-(1-pyrrolidinyl).

140. The compound according to claim 1, wherein, The compound is any one of Examples 1-735.

141. A pharmaceutical composition comprising the compound according to any one of claims 1-140, and a pharmaceutically acceptable carrier.

142. A method for degrading CK1α in cells, comprising contacting the cells with the compound according to any one of claims 1-140 or the composition according to claim 141.

143. A method for degrading CK1α in a subject, comprising administering to the subject the compound according to any one of claims 1-140 or the composition according to claim 128.

144. A method for inhibiting the activation of the Card11 / BCL10 / MALT1 (CBM) complex in a subject, comprising administering to the subject the compound according to any one of claims 1-140 or the composition according to claim 128.

145. A method for regulating cell proliferation in a subject, comprising administering to the subject the compound according to any one of claims 1-140 or the composition according to claim 128.

146. A method for treating a subject suffering from a proliferative disease, comprising administering to the subject the compound according to any one of claims 1-140 or the composition according to claim 128.

147. A method for treating a subject suffering from cancer, comprising administering to the subject the compound according to any one of claims 1-140 or the composition according to claim 128.

148. The method according to claim 147, 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).

149. The method according to claim 147 or 148, wherein, The cancer is B-cell lymphoma.

150. The method according to claim 148 or 149, wherein, The B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).

151. The method according to claim 150, wherein, The DLBCL is ABC DLBCL.

152. The method according to claim 147, wherein, The cancer is a BTK inhibitor-resistant cancer.

153. The method according to claim 152, wherein, The BTK inhibitor-resistant cancer is an ibrutinib-resistant cancer.

154. The method according to claim 153, wherein, The ibrutinib-resistant cancer is ABC DLBCL.

155. The method according to claim 152, wherein, The BTK inhibitor-resistant cancer is resistant to one or more of acalabrutinib, zanubrutinib, pirtobrutinib, spebrutinib, evobrutinib, olmutinib, tirabrutinib, elsubrutinib (ABBV-105), tolebrutinib (SAR442168), fenebrutinib, vacabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068, or DTRMWXHA-12.

156. The method according to claim 152, 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.

157. A method of degrading CK1α and GSPT1 in a cell, comprising contacting the cell with a compound according to any one of claims 1-140 or a composition according to claim 141.

158. A method of degrading CK1α and GSPT1 in a subject, comprising administering to the subject a compound according to any one of claims 1-140 or a composition according to claim 141.

159. A method of treating AML, glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, multiple myeloma, hepatocellular carcinoma, or gastric cancer in a subject, comprising administering to the subject a compound according to any one of claims 1-140 or a composition according to claim 141.

160. A method of treating a subject with an autoimmune disease, comprising administering to the subject a compound according to any one of claims 1-140 or a composition according to claim 141.

161. The method according to claim 160, wherein, The autoimmune disease is Addison disease, Celiac disease-sprue (gluten-sensitive enteropathy), dermatomyositis, Graves' disease, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, or type I diabetes mellitus.

162. The method according to claim 161, further comprising administering a second active agent to the subject.

163. The method according to claim 162, wherein, The second active agent is a checkpoint inhibitor, such as an anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibody.

164. The method according to claim 162 or 163, wherein The second active agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tramelimumab, or a combination thereof. The method according to any one of claims 162-164, wherein, The proliferative disease to be treated is: melanoma, including unresectable or metastatic melanoma, BRAF 600 mutation-positive, and lymph node-involved melanoma; non-small cell lung cancer, including metastatic non-small cell lung cancer; renal cell carcinoma; Hodgkin lymphoma, including relapsed / refractory Hodgkin lymphoma; head and neck squamous cell carcinoma, including metastatic disease; urothelial carcinoma, including metastatic disease; colorectal cancer, including metastatic disease; or hepatocellular carcinoma.

166. A method of treating a RAS-driven cancer in a subject, comprising administering to the subject a compound according to any one of claims 1-140 or a composition according to claim 141.

167. The method according to claim 166, wherein, The RAS-driven cancer is a RAS mutant cancer.

168. The method according to claim 166, wherein The RAS-driven cancer is a KRAS G12D -driven cancer.

169. The method according to any one of claims 166 - 168, wherein The RAS-driven cancer is lung cancer, head and neck cancer, pancreatic cancer, breast cancer, colorectal cancer, gastrointestinal cancer, melanoma, medullary carcinoma, bladder cancer, cervical cancer, ovarian cancer, or uterine cancer.

170. A method of preventing acquired resistance to erlotinib in a subject with EGFR mutant non-small cell lung cancer, comprising administering to the subject a compound according to any one of claims 1-140 or a composition according to claim 141.

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