CK1α and dual CK1α / GSPT1 degrading compounds

Abstract

Provided herein are compounds that act as molecular adhesives and induce degradation of CK1α or CK1α / GSPT1, and pharmaceutically acceptable derivatives thereof. Also provided are pharmaceutical compositions containing the compounds and methods of using the compounds to treat subjects with proliferative diseases.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 375,167, filed September 9, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] Field Provided herein are compounds and compositions for degrading CK1α protein or degrading both CK1α and GSPT1, which are useful for treating proliferative diseases such as cancer and autoimmune disorders. [Background technology]

[0003] background Recently, extensive research has been conducted to discover compounds that bind to two different proteins without necessarily inhibiting the function of either protein. Such compounds have been termed "molecular glues." Of particular interest are molecular glues that degrade one of the proteins upon contact with the target protein. This strategy has proven useful for modulating the activity of proteins previously considered "undruggable."

[0004] For example, certain molecular adhesives bind to E3 ubiquitin ligases, which specifically ubiquitinate substrate proteins for degradation by the proteasome. Cereblon is a key component of the E3 ubiquitin ligase complex and is an attractive target for molecular adhesives. Cereblon can be reprogrammed by compounds such as thalidomide, lenalidomide, and pomalidomide (Imide), inducing the degradation of new substrate proteins such as IKZF1 (Ikaros) and IKAF3 (Aeolus) (see, e.g., Charlinski et al. Cancers, 2021, 13, 4666). Thus, molecular adhesives that bind to cereblon ubiquitinate target proteins for degradation by the proteasome. Extensive research has been conducted in the field of cereblon-binding compounds, and many such compounds have been discovered (e.g., WO 2022 / 066835, WO 2020 / 118098, WO 2021 / 041664, WO 2019 / 078522, WO 2021 / 188537, WO 2021 / 105334, WO 2022 / 144416, WO 2021 / 143816, WO 2022 / 017365, WO 2022 / 146151, WO 2022 / 148358, WO 2021 / 147889, WO 2021 / 143822, WO 2020 / 181232, WO 2019 / 043214, WO 2020 / 263832, WO 2020 / 006233, WO 2015 / 200795, WO 2019 / 043217, WO 2019 / 204354, US Patent Publication Nos. US 2022 / 0062248, US 2019 / 0017998, 2020 / 0206201, 2020 / 0155690, 2021 / 0009559, 2018 / 0215731, 2021 / 0177825, 2019 / 0076541, 2021 / 0403454, 2021 / 0284624, 2021 / 0032245, See 2020 / 0207764, 2022 / 0112211, 2019 / 0233433, 2020 / 0207733).

[0005] Casein kinase 1α ("CK1α"), a member of the CK1 protein family, regulates signaling pathways related to membrane trafficking, cell cycle progression, chromosome segregation, apoptosis, autophagy, cellular metabolism, and differentiation in development, circadian rhythms and immune responses, as well as neurodegeneration and cancer (see, e.g., Jiang et al., Cell Commun. Signaling 2018, 16, 23; Spinello et al., Int. J. Mol. Sci. 2021, 22, 3716). CK1α is therefore an attractive therapeutic target for a variety of indications and applications, including oncology, immuno-oncology, and autoimmune diseases. Mechanistically, CK1α is required for BCR (via BTK) and TCR-induced activation of the Card11 / BCL10 / MALT1 (CBM) complex (see e.g., Gehring et al., Cell Reports 2019, 29, 873-888; Bidere et al., Nature 2009, 458, 7234; Yin et al. Cell. Mol. Life Sci. 2022, 79, 112). CBM activation has been implicated in the progression of various lymphoid malignancies, including non-Hodgkin's lymphoma (NHL) (see, e.g., Bedsaul et al. Front. Onc. 2018, 9, Article 2105), diffuse large B-cell lymphoma (DLBCL) such as ABC DLBCL (see, e.g., Thys et al., Front. Onc. 2018, 8, Article 498; Bidere et al., Nature 2009, 458(7234), 92-96), mucosa-associated lymphoid tissue (MALT) 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), while MALT1 inhibition has been shown to be an effective strategy in the treatment of both naive and ibrutinib-resistant chronic lymphocytic leukemia (CLL) (see, e.g., Saba et al., Cancer Res. 2017, 77(24), 7038-7048). In immuno-oncology, regulation of the CBM complex has been shown to prime tumors for immune checkpoint therapy by regulatory T cells (see, e.g., Di Pilato et al., Nature 2019, 570(7759), 112-116), while MALT1 activity is involved in T cell immunosuppression (see, e.g., Rosenbaum et al., Nat. Commun. 2019, 10(1), 2352). Inhibition of MALT1 has also been shown to ameliorate autoimmune pathology (see, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320).

[0006] Deletion of CK1α by siRNA or kinase inhibitors has also been shown to result in stabilization of the tumor suppressor p53 and inhibition of cell cycle progression (see, e.g., Huart et al., J. Biol. Chem. 2009, 284(47), 32384-32394). Briefly, CK1α binds to MDM2, an E3 ubiquitin ligase for p53 (see, e.g., Wu et al. Mol. Cell. Biol. 2012, 32(23), 4821-4832). Binding of the CK1α-MDM2 active complex to p53 promotes p53 degradation and prevents the expression of the cell cycle progression inhibitor p21 (see, e.g., Kocik et al., Cancers 2019, 11, 1014). Thus, degradation of CK1α stabilizes p53 and induces growth arrest (see, e.g., Huart et al., PLoS One 2012, 7(8), e43391). Increased p53 activity has been shown to have antiproliferative and proapoptotic 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 currently being explored as a therapeutic target for acute myeloid leukemia (AML). Recent studies have identified molecular adhesives that degrade GSPT1 without degrading CK1α (see, e.g., Powell et al., ACS Chem. Biol. 2020, 15, 2722-2730) or IKZF1 (Ikaros) (see, e.g., Nishiguchi et al., J. Med. Chem. 2021, 64, 7296-7311).

[0008] Therefore, there is a need for molecular adhesives that degrade CK1α or CK1α / GSPT1, which would offer treatment options for various proliferative disorders, such as cancer and autoimmune diseases.

[0009] summary Provided herein are compounds and compositions that degrade CK1α or CK1α / GSPT1. In one embodiment, the compound is a molecular adhesive that binds E3 ubiquitin ligase and CK1α. In another embodiment, the compound is a molecular adhesive that binds cereblon and CK1α.

[0010] In one embodiment, the compounds for use in the compositions and methods provided herein have Formula I or II:

[0011] [ka]

[0012] where the variables Ar, E and X 1 ~X 5 are as defined elsewhere herein).

[0013] In another embodiment, there is provided a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0014] In another embodiment, provided herein is a method for degrading CK1α or CK1α / GSPT1 using a compound or composition provided herein. The methods provided herein include methods for treating a disease mediated by CK1α or CK1α / GSPT1. In one embodiment, the CK1α disease is B-cell lymphoma or a BTK inhibitor-resistant cancer. In another embodiment, the CK1α / GSPT1 disease is AML or breast cancer. In another embodiment, the CK1α degraders provided herein are used in combination with a checkpoint inhibitor, such as a CTLA-4, PD-1, or PD-L1 inhibitor, such as an anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibody, in the treatment of cancer. Summary of the Invention

[0015] Detailed Description I. Definition To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.All patents, applications, published applications and other publications are incorporated by reference in their entirety.If there are multiple definitions of terms in this specification, the definition in this section shall prevail unless otherwise specified.

[0017] The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0018] As used herein, a "subject" is an animal, such as a mammal, including a human patient.

[0019] As used herein, biological activity refers to the in vivo activity of a compound or the physiological response that occurs upon in vivo administration of a compound, composition, or other mixture. 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.

[0020] As used herein, 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 methods for such derivatization. The compounds produced can be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts such as, but not limited to, lithium, potassium and sodium; 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, sodium hydrogen phosphate and disodium phosphate; and also mineral acid salts such as, but not limited to, hydrochloride and sulfate; and organic acid salts such as, but not limited to, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, mesylate, and fumarate. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups such as, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of 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 hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvent or water molecules.

[0021] As used herein, treatment means any manner in which one or more symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use to treat a disease mediated by CK1α or CK1α / GSPT1.

[0022] As used herein, amelioration of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the compound or pharmaceutical composition.

[0023] As used herein, unless otherwise indicated, the terms "manage," "managing," and "management" include preventing the recurrence of a particular disease or disorder in a subject already suffering from the disease or disorder and / or lengthening the time a subject suffering from a disease or disorder remains in remission. The term also includes modulating the threshold, onset, and / or duration of the disease or disorder, or altering the way a subject responds to a disease or disorder.

[0024] As used herein, DC 50 refers to the amount, concentration or dosage of a particular test compound that achieves 50% of the maximum response in an assay that measures such response.

[0025] Where moieties are designated by conventional chemical formulas written from left to right, they equally encompass the chemically identical moieties that result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0026] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, alkyl having the specified number of carbon atoms (i.e., C-C 10 means 1 to 10 carbons), and can include divalent and polyvalent radicals. Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0027] The term "alkenyl," by itself or as part of another substituent, means, unless otherwise stated, an alkyl group having the specified number of carbon atoms (i.e., C-C 10 means a straight-chain (i.e., unbranched) or branched-chain hydrocarbon radical having one or more carbon-carbon double bonds, which may include divalent and polyvalent radicals, having from 1 to 10 carbons. Examples of alkenyl groups include, but are not limited to, vinyl (i.e., ethenyl), 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and the higher homologs and isomers.

[0028] The term "alkynyl," by itself or as part of another substituent, means, unless otherwise stated, an alkynyl group having the specified number of carbon atoms (i.e., C-C 10means a straight-chain (i.e., unbranched) or branched-chain hydrocarbon radical having one or more carbon-carbon triple bonds, which may include divalent and polyvalent radicals, having from 1 to 10 carbons (where 1 means 1 to 10 carbons). Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0029] The term "alkylene," by itself or as part of another substituent, means a divalent radical derived from alkyl, exemplified by, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, such as groups having 10 or fewer carbon atoms. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having six or fewer carbon atoms.

[0030] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in the conventional sense to refer to an alkyl group attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.

[0031] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a straight- or branched-chain hydrocarbon radical consisting of heteroatoms selected from the group consisting of O, N, P, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized, the nitrogen atoms may have alkyl substituents to satisfy valences, and / or may be optionally quaternized. The heteroatoms O, N, P, Si, and S may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH-CH-O-CH, -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -CH-S-CH-CH, -CH-CH-S(O)-CH, -CH-CH-S(O)-CH, -CH=CH-O-CH, -CH-CH=N-OCH, and -CH=CH-N(CH)-CH. Up to two heteroatoms may be consecutive, such as, for example, -CH-NH-OCH and -CH-O-Si(CH). Similarly, the term "heteroalkylene," by itself or as part of another substituent, refers to a divalent radical derived from a heteroalkyl, exemplified, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-.

[0032] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, represent, unless otherwise specified, cyclic versions of "alkyl" and "heteroalkyl," respectively, and include bicyclic, tricyclic, and bridged bicyclic groups. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornanyl, bicyclo[2.2.2]octanyl, and the like. Heterocycloalkyl includes, but is not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, 1- or 2-azabicyclo[2.2.2]octanyl, and the like.

[0033] The term "halo," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is meant to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0034] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (1 to 3 rings in one embodiment) fused together or covalently linked. The term "heteroaryl" refers to an aryl group having from 1 to 4 heteroatoms selected from N, O, and S in the ring, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group can be connected to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, Examples of heteroaryl groups include 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituent moieties for the aryl and heteroaryl ring systems may be selected from the group of acceptable substituent moieties described herein. The term "heteroarylium" refers to a heteroaryl group bearing a positive charge at one or more heteroatoms.

[0035] The term "oxo" as used herein means an oxygen atom that is double bonded to a carbon atom.

[0036] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl") is meant to include both substituted and unsubstituted forms of the indicated radical. Non-limiting examples of substituent moieties for each type of radical are provided below.

[0037] Substituent portions of alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups may, in one embodiment, be selected from deuterium, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halo, —SiR′R″R′″, —OC In one embodiment, the substituent moieties on the cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. Each of R', R", R'", and R"", in one embodiment, is independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy group, or arylalkyl group. When the compounds provided herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituent moieties, one of skill in the art will understand that the term "alkyl" is meant to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0038] Substituent moieties for aryl and heteroaryl groups, in one embodiment, include deuterium, halo, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(N R'R'') = NR''', -S(O)R', -S(O)R', -S(O)NR'R'', -NRSOR', -CN and -NO, -R', -N, -CH(Ph), fluoro(C-C)alkoxy, and fluoro(C-C)alkyl, where R', R'', R''', and R'''' are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds provided herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R'''' groups when more than one of these groups is present.

[0039] Two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -Q'-C(O)-(CRR') qAlternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may form a ring of the formula -Q"- (Q' and Q" are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3). Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may form a ring of the formula -A-(CH2) r A and B may optionally be replaced with a substituent of the formula -B- (A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 4). One of the single bonds in the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may be replaced with a group of the formula -(CRR') s -X'-(CR''R''') d -(s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-) substituents. The substituent moieties R, R', R'', and R''' in one embodiment are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0040] As used herein, the term "heteroatom" or "cyclic heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0041] As used herein, a prodrug is a compound that is metabolized upon in vivo administration, or undergoes chemical changes or other conversions through one or more steps or processes under physiological conditions, into a biologically, pharmaceutically, or therapeutically active form of the compound.Furthermore, a prodrug can be converted into a biologically, pharmaceutically, or therapeutically active form of the compound by chemical or biochemical methods in an ex vivo environment.For example, a prodrug can be converted into a compound of the present invention when placed in a transdermal patch reservoir using an appropriate enzyme or chemical reagent.

[0042] Certain compounds provided herein can exist in non-solvated form and solvated form, including hydrated form.Generally, solvated form is equivalent to non-solvated form and is included in the scope of the present disclosure.Specific compounds provided herein can exist in multiple crystalline forms or amorphous forms.Generally, all physical forms are equivalent for the use contemplated herein and are intended to be within the scope of the present disclosure.

[0043] Certain compounds provided herein possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, tautomers, geometric isomers, and individual isomers are encompassed within the scope of this disclosure. The compounds provided herein do not include those known in the art to be too unstable to synthesize and / or isolate.

[0044] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds provided herein, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0045] II. COMPOUNDS FOR USE IN COMPOSITIONS AND METHODS In one embodiment, provided herein are compounds for use in the compositions and methods provided herein having formula I or II:

[0046] [ka]

[0047] (Wherein, Ar is aryl, heteroaryl, C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, 5- to 7-membered heterocyclyl, or 5- to 7-membered heterocycloalkenyl; E is a moiety that binds to an E3 ubiquitin ligase; X 1 ~X 2 are each independently N or C; X 3 ~X 5 are each independently CR, N, NR, S, or O, and each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl; or two R groups at adjacent positions on the ring are joined to form an alkylene; or R and Ar at adjacent positions on a five-membered ring are joined to form a fused ring).

[0048] In one embodiment, provided herein are compounds for use in the compositions and methods provided herein having formula I or II:

[0049] [ka]

[0050] (Wherein, Ar is aryl, heteroaryl, C 5-7 is a cycloalkyl or 5- to 7-membered heterocyclyl; E is a moiety that binds to an E3 ubiquitin ligase; X 1 ~X 2 are each independently N or C; and X 3 ~X 5are each independently CR, N, NR, S, or O, and each R is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two R groups at adjacent positions on the ring together form an alkylene).

[0051] In another embodiment, provided herein are compounds for use in the compositions and methods provided herein having formula I or II:

[0052] [ka]

[0053] where Ar is aryl; E is a moiety that binds to an E3 ubiquitin ligase; and X 1 ~X 2 are each independently N or C; X 3 ~X 5 are each independently CR, N, NR, S, or O, and each R is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two R groups at adjacent positions on the ring together form an alkylene).

[0054] 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.

[0055] In another embodiment, the compound of formula II is X 1 C, X 2 , X 4 and X 5 is N, and then X 3is selected with the proviso that when X is CH, E is not an isoindolinedione moiety. 4 and X 5 If N, then X 2 is selected under the condition that is not N.

[0056] In another embodiment, the compound of formula II is X 1 and X 2 C, X 3 NMe, X 4 N and X 5 is selected with the proviso that when X is CH, E is not an isoindolinedione moiety. 4 If N, then X 3 is selected with the proviso that X is not NMe. 3 If NMe, then X 4 is selected on the condition that it is not N.

[0057] In another embodiment, the compound of formula II is X 1 and X 2 C, X 3 CH, X 4 N and X 5 is selected with the proviso that when X is NMe, Ar is not 5-fluoro-2-pyridyl. 1 and X 2 C, X 3 CH, X 4 N and X 5 is NMe, then Ar is selected with the proviso that it is not heteroaryl.

[0058] In another embodiment, the compound of formula I is X 1 N, X 2 C, X 3 and X 4 is CH and X 5 is selected with the proviso that when X is N, Ar is not cyclopropyl. 1 N, X2 C, X 3 and X 4 is CH and X 5 is N, then Ar is not cycloalkyl.

[0059] In another embodiment, the compound of formula II is X 1 N, X 2 C, X 3 and X 4 is CH and X 5 is N, then Ar is not phenyl. In another embodiment, the compound of formula II is 1 N, X 2 C, X 3 and X 4 is CH and X 5 is N, then Ar is selected with the proviso that it is not aryl.

[0060] In another embodiment, the compound of formula II is X 1 and X 3 N, X 2 C, and X 4 and X 5 is selected with the proviso that when X is CH, Ar is not phenyl. 1 and X 3 N, X 2 C, and X 4 and X 5 is CH, then Ar is not aryl.

[0061] In another embodiment, the compound of formula II is X 1 ~X 5 is selected with the proviso that the ring having the formula: is not 1,2,3-triazole-1,4-diyl.

[0062] In another embodiment, compounds of formula I and II are selected with the proviso that Ar is not tetrahydropyran-2-yl. In another embodiment, compounds of formula I and II are selected with the proviso that Ar is not tetrahydropyranyl.

[0063] In another embodiment, the compound of 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 of 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 of 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.

[0064] In certain embodiments, the compounds provided herein include multiple E groups. In other embodiments, the compounds provided herein have one of the following formulas:

[0065] [ka]

[0066] (where Ar, E and X 1 ~X 5 is as defined elsewhere herein).

[0067] In one embodiment, X 1 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 both C and the compound has the following structure:

[0068] [ka]

[0069] (where Ar, E and X 3 ~X5 are as defined elsewhere herein).

[0070] In another embodiment, the compounds provided herein have one of the following formulae:

[0071] [ka]

[0072] [ka]

[0073] In another embodiment, X 1 and X 2 are both C and X 5 is NR and the compound has the following structure:

[0074] [ka]

[0075] (where Ar, E, X 3 and X 4 are as defined elsewhere herein).

[0076] In another embodiment, X 1 and X 2 are both C and X 3 is CR, X 4 is N and X 5 is NR and the compound has the following structure:

[0077] [ka]

[0078] wherein Ar, E, and R are as defined elsewhere herein. In another embodiment, X 3 is CH and the compound has the following structure:

[0079] [ka]

[0080] (where Ar, E, and R are as defined elsewhere herein.) In another embodiment, the compound has the structure:

[0081] [ka]

[0082] (Ar and E are as defined elsewhere herein).

[0083] In another embodiment, X 1 and X 2 are both C and X 3 is N, X 4 is CR and X 5 is NR and the compound has the following structure:

[0084] [ka]

[0085] (Ar, E and R are as defined elsewhere herein). In another embodiment, X 4 is CH and the compound has the following structure:

[0086] [ka]

[0087] (Ar, E, and R are as defined elsewhere herein.) In another embodiment, the compound has the structure:

[0088] [ka]

[0089] (Ar and E are as defined elsewhere herein).

[0090] In another embodiment, the compound has the structure:

[0091] [ka]

[0092] (R, Ar and E are as defined elsewhere herein). In another embodiment, the compound has the structure:

[0093] [ka]

[0094] (Ar and E are as defined elsewhere herein).

[0095] In another embodiment, the compound has the structure:

[0096] [ka]

[0097] (R, Ar and E are as defined elsewhere herein).

[0098] In another embodiment, the compound has the structure:

[0099] [ka]

[0100] (R, Ar and E are as defined elsewhere herein).

[0101] In another embodiment, the compound has the structure:

[0102] [ka]

[0103] (R, Ar and E are as defined elsewhere herein).

[0104] In another embodiment, the compound has the structure:

[0105] [ka]

[0106] (X 1 , X 3 , X 4 , R, Ar and E are as defined elsewhere herein).

[0107] In another embodiment, each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl; or two R groups at adjacent positions on the ring are joined together to form an alkylene. In another embodiment, each R is independently H, alkyl, alkenyl, or alkynyl. In another embodiment, each R is independently H, alkyl, cycloalkyl, heterocyclyl, or aryl; or two R groups at adjacent positions on the ring are joined together to form a lower alkylene. In another embodiment, each R is independently H, alkyl, cycloalkyl, or aryl; or two R groups at adjacent positions on the ring are joined together to form a lower alkylene. In another embodiment, each R is independently H or alkyl; or two R groups at adjacent positions on the ring are joined together to form a lower alkylene. 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, trideuteromethyl, 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. In another embodiment, each R is independently H, methyl, difluoromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoro-1-ethyl, cyclopropyl, trideuteromethyl, ethyl, 2-hydroxy-2-methylpropyl, cyclohexyl, 4-pyranyl, or phenyl; or two R groups at adjacent positions on the ring together form propylene. In another embodiment, each R is independently H, methyl, difluoromethyl, fluoromethyl, trifluoromethyl, cyclopropyl, trideuteromethyl, ethyl, 2-hydroxy-2-methylpropyl, or phenyl; or two R groups at adjacent positions on the ring together form propylene.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.

[0108] In another embodiment, E is a moiety that binds to cereblon. In another embodiment, E has an imide, amide, thioamide, or thioimide-derived moiety. In another embodiment, E has a phthalimide group or an analog or derivative thereof. In another embodiment, E has a phthalimide-glutarimide group or an analog or derivative thereof. In another embodiment, E has a thalidomide, lenalidomide, or pomalidomide moiety or an analog or derivative thereof.

[0109] In another embodiment, E has one of the following general formulas:

[0110] [ka]

[0111] (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, heterocyclyl, aryl, or heteroaryl; Y 1 and Y 2 One of them is S and the other is CR 3 (R 3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z 1 ~Z 4 are each independently N or CR 4 (Each R 4are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl). In one embodiment, up to Z 1 ~Z 4 are N. In another embodiment, Z 1 and R 1 form a fused phenyl ring together with the atoms to which they are attached; R 2 does not exist; E has the formula:

[0112] [ka]

[0113] (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 (Each R 4 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl).

[0114] In one embodiment, A is a cyclic imide having the structure:

[0115] [ka]

[0116] (R 5 is H or alkyl; R 6 and R 7 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl; and m is an integer from 1 to 4.

[0117] In another embodiment, R 5 is H or lower alkyl. In another embodiment, R 5 is H or methyl. In another embodiment, R 5is H. In another embodiment, R 5 is methyl.

[0118] In another embodiment, R 6 and R 7 are each independently H or alkyl. 6 and R 7 are each independently H or methyl. In another embodiment, R 6 and R 7 are both H.

[0119] 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.

[0120] In another embodiment, A has the structure:

[0121] [ka]

[0122] (R 5 ~R 7 are selected as described elsewhere herein).

[0123] In another embodiment, A has the structure:

[0124] [ka]

[0125] (R 5 are selected as described elsewhere herein).

[0126] In another embodiment, A has one of the following structures with the absolute stereochemistry shown:

[0127] [ka]

[0128] In another embodiment, R 1 and R 2 are each independently H, alkyl, alkenyl, or alkynyl. 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 H respectively.

[0129] In another embodiment, R 3 is H, alkyl, alkenyl, or alkynyl. 3 is H or alkyl. In another embodiment, R 3 is H or methyl. In another embodiment, R 3 is H.

[0130] In another embodiment, R 4 is H, alkyl, alkenyl, or alkynyl. 4 is H or alkyl. In another embodiment, R 4 is H or methyl. In another embodiment, R 4 is H.

[0131] 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 CH and Y 2is S.

[0132] In another embodiment, Z 1 are N and Z 2 ~Z 4 is CR 4 In another embodiment, Z 1 are N and Z 2 ~Z 4 is CH.

[0133] In another embodiment, Z 2 are N and Z 1 , Z 3 and Z 4 is CR 4 In another embodiment, Z 2 are N and Z 1 , Z 3 and Z 4 is CH.

[0134] In another embodiment, Z 3 are N and Z 1 , Z 2 and Z 4 is CR 4 In another embodiment, Z 3 are N and Z 1 , Z 2 and Z 4 is CH.

[0135] In another embodiment, Z 4 are N and Z 1 ~Z 3 is CR 4 In another embodiment, Z 4 are N and Z 1 ~Z 3 is CH.

[0136] In another embodiment, E is imide. In another embodiment, E is selected from:

[0137] [ka]

[0138] (R 5 are as defined elsewhere herein).

[0139] In another embodiment, E has the structure:

[0140] [ka]

[0141] (R 5 is as defined elsewhere herein. In another embodiment, E is selected from:

[0142] [ka]

[0143] In another embodiment, Ar is aryl, heteroaryl, C 5-7 Cycloalkyl, C 5-7 Cycloalkenyl, 5- to 7-membered heterocyclyl having at least one N atom in the ring, or 5- to 7-membered heterocycloalkenyl having at least one N atom in the ring.

[0144] 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 pyridopyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted benzofuryl, optionally substituted imidazopyridyl, optionally substituted benzopyrazolyl, optionally substituted pyrrolopyridyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted thienopyridyl, optionally substituted dihydrobenzofuryl, 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 azepinyl, optionally substituted isoquinolinyl, optionally substituted cycloheptenyl, optionally substituted indenyl, optionally substituted dihydronaphthyl, optionally substituted 8-azabicyclooctanyl, optionally substituted adamantanyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl or optionally substituted cyclohexyl.

[0145] In one embodiment, Ar is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted pyridopyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted dihydrobenzofuryl, 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.

[0146] In another embodiment, Ar is phenyl, biphenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, pyridopyrazolyl, isoxazolyl, indolyl, isoindolyl, thienyl, dihydrobenzoyl, dihydroindenyl, cyclopropyl, or cyclohexyl, each of which is selected from halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 and optionally substituted with one or more substituents each independently selected from: R 8 is alkyl, OR 13 or NR 14 R 15 ; R 9 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or COR 16 ; R 10 and R 11 are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or COR 17 ; R 12is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 18 or NR 14 R 15 ; Each R 13 , R 14 and R 15 are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 16 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 17 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 18 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and n is 0, 1 or 2.

[0147] In another embodiment, Ar is phenyl, biphenyl, or naphthyl, each of which is selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 and optionally substituted with one or more substituents each independently selected from: R 8 is alkyl, OR 13 or NR 14 R 15 ; R 9 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or COR 16 ; R 10 and R11 are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or COR 17 ; R 12 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 18 or NR 14 R 15 ; Each R 13 , R 14 and R 15 are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 16 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 17 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 13 or NR 14 R 15 ; R 18 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and n is 0, 1 or 2.

[0148] 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.

[0149] In another embodiment, Ar is halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15 , OR 9 , N.R. 10 R 11 and S(O)R 12 and phenyl optionally substituted with one or more substituents each independently selected from:

[0150] In another embodiment, Ar is chloro, fluoro, 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-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, 1-pyrazolyl, 2- Phenyl optionally substituted with one or more substituents independently selected from pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, SONH-cyclohexyl, and SO-(1-pyrrolidinyl).

[0151] In another embodiment, Ar is chloro, fluoro, 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-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 4-cyanophenyl, 4-hydroxyphenyl, and phenyl optionally substituted with one or more substituents independently selected from 1-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, (3-methoxybenzyl)oxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, SONH-cyclohexyl, and SO-(1-pyrrolidinyl).

[0152] In another embodiment, Ar is chloro, fluoro, 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-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 1-pyrazolyl, 3- Phenyl optionally substituted with one or more substituents independently selected from pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0153] In another embodiment, Ar is phenyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0154] In another embodiment, Ar is phenyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, 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.

[0155] In another embodiment, Ar is unsubstituted phenyl, unsubstituted 4-biphenyl or unsubstituted 1-naphthyl.In another embodiment, Ar is unsubstituted phenyl.

[0156] In another embodiment, Ar is halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 and thienyl optionally substituted with one or more substituents each independently selected from:

[0157] In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 and thienyl optionally substituted with one or more substituents each independently selected from:

[0158] In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15, OR 9 , N.R. 10 R 11 and S(O)R 12 and thienyl optionally substituted with one or more substituents each independently selected from:

[0159] In another embodiment, Ar is chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, SONH-cyclohexyl, and SO-(1-pyrrolidinyl).

[0160] In another embodiment, Ar is thienyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0161] In another embodiment, Ar is thienyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, 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.

[0162] In another embodiment, Ar is unsubstituted thienyl.

[0163] In another embodiment, Ar is halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 and pyrazolyl, optionally substituted with one or more substituents each independently selected from:

[0164] In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 and pyrazolyl, optionally substituted with one or more substituents each independently selected from:

[0165] In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15 , OR 9 , N.R. 10 R 11 and S(O)R 12 and pyrazolyl, optionally substituted with one or more substituents each independently selected from:

[0166] In another embodiment, Ar is chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 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).

[0167] In another embodiment, Ar is pyrazolyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0168] In another embodiment, Ar is pyrazolyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, 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.

[0169] In another embodiment, Ar is unsubstituted pyrazolyl.

[0170] In another embodiment, the compounds provided herein have the structure:

[0171] [ka]

[0172] (R 5 , Ar and X 1 ~X 5 are as defined elsewhere herein).

[0173] In another embodiment, the compounds provided herein have the structure:

[0174] [ka]

[0175] (R 5 , Ar and X 1 ~X 5 are as defined elsewhere herein).

[0176] In another embodiment, the compounds provided herein have the structure:

[0177] [ka]

[0178] (X 3 , X 4 , R, Ar and R 5 are as defined elsewhere herein).

[0179] In another embodiment, the compounds provided herein have the structure:

[0180] [ka]

[0181] (X 4 , R, Ar and R 5 are as defined elsewhere herein).

[0182] In another embodiment, the compounds provided herein have the structure:

[0183] [ka]

[0184] (X 4 , R, Ar and R 5 are as defined elsewhere herein).

[0185] In another embodiment, the compounds provided herein have the structure:

[0186] [ka]

[0187] (R, R 5 and Ar are as defined elsewhere herein).

[0188] In another embodiment, the compounds provided herein have the structure:

[0189] [ka]

[0190] (Ar is as defined elsewhere herein).

[0191] In another embodiment, the compounds provided herein have the structure:

[0192] [ka]

[0193] (Ar is as defined elsewhere herein.) In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15 , OR 9 , N.R. 10 R 11 and S(O)R 12In another embodiment, Ar is phenyl optionally substituted with one or more substituents independently selected from chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0194] In another embodiment, the compounds provided herein have the structure:

[0195] [ka]

[0196] (R, R 5 and Ar are as defined elsewhere herein).

[0197] In another embodiment, the compounds provided herein have the structure:

[0198] [ka]

[0199] (Ar is as defined elsewhere herein).

[0200] In another embodiment, the compounds provided herein have the structure:

[0201] [ka]

[0202] (Ar is as defined elsewhere herein.) In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15 , OR 9 , N.R. 10 R 11 and S(O)R 12 In another embodiment, Ar is phenyl optionally substituted with one or more substituents independently selected from chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0203] In another embodiment, the compounds provided herein have the structure:

[0204] [ka]

[0205] (R, R 5 and Ar are as defined elsewhere herein).

[0206] In another embodiment, the compounds provided herein have the structure:

[0207] [ka]

[0208] (Ar is as defined elsewhere herein).

[0209] In another embodiment, the compounds provided herein have the structure:

[0210] [ka]

[0211] (Ar is as defined elsewhere herein.) In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15 , OR 9 , N.R. 10 R 11and S(O)R 12 In another embodiment, Ar is phenyl optionally substituted with one or more substituents each independently selected from chloro, fluoro, 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.

[0212] In another embodiment, the compounds provided herein have the structure:

[0213] [ka]

[0214] (R, Ar and R 5 are as defined elsewhere herein).

[0215] In another embodiment, the compounds provided herein have the structure:

[0216] [ka]

[0217] (Ar and R 5 are as defined elsewhere herein).

[0218] In another embodiment, the compounds provided herein have the structure:

[0219] [ka]

[0220] (Ar is as defined elsewhere herein).

[0221] In another embodiment, the compounds provided herein have the structure:

[0222] [ka]

[0223] (Ar is as defined elsewhere herein.) In another embodiment, Ar is halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from chloro, fluoro, 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-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, 1-pyrrolidinyl, phenyl, 1-pyrazolyl, 3- Phenyl optionally substituted with one or more substituents independently selected from pyridinyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0224] In another embodiment, the compounds provided herein have the structure:

[0225] [ka]

[0226] (X 5 , R, Ar and R 5 are as defined elsewhere herein).

[0227] In another embodiment, the compounds provided herein have the structure:

[0228] [ka]

[0229] (Ar and R 5 are as defined elsewhere herein).

[0230] In another embodiment, the compounds provided herein have the structure:

[0231] [ka]

[0232] (Ar is as defined elsewhere herein).

[0233] In another embodiment, the compounds provided herein have the structure:

[0234] [ka]

[0235] (Ar is as defined elsewhere herein.) In another embodiment, Ar is halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR 8 , OR 9 , N.R. 10 R 11 and S(O) n R 12 In another embodiment, Ar is phenyl, optionally substituted with one or more substituents each independently selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR 14 R 15 , OR 9 , N.R. 10 R 11 and S(O)R 12 In another embodiment, Ar is phenyl optionally substituted with one or more substituents independently selected from chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH, CONHMe, CONMe, CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH, NMe, NHCOPh, SOMe, and SO-(1-pyrrolidinyl).

[0236] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0237] [ka]

[0238] [ka]

[0239] [ka]

[0240] [ka]

[0241] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0242] [ka]

[0243] [ka]

[0244] [ka]

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] [ka]

[0250] [ka]

[0251] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0252] [ka]

[0253] [ka]

[0254] [ka]

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0262] [ka]

[0263] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0264] [ka]

[0265] [ka]

[0266] [ka]

[0267] [ka]

[0268] [ka]

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] [ka]

[0277] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0278] [ka]

[0279] [ka]

[0280] [ka]

[0281] [ka]

[0282] [ka]

[0283] [ka]

[0284] In another embodiment, the compounds provided herein for use in the compositions and methods provided herein are selected from the following:

[0285] [ka]

[0286] [ka]

[0287] [ka]

[0288] [ka]

[0289] [ka]

[0290] [ka]

[0291] III. Compound Synthesis The compounds provided herein may be synthesized using standard methods known to those skilled in the art starting from commercially available raw materials. In one embodiment, the compounds provided herein are synthesized according to one of the methods shown below.

[0292] [ka]

[0293] In another embodiment, a library of compounds may be synthesized according to the methods set forth below (see, e.g., WO 2021 / 226269, WO 2020 / 127685, WO 2010 / 068242):

[0294] [ka]

[0295] (R 20 is a substituent on Ar as defined herein, and x is an integer from 1 to 5, or from 1 to 3, or 1 or 2).

[0296] In another embodiment, a library of compounds may be synthesized according to the following method (see, e.g., WO 2014 / 151945, WO 2010 068242):

[0297] [ka]

[0298] (R 20is a substituent on Ar as defined herein, and x is an integer from 1 to 5, or from 1 to 3, or 1 or 2).

[0299] In another embodiment, a library of compounds may be synthesized according to the following method (see, e.g., WO 2014 / 151945, WO 2010 068242):

[0300] [ka]

[0301] (R 20 is a substituent on Ar as defined herein, and x is an integer from 1 to 5, or from 1 to 3, or 1 or 2).

[0302] In another embodiment, a library of compounds may be synthesized according to one of the following methods:

[0303] [ka]

[0304] (R is Ar as defined herein).

[0305] IV. Pharmaceutical Compositions Pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0306] Compound can be formulated into suitable pharmaceutical preparations such as solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained-release preparation or elixir for oral administration, or sterile solution or suspension for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhaler.Typically, above-mentioned compound is formulated into pharmaceutical composition by using well-known technology and procedure in the art (for example, see Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0307] 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 to deliver an amount that, when administered, treats, prevents, or ameliorates one or more of the symptoms and / or progression of the diseases or disorders disclosed herein.

[0308] Typically, composition is formulated for single dose administration.To formulate composition, the weight fraction of compound is dissolved, suspended, dispersed or mixed in selected vehicle at effective concentration, so that the treated condition is alleviated or improved.The pharmaceutical carrier or vehicle suitable for administering provided herein compound includes those carriers known by those skilled in the art to be suitable for specific administration mode.

[0309] Furthermore, the compound may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, such as tissue-targeted liposomes, including tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as is well known in the art. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0310] The active compound is contained in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically beneficial effect without undesirable side effects in the treated subject. The therapeutically effective concentration can be empirically determined by testing the compound in the in vitro and in vivo systems described herein, and then extrapolated therefrom for human administration. In some embodiments, the active compound is administered in a manner to achieve a therapeutically effective concentration of the drug. In some embodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen JT, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389 / fonC.2014.00105) is used to determine the therapeutic concentration and safety profile of the active compound in a particular subject or subject population.

[0311] The concentration of active compound in pharmaceutical composition depends on the absorption, tissue distribution, inactivation and excretion rate of active compound, the physicochemical properties of compound, administration schedule and dosage and other factors known to those skilled in the art.For example, the amount delivered is sufficient to improve one or more symptoms of the disease or disorder disclosed herein.

[0312] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of the active ingredient of about 0.1 ng / mL to about 50-100 μg / mL. In one embodiment, the pharmaceutical composition provides a dosage of about 0.001 mg to about 2000 mg of compound per kg of body weight per day. Pharmaceutical dosage unit forms are prepared to provide about 1 mg to about 1000 mg, and in certain embodiments, about 10 mg to about 500 mg, of the essential active ingredient or combination of essential ingredients per dosage unit form.

[0313] The active ingredient may be administered at once, or may be divided into several smaller doses for administration at intervals of time.It is understood that the exact dosage and duration of treatment are a function of the disease to be treated, and can be empirically determined using known testing protocols, or determined by extrapolation from in vivo or in vitro test data.It should be noted that concentration and dosage values ​​can also vary according to the severity of the condition to be alleviated.In addition, for any specific subject, specific dosage regimen should be adjusted over time according to individual need and the professional judgment of the person who directs or supervises the administration of the composition, and it should be understood that the concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed compositions.

[0314] Therefore, the effective concentration or effective amount of one or more of the compounds described herein or their pharmaceutically acceptable salts is mixed with a suitable pharmaceutical carrier or vehicle for systemic administration, external administration or local administration to form a pharmaceutical composition.The compound is contained in an amount that is effective for improving, treating, delaying the progression or preventing one or more symptoms.The concentration of the active compound in the composition depends on the absorption, tissue distribution, inactivation, excretion rate, administration schedule, dosage, specific formulation of the active compound, and other factors known to those skilled in the art.

[0315] The compositions are intended to be administered by any suitable route, including, but not limited to, oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, transdermal, transcutaneous, buccal, rectal, topical, local, intranasal, or inhalation. For oral administration, they may also be formulated into capsules or tablets. The compositions may be in liquid, semi-liquid, or solid form and are formulated in a manner appropriate for each route of administration.

[0316] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can contain any of the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and tonicity adjusters such as sodium chloride and glucose. Parenteral preparations can be enclosed in ampoules, pens, disposable syringes, or single- or multi-dose vials made of glass, plastic, or other suitable material.

[0317] If the compound exhibits insufficient solubility, methods for solubilizing the compound can be used, which are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[0318] Upon mixing or addition of the compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends upon many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder, or condition being treated and may be empirically determined.

[0319] Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions, containing an appropriate amount of the compound or its pharmaceutically acceptable salts. Pharmaceutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. As used herein, unit dosage form refers to a physically discrete unit suitable for human and animal subjects, packaged individually as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets or capsules. Unit dosage forms may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses that are not segregated in packaging.

[0320] Sustained-release formulations can also be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing a compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl-1-methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, LUPRON DEPOT TMExamples of suitable stabilization strategies include degradable lactic acid-glycolic acid copolymers, such as lactic acid-glycolic acid copolymers (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyrate. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter periods. If encapsulated compounds remain in the body for extended periods, exposure to humidity at 37°C can result in denaturation or aggregation, leading to loss of biological activity and structural changes. Depending on the mechanism of action, rational strategies for stabilization can be devised. For example, if the aggregation mechanism is determined to be intermolecular S--S bond formation via thio-disulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilization from acidic solution, controlling water content, using appropriate additives, and developing specific polymer matrix compositions.

[0321] Dosage forms or compositions can be prepared containing the active ingredient in the range of 0.005% to 100%, with the remainder consisting of non-toxic carriers. For oral administration, pharmaceutically acceptable, non-toxic compositions can be formed by incorporating any of the commonly used excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or saccharin sodium. Such compositions include, but are not limited to, solutions, suspensions, tablets, capsules, powders, and sustained-release formulations, such as implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, and polylactic acid. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions can contain about 0.001% to 100% active ingredient, and in certain embodiments, about 0.1-85% or about 75-95%.

[0322] The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings.

[0323] The composition may contain other active compounds to obtain the desired combination of properties.The compounds provided herein or their pharmaceutically acceptable salts as described herein may also be advantageously administered for therapeutic or prophylactic purposes with other pharmacological agents that are generally known in the art to be valuable in treating one or more of the diseases or medical conditions mentioned above, such as diseases associated with oxidative stress.It should be understood that such combination therapy constitutes a further aspect of the compositions and treatment methods provided herein.

[0324] The lactose-free compositions provided herein can contain excipients that are well known in the art, such as those listed in the United States Pharmacopoeia (USP) SP(XXI) / NF(XVI).Generally, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts.An exemplary lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0325] Also included are anhydrous pharmaceutical compositions and dosage forms containing the compounds provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine properties such as shelf life or stability over time of a formulation. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of moisture on a formulation is very important, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipping, and use of formulations.

[0326] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture-containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient that contains a primary or secondary amine are anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0327] Anhydrous pharmaceutical compositions should be prepared and stored so as to maintain their anhydrous nature.Therefore, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0328] A. Oral Dosage Forms Oral dosage forms of pharmaceuticals can be solid, gel, or liquid.Solid dosage forms include tablets, capsules, granules, and bulk powders.Oral tablets include compressed tablets, chewable tablets, lozenges, and enteric-coated, sugar-coated, or film-coated tablets.Capsules can be hard or soft gelatin capsules, and granules and powders can be provided in non-effervescent or effervescent form by combining with other ingredients known to those skilled in the art.

[0329] In certain embodiments, the formulation is a solid dosage form such as a capsule or tablet. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients, or compounds of a similar nature: binders; diluents; disintegrants; lubricants; flow agents; sweeteners; and flavoring agents.

[0330] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste.Lubricants include talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid.Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and calcium hydrogen phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose.Coloring agents include, for example, any of the approved water-soluble FD and C dyes, their mixtures; and water-insoluble FD and C dyes suspended in alumina hydrate. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, as well as many spray-dried flavors. Flavoring agents include natural flavors extracted from fruits and other plants that provide a pleasant sensation, as well as synthetic blends of compounds, such as, but not limited to, peppermint and methyl salicylate. Humectants 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 hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0331] When oral administration is desired, the compound can be provided in a composition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.The composition can also be formulated in combination with antacids or other such ingredients.

[0332] When the dosage unit is a capsule, in addition to the above-mentioned materials, it can contain liquid carriers such as fatty oils.In addition, dosage unit can contain various other materials that modify the physical form of dosage unit, such as sugar coating and other enteric coatings.The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups can contain sucrose as a sweetener, certain preservatives, dyes and colorings, and flavorings in addition to the active compound.

[0333] The active material can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a pharmaceutically acceptable salt thereof. Higher concentrations, up to about 98% by weight, of the active ingredient may also be included.

[0334] Pharmaceutically acceptable carriers contained in tablets include binders, lubricants, diluents, disintegrants, colorants, flavoring agents, and wetting agents. Enteric-coated tablets resist the action of stomach acid and dissolve or disintegrate in neutral or alkaline intestines due to the enteric coating. Sugar-coated tablets are compressed tablets coated with different layers of pharmaceutically acceptable materials. Film-coated tablets are compressed tablets coated with polymers or other suitable coatings. Multiple-compressed tablets are compressed tablets produced by two or more compression cycles using the aforementioned pharmaceutically acceptable materials. Colorants can also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar-coated tablets, multiple-compressed tablets, and chewable tablets. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0335] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil. In some embodiments, suspensions are suspensions of microparticles or nanoparticles. In some embodiments, emulsions are emulsions of microparticles or nanoparticles.

[0336] Elixirs are clear, sweetened hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. Emulsions are two-phase systems, with one liquid dispersed in the other in the form of small globules. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers, 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 carbon dioxide sources. Coloring and flavoring agents are used in all of the above dosage forms.

[0337] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Preservatives include glycerin, methylparaben, propylparaben, benzoic acid adduct, sodium benzoate, and alcohol. Non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Emulsifiers include surfactants such as gelatin, acacia, tragacanth, bentonite, and polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and acacia. Diluents include lactose and sucrose. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic additives include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds which produce a pleasant taste sensation.

[0338] For a solid dosage form, the solution or suspension, for example, in propylene carbonate, vegetable oils, or triglycerides, is enclosed in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, for example, water, to be easily measured for administration.

[0339] Alternatively, liquid or semisolid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or polyalkylene glycol such as, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants such as, for example, 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.

[0340] Other formulations include, but are not limited to, pharmaceutically acceptable aqueous alcoholic solutions, such as acetal.The alcohols used in these formulations are pharmaceutically acceptable water-miscible solvents with one or more hydroxyl groups, such as but not limited to propylene glycol and ethanol.Acetals include, but are not limited to, the di(lower alkyl) acetal of lower alkyl aldehyde, such as acetaldehyde diethyl acetal.

[0341] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient, for example, with conventional enterically digestible coatings such as phenyl salicylate, waxes, and cellulose acetate phthalate.

[0342] B. Injections, solutions and emulsions Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly, or intravenously, although parenteral administration is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. In some embodiments, suspensions are suspensions of microparticles or nanoparticles. In some embodiments, emulsions are emulsions of microparticles or nanoparticles. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. If desired, the administered pharmaceutical composition may also contain small amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained, is also contemplated herein.Briefly, the compounds provided herein are dispersed in a solid internal matrix such as, for example, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, cross-linked partially hydrolyzed polyvinyl acetate, and the like, e.g., polyethylene. These parenteral compositions are insoluble in body fluids and surrounded by an outer polymeric membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate copolymer, vinylidene chloride, ethylene and propylene, ionomer-polyethylene terephthalate, butyl rubber-epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. The compound diffuses through the outer polymeric membrane in a release-rate-controlling process. The percentage of active compound contained in such parenteral compositions varies greatly depending on the specific nature of the composition, as well as the activity of the compound and the needs of the subject.

[0343] Parenteral administration of the composition includes intravenous administration, subcutaneous administration and intramuscular administration.Preparation for parenteral administration includes sterile solution ready for injection, sterile dry soluble product ready for mixing with solvent immediately before use, such as freeze-dried powder, including subcutaneous injection tablets, sterile suspension ready for injection, sterile dry insoluble product ready for mixing with vehicle immediately before use, and sterile emulsion.Solution can be aqueous or non-aqueous.

[0344] For intravenous administration, suitable carriers include physiological saline or phosphate buffered saline (PBS) and solutions containing thickening agents and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0345] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances.

[0346] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Parenteral formulations packaged in multidose containers must contain antibacterial agents in bacteriostatic or fungistatic concentrations, including phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonicity agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Examples of emulsifying agents include polysorbate 80 (TWEEN® 80). Examples of sequestering or chelating agents for metal ions include EDTA. Examples of pharmaceutical carriers include water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and propylene glycol, and pH adjusters such as sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.

[0347] The concentration of the pharmaceutically active compound is adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dosage depends on the age, weight, and condition of the subject or animal, as is known in the art.

[0348] Unit-dose parenteral preparations are packaged in ampoules, vials, or syringes with needles. All preparations for parenteral administration must be sterile, as known and practiced in the art.

[0349] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material injected as needed to produce the desired pharmacological effect.

[0350] Injectables are designed for local and systemic administration. Typically, a therapeutically effective dose is formulated to contain a concentration of the active compound in the treated tissue of at least about 0.1% w / w up to about 90% w / w or more, e.g., greater than 1% w / w. The active ingredient may be administered at once or divided into several smaller doses for administration over time. It is understood that the precise dosage and duration of treatment are a function of the tissue being treated and are determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​may also vary with the age of the individual being treated. Furthermore, for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person directing or supervising the administration of the formulations, and it should be understood that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed formulations. It should be noted that concentration and dosage values ​​may also vary with the severity of the condition to be alleviated. Further, for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and it should be understood that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0351] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on many factors, such as the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is a concentration sufficient to improve the symptoms of the condition and can be empirically determined.

[0352] C. Freeze-dried powder Also provided herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions, and other mixtures, or they may be reconstituted and formulated as solids or gels.

[0353] Sterile lyophilized powders are prepared by dissolving a compound provided herein or a pharmaceutically acceptable salt thereof in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citrate, sodium phosphate, or potassium phosphate, or other such buffers known to those of skill in the art, in one embodiment at approximately neutral pH. The solution is then sterile filtered, followed by lyophilization under standard conditions known to those of skill in the art to obtain the desired formulation. Typically, the resulting solution is dispensed into vials for lyophilization. Each vial contains 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 at about 4°C to room temperature.

[0354] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, add approximately 1-50 mg, approximately 5-35 mg, or approximately 9-30 mg of lyophilized powder per mL of sterile water or other suitable carrier. The exact amount will depend on the compound selected; such amounts can be determined empirically.

[0355] D. Topical administration Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, douche, spray, suppository, bandage, skin patch, or other formulation suitable for topical administration.

[0356] The compound or its pharmaceutically acceptable salt can be formulated as an aerosol for topical application, such as inhalation (see, e.g., US Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids useful for treating inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for nebulizers, or as fine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particle diameter of the formulation will be less than 50 microns or less than 10 microns.

[0357] The compound can be formulated for topical or external application, such as topical application to the skin and mucous membranes, including the inside of the eye, in the form of gel, cream, and lotion, and application to the eye, or intrathoracic or intraspinal application.External administration also contemplates transdermal delivery, administration to the eye or mucous membranes, or inhalation therapy.Nasal drops containing the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0358] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions with appropriate salts and a pH of about 5 to 7.

[0359] E. Compositions for Other Routes of Administration Other routes of administration, such as topical application, transdermal patches, and rectal administration, are also contemplated herein.

[0360] For example, pharmaceutical dosage forms for rectal administration include rectal suppositories, capsules, and tablets for systemic use. As used herein, a rectal suppository refers to a solid body for insertion into the rectum that melts or softens at body temperature and releases one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and melting point elevating agents. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), and appropriate mixtures of mono-, di-, and triglycerides of fatty acids. Various bases may be used in combination. Agents that elevate the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by either compression or molding. An exemplary weight of a rectal suppository is approximately 2 to 3 grams.

[0361] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.

[0362] F. Sustained release composition The active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos. 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, Such dosage forms include, but are not limited to, those described in Nos. 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500, and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide delayed or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide desired release profiles at various rates. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0363] All controlled-release pharmaceutical products share a common goal of improving drug therapy over that achieved by their non-controlled counterparts. In one embodiment, the use of optimally designed controlled-release formulations in medical treatments is characterized by the use of a minimum amount of drug substance to cure or control a condition in a minimum amount of time. In certain embodiments, the benefits of controlled-release formulations include extended drug activity, reduced dosing frequency, and improved subject compliance. Furthermore, controlled-release formulations can be used to affect other characteristics of the drug, such as its onset of action or blood concentration, which can in turn affect the occurrence of side effects (e.g., adverse effects).

[0364] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, and then gradually and continuously release another amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0365] In certain embodiments, the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, e.g., 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 may be used. In yet another embodiment, a controlled release system may be placed in the vicinity of the therapeutic target, i.e., requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)).

[0366] In some embodiments, a controlled-release device is introduced into a subject in proximity to a site of inappropriate immune activation or a tumor. Other controlled-release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)). The active ingredient is dispersed within a solid internal matrix, such as, for example, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, cross-linked partially hydrolyzed polyvinyl acetate, and the like, e.g., polyethylene, polypropylene, polypropylene copolymer ... These compositions are typically surrounded by an outer polymeric membrane that is insoluble in body fluids and includes polymers such as polyethylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate copolymers, vinylidene chloride, ethylene and propylene, ionomer-polyethylene terephthalate, butyl rubber-epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers. The active ingredient then diffuses through the outer polymeric membrane in a release-rate-controlling process. The percentage of active compound contained in such parenteral compositions varies greatly depending on the specific nature of the composition and the needs of the subject.

[0367] G. Targeted Formulations The compound provided herein or its pharmaceutically acceptable salt can be formulated to be targeted to specific tissue, receptor or other area of ​​the body of the subject to be treated, such as liposome delivery system, resealed erythrocyte delivery system and antibody-based delivery system.Many such targeting methods are well known to those skilled in the art.All such targeting methods are contemplated herein for use in the present composition. For non-limiting examples of targeting methods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0368] In one embodiment, the antibody-based delivery system is an antibody-drug conjugate ("ADC"), e.g., as described in Hamilton GS, Biologicals, 2015 September, 43(5):318-32; Kim EG and Kim KM, Biomol. Ther. (Seoul), 2015 November, 23(6):493-509; and Peters C and Brown S, Biosci. Rep., 2015 June 12, 35(4) pii: e00225, each of which is incorporated herein by reference.

[0369] In one embodiment, liposome suspensions, such as tissue-targeted liposomes, including tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in US Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLVs), can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) on the inside of a flask. A solution of a compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0370] H.Manufactured products The compound or pharmaceutically acceptable salt can be packaged as an article of manufacture comprising packaging material, a compound provided herein or a pharmaceutically acceptable salt thereof for use in the treatment, prevention, or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein, and a label indicating that the compound or a pharmaceutically acceptable salt thereof is used for the treatment, prevention, or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein.

[0371] The products provided herein include packaging materials. Packaging materials used for packaging pharmaceuticals are well known to those skilled in the art. For example, see US Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated.

[0372] In certain embodiments, the present invention also provides a kit that can be used by medical professionals to simplify the administration of an appropriate amount of active ingredient to a subject.In certain embodiments, the present invention provides a kit that includes a container and a dosage form of the compound provided herein, such as a single enantiomer or a mixture of diastereomers thereof; or its pharmaceutically acceptable salt, solvate or prodrug.

[0373] In certain embodiments, the kit includes a container containing a compound provided herein, such as a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container containing one or more other therapeutic agents described herein.

[0374] The kit provided herein can further include a device used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringes, drip bags, patches, and inhalers. The kit provided herein can also include condoms for administering the active ingredient.

[0375] The kits provided herein can 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 a solid form that must be reconstituted for parenteral administration, the kit can include a sealed container of 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 include, but are 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 include, but are not limited to, ethyl alcohol, polyethylene glycol, polypropylene glycol; and non-aqueous vehicles include, but are not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0376] V. Administration The compounds and pharmaceutical compositions provided herein may be administered in specific therapeutically or prophylactically effective amounts, at specific time intervals, in specific dosage forms, and by specific administration methods, as described below.

[0377] In certain embodiments, the therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day , from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day.

[0378] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100 or about 150 mg per day.

[0379] In one embodiment, the recommended daily dose range of the compounds provided herein or derivatives thereof for the conditions described herein is in the range of about 0.5 mg to about 50 mg per day, given as a single dose once a day or in divided doses throughout the day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 mg to about 5 mg per day. Specific daily doses are 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

[0380] In specific embodiments, the recommended starting dose may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, or 50 mg per day. In another embodiment, the recommended starting dose may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be gradually increased to 15, 20, 25, 30, 35, 40, 45, and 50 mg per day. In specific embodiments, the compound may be administered in an amount of about 25 mg per day. In particular embodiments, the compound may be administered in an amount of about 10 mg per day. In particular embodiments, the compound may be administered in an amount of about 5 mg per day. In particular embodiments, the compound may be administered in an amount of about 4 mg per day. In particular embodiments, the compound may be administered in an amount of about 3 mg per day.

[0381] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg / kg / day, from about 0.01 to about 50 mg / kg / day, from about 0.01 to about 25 mg / kg / day, from about 0.01 to about 10 mg / kg / day, from about 0.01 to about 9 mg / kg / day, 0.01 to about 8 mg / kg / day, from about 0.01 to about 7 mg / kg / day, from about 0.01 to about 6 mg / kg / day, from about 0.01 to about 5 mg / kg / day, from about 0.01 to about 4 mg / kg / day, from about 0.01 to about 3 mg / kg / day, from about 0.01 to about 2 mg / kg / day, from about 0.01 to about 1 mg / kg / day, or from about 0.01 to about 0.05 mg / kg / day.

[0382] Dosages may be expressed in units other than mg / kg / day. For example, dosages for parenteral administration may be expressed in mg / m 2 One skilled in the art can easily determine the dosage based on the subject's height and / or weight, ranging from mg / kg / day to mg / m 2 It will be readily apparent how to convert this to a dose of 38 mg / m² / day (see www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg human is 38 mg / m². 2 Approximately equal to / day.

[0383] In certain embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound 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.

[0384] In other embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound 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.

[0385] As used herein, the term "steady-state plasma concentration" refers to the concentration achieved after administration of a compound provided herein or a derivative thereof for a period of time. When steady state is reached, there are few peaks and troughs on the time-dependent curve of the plasma concentration of the compound.

[0386] In certain embodiments, the amount of compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound in the range of about 0.001 to about 50 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, 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.

[0387] In certain embodiments, the amount of compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound 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 0.01 to about 25 μM, about 0.01 to about 20 μM, about 0.02 to about 20 μM, about 0.02 to about 20 μM, or about 0.01 to about 20 μM.

[0388] In certain embodiments, the amount of compound administered is 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 about 5,000 to about 10,000 ng * It is sufficient to provide the area under the curve (AUC) of the compound in the range up to hr / mL.

[0389] The methods provided herein encompass treating patients regardless of the subject's age, although some diseases or disorders are more prevalent in certain age groups.

[0390] Depending on the disease to be treated and the condition of the subject, the compounds provided herein or their derivatives can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, CIV, intrathoracic injection or infusion, subcutaneous injection, or implant), by inhalation, intranasally, intravaginally, rectally, sublingually, or topically (e.g., transdermally or topically). The compounds provided herein or their derivatives can be formulated into suitable dosage units, either alone or together, with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles suitable for each administration route.

[0391] In one embodiment, the compounds provided herein or derivatives thereof are administered orally. In another embodiment, the compounds provided herein or derivatives thereof are administered parenterally. In yet another embodiment, the compounds provided herein or derivatives thereof are administered intravenously.

[0392] The compounds provided herein or derivatives thereof can be delivered as a single dose, for example, a single bolus injection, or as an oral tablet or pill; or as a sequential dose, for example, a continuous infusion or divided bolus doses over time. The compound can be administered repeatedly as needed, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease in solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more since the previous measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease, or lack thereof, is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor using X-ray, CAT, PET, or MRI scans, and other commonly accepted evaluation modalities.

[0393] The compounds provided herein or derivatives thereof can be administered once daily (QD), or multiple times daily, such as twice daily (BID), three times daily (TID), and four times daily (QID). Furthermore, administration can be continuous (i.e., consecutive days or every day), intermittent, for example, periodically (i.e., drug-free rest days, weeks, or months, etc.). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as a compound provided herein or a derivative thereof, is administered once or more times each day, for example, for a period of time. The term "continuously" is intended to mean that a therapeutic compound, such as a compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. As used herein, the terms "intermittent" or "intermittent" are intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein or a derivative thereof can be administration 1 to 6 days per week, cyclical administration (e.g., daily administration for 2 to 8 consecutive weeks followed by a rest period of up to 1 week without administration), or administration on alternating days. As used herein, the term "cyclical" means that a therapeutic compound, such as a compound provided herein or a derivative thereof, is administered daily or continuously, with a rest period. In some such embodiments, administration is once daily for 2 to 6 days, followed by a rest period of 5 to 7 days without administration.

[0394] In some embodiments, the administration frequency ranges from about once a day to about once a month. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, 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 provided herein or a derivative thereof is administered once a day. In another embodiment, the compound provided herein or a derivative thereof is administered twice a day. In yet another embodiment, the compound provided herein or a derivative thereof is administered three times a day. In yet another embodiment, the compound provided herein or a derivative thereof is administered four times a day.

[0395] In certain embodiments, a compound provided herein or a derivative thereof is 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, a compound provided herein or a derivative thereof is administered once daily for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, a compound provided herein or a derivative thereof is administered once daily for 4 days. In one embodiment, a compound provided herein or a derivative thereof is administered once daily for 5 days. In one embodiment, a compound provided herein or a derivative thereof is administered once daily for 6 days. In one embodiment, a compound provided herein or a derivative thereof is administered once daily for 1 week. In another embodiment, a compound provided herein or a derivative thereof is administered once daily for 2 weeks. In yet another embodiment, a compound provided herein or a derivative thereof is administered once daily for 3 weeks. In yet another embodiment, a compound provided herein or a derivative thereof is administered once daily for 4 weeks.

[0396] VI. Treatment Method Provided herein are methods for degrading CK1α in cells by contacting the cells with a compound or composition provided herein. In another embodiment, provided herein are methods for degrading CK1α in a subject by administering to the subject a compound or composition provided herein.

[0397] In another embodiment, a method for inhibiting the activation of Card11 / BCL10 / MALT1 (CBM) complex is provided.It is known in the art that CK1α is required for the activation of CBM complex by TCR and BCR control (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).The activation of CBM complex causes IL-2 induction, JNK signaling, and standard NF-κB pathway signaling, ultimately leading to cell proliferation.Therefore, the degradation of CK1α leads to the inhibition of CBM complex and the control of cell proliferation.

[0398] Thus, in one embodiment, provided are methods for treating a subject having a proliferative disease by administering to the subject a compound or composition provided herein. In another embodiment, provided are methods for treating a subject having cancer by administering to the subject a compound or composition provided herein.

[0399] In one embodiment, the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) (such as 5q-MDS), colon cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), B-cell lymphoma, or mantle cell lymphoma (MCL). For example, 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), See 7038-7048.

[0400] 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.

[0401] 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.

[0402] 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, elsbrutinib (ABBV-105), trebrutinib (SAR 442168), fenebrutinib, bakabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068, or DTRMWXHA-12.

[0403] 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's macroglobulinemia, or chronic graft-versus-host disease.

[0404] In another embodiment, a method for degrading CK1α and GSPT1 in a cell is provided by contacting the cell with a compound or composition provided herein. In another embodiment, a method for degrading CK1α and GSPT1 in a subject is provided by administering a compound or composition provided herein to the subject. It is known in the art that 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 and MDM2 form a complex that regulates p53 and E2F-1 protein stability. The CK1α-MDM2 complex promotes p53 degradation, resulting in the inhibition of expression of p53 targets, such as p21 (a cell cycle progression inhibitor). GSPT1 degraders have shown efficacy in clinical trials for acute myeloid leukemia (AML). Degradation of CK1α (leading to elevated p53) and degradation of GSPT1 improves the therapeutic window and safety profile.

[0405] It is also known in the art that GSPT1 is involved in various cancers such as 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 adenocarcinoma. See, e.g., WO 2022 / 066835, WO 2022 / 029138, WO 2021 / 069705, WO 2018 / 169777, WO 2019 / 173224, WO 2019 / 241271, WO 2021 / 086830, WO 2022 / 007659, WO 2022 / 066835 and WO 2022 / 073469.

[0406] Thus, in another embodiment, a method is provided for treating AML in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating a solid tumor in a subject by administering a compound or composition provided herein to the subject. In another embodiment, the solid tumor is breast cancer. In another embodiment, a method is provided for treating glioma in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating thyroid cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating lung cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating colorectal cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating head and neck cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating gastric cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method is provided for treating liver cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating pancreatic cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating kidney cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating urothelial cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating prostate cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating testicular cancer in a subject is provided by administering a compound or composition provided herein to the subject.In another embodiment, a method for treating cervical cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating endometrial cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating ovarian cancer in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating melanoma in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating multiple myeloma in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating hepatocellular carcinoma in a subject is provided by administering a compound or composition provided herein to the subject. In another embodiment, a method for treating gastric adenocarcinoma in a subject is provided by administering a compound or composition provided herein to the subject.

[0407] As mentioned above, CK1α is required for activation of the Card11 / BCL10 / MALT1 (CBM) complex. It is known in the art that inhibition of MALT1 ameliorates autoimmune pathologies. See, e.g., Biswas et al., Frontiers in Immunology 2022, 13, 875320. Degradation of CK1α leads to activation of CBM and inhibition of MALT1 signaling.

[0408] Therefore, in another embodiment, a method for treating a subject with an autoimmune disorder is provided by administering a compound or composition provided herein to the subject. In one embodiment, the autoimmune disorder is Addison's disease, celiac sprue (gluten-sensitive enteropathy), dermatomyositis, Graves' disease, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, or type I diabetes.

[0409] It is known in the art that CK1α plays a role in promoting RAS-driven cancer, for example, by destabilizing forkhead box O (FOXO)3A / 4 tumor suppressor, regulating oncogenic RAS-induced autophagy, and phosphorylating Fas-associated death domain (FADD).See, for example, Zhang et al. Oncogene, 2018, 37, 363-376; Cheong et al. J. Clin. Invest. 2015, 125(4), 1401-1418; Bowman et al. Sci. Signal. 2016, 8(361), ra9; Cheong et al. Mol. Cell. Onc. 2016, 3(3), e1045117.Therefore, in one embodiment, the present invention provides a method for treating a subject's RAS-driven cancer by administering the compound or composition provided herein to the subject.In another embodiment, the RAS-driven cancer is a RAS-mutated cancer. In another embodiment, the RAS-driven cancer is KRAS G12D In another embodiment, the RAS-driven cancer is lung cancer, head and neck cancer, pancreatic cancer, breast cancer, colorectal cancer, gastrointestinal cancer, melanoma, myeloid cancer, bladder cancer, cervical cancer, ovarian cancer or uterine cancer.

[0410] It is known in the art that inhibition of CK1α prevents acquired resistance to erlotinib in EGFR-mutated non-small cell lung cancer. See, for example, Lantermann et al. Cancer Res. 2015, 75(22), 4937-4948. Thus, in one embodiment, the present disclosure provides a method for preventing acquired resistance to erlotinib in EGFR-mutated non-small cell lung cancer in a subject by administering a compound or composition provided herein to the subject.

[0411] VII. Combination Therapy with a Second Active Agent The compounds provided herein, or derivatives thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of proliferative diseases, such as cancer and autoimmune disorders.

[0412] In one embodiment, provided herein is a method of treating, preventing, or managing a proliferative disorder, comprising administering to a subject a compound provided herein or a derivative thereof in combination with one or more second active agents.

[0413] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein, a compound provided herein, e.g., a compound provided herein or a derivative thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapy (e.g., a prophylactic or therapeutic agent). Triple therapy is also contemplated herein.

[0414] The administration of a compound provided herein or a derivative thereof and one or more second active agents to a subject can be performed simultaneously or sequentially by the same or different administration routes. The suitability of a particular administration route for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without being degraded before entering the bloodstream) and the disease or disorder being treated.

[0415] The route of administration of the compound provided herein or a derivative thereof is independent of the route of administration of the second therapy. In one embodiment, the compound provided herein or a derivative thereof is administered orally. In another embodiment, the compound provided herein or a derivative thereof is administered intravenously. Thus, according to these embodiments, the compound provided herein or a derivative thereof is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, via inhalation, intravaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposely, intraarticularly, intrathecally, or in a delayed-release dosage form. In one embodiment, the compound provided herein or a derivative thereof and the second therapy are administered by the same mode of administration, oral or intravenous. In another embodiment, the compound provided herein or a derivative thereof is administered by one mode of administration, for example, IV, while the second agent is administered by another mode of administration, for example, orally.

[0416] In one embodiment, the second active agent is administered intravenously or subcutaneously in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg, once or twice daily. The specific amount of the second active agent will depend on the particular agent used, the type of disease being treated or managed, the severity and stage of the disease, and the amount of a compound provided herein or a derivative thereof, and any additional active agents co-administered to the subject.

[0417] In the methods and compositions provided herein, one or more second active ingredients or agents can be used in conjunction with the compounds provided herein or their derivatives. The second active agent can be a large molecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

[0418] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical large molecule active agents are biological molecules such as naturally occurring, synthetic, or recombinant proteins.

[0419] It is known in the art that targeting the CBM complex primes tumors for immune checkpoint therapy by regulatory T cells. MALT1 activity is also known to be key to regulatory T cell immunosuppression. Thus, in one embodiment, the second active agent is a checkpoint inhibitor such as an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. In another embodiment, the second active agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tramelimumab, or a combination thereof. In these embodiments, the proliferative disease to be treated is cancer, including melanoma, including unresectable or metastatic melanoma, BRAF 600 mutation-positive, and melanoma with lymph node metastasis; 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.

[0420] In one embodiment, a compound provided herein or a derivative thereof can be administered orally daily in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg, either alone or in combination with a second active agent, before, during, or after conventional therapy. [Example]

[0421] VIII. Working Examples The following examples are meant to illustrate certain embodiments provided herein and are not intended to limit the scope of the disclosure.

[0422] Intermediate Example 1 Synthesis of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0423] [ka]

[0424] Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0425] [ka]

[0426] To a solution of methyl 4-bromo-2-(bromoethyl)benzoate (20.0 g, 64.9 mmol, 1.00 eq) in DMF (170 mL) was added 3-aminopiperidine-2,6-dione (11.8 g, 71.4 mmol, 1.10 eq, HCl) and K2CO3 (26.9 g, 194 mmol, 3.00 eq). 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 resulting solid 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, 98.6% purity by HPLC at 220 nm) as a white solid. 1 H NMR: (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, (ESI + ) m / z: 322.7 (M+H) + , (C13 H 11 BrN2O3).

[0427] Preparation of 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione:

[0428] [ka]

[0429] A solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (10.0 g, 31.0 mmol, 1.00 eq) in DMF (60.0 mL) was placed in a sealed tube, and bis(pinacolato)diboron (BPD) (8.64 g, 34.0 mmol, 1.10 eq), KOAc (9.11 g, 92.8 mmol, 3.00 eq), and Pd(dppf)Cl (1.36 g, 1.86 mmol, 0.06 eq) were added. The reaction mixture was heated at 100 °C under N for 2 h. 200 mL of water was added to the reaction mixture, and the mixture was stirred at 25 °C for 0.25 h. The solid was precipitated, filtered, and dried under vacuum to give the title compound (8.90 g, 23.5 mmol, 76.0% yield, 97.8% purity by HPLC at 220 nm) as a white solid. 1 H 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).

[0430] Example 1 Synthesis of 3-(5-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0431] [ka]

[0432] A. 3-(5-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-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 (93.7 mg, 253 μmol, 1.20 eq), 4 in dioxane (1.25 mL) and HO (0.10 mL). To a solution of 1-bromo-1-methyl-5-phenyl-1H-pyrazole (50.0 mg, 211 μmol, 1.00 eq) and KPO (89.5 mg, 422 μmol, 2.00 eq) was added (2-(2-aminophenyl)phenyl)-methylsulfonyloxy-palladium; dicyclohexyl-(2-(2,6-diisopropoxyphenyl)phenyl)phosphane (17.6 mg, 21.1 μmol, 0.10 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h. The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (2 × 20.0 mL). The filtrate was concentrated under vacuum at 40 °C to give a residue. The mixture was purified by preparative HPLC using a Welch Xtimate (150 mm x 25 mm, 5 μm) and a gradient of 13-43% acetonitrile in water containing 0.05% HCl over 8 minutes at a flow rate of 25 mL / min to give the title compound as a yellow solid (11.1 mg, 26.0 μmol, 12.3% yield). 1H 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).

[0433] Example 2 Synthesis of 3-(5-(1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0434] [ka]

[0435] A. 1-Methyl-5-phenyl-1H-imidazole: To a solution of methanamine hydrochloride (5.19 g, 76.8 mmol, 2.00 eq) in DMF (40.0 mL) was added benzaldehyde (4.08 g, 38.4 mmol, 3.89 mL, 1.00 eq) and DIEA (9.93 g, 76.8 mmol, 13.4 mL, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. KCO (7.96 g, 57.63 mmol, 1.5 eq) and 1-((isocyanomethyl)-sulfonyl)-4-methylbenzene (9.00 g, 46.1 mmol, 1.20 eq) were then added to the mixture at 25 °C. 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 × 100 mL), and the organic layers were collected. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, ethyl acetate:petroleum ether = 10 / 1 to dichloromethane:methanol = 30 / 1) to give the title compound as a yellow solid (2.20 g, 13.9 mmol, 36.1% yield, 99.7% purity by HPLC at 220 nm). 1 H 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).

[0436] B. 4-Bromo-1-methyl-5-phenyl-1H-imidazole: 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) was added NBS (624 mg, 3.51 mmol, 1.05 eq) at 20 °C. 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 residue was purified by column chromatography (SiO, ethyl acetate:petroleum ether = 8 / 1 to 1 / 5). The residue was then dissolved in DCM (20.0 mL) and washed with water (3 × 15.0 mL). The organic layer was dried over NaSO, filtered, and the filtrate was concentrated under vacuum to give the title compound as a yellow solid (270 mg, 1.13 mmol, 33.8% yield, 99.5% purity by LCMS at 220 nm). 1 H 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).

[0437] C. 3-(5-(1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-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 (224 mg, 604 μmol, 1.20 eq), 4-bromo- in dioxane (3.00 mL) and HO (0.15 mL). To a solution of 1-methyl-5-phenyl-1H-imidazole (120 mg, 504 μmol, 99.5% purity, 1.00 eq) and KPO (214 mg, 1.01 mmol, 2.00 eq) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (42.1 mg, 50.4 μmol, 0.10 eq) at 25 °C under N. The mixture was stirred at 100 °C under N for 1 h. The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (2 × 2.00 mL). The filtrate was concentrated under vacuum at 40 °C to give a residue. The residue was purified by preparative HPLC using a Welch Ultimate C18 (150 mm x 25 mm 5 μm) and a gradient of 0-30% acetonitrile in water containing 0.1% FA over 10 minutes at a flow rate of 25 mL / min to give the title compound as an off-white solid (40.4 mg, 99.3 μmol, 19.7% yield, 98.4% purity by HPLC at 220 nm). 1 H 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).

[0438] Example 3 Synthesis of 3-(5-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0439] [ka]

[0440] A. 3-(5-(1-Methyl-3-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 309 μmol, 1.00 eq), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg, 402 μmol, 1.30 eq) in DMF (1.00 mL) was added Pd(dppf)Cl (50.5 mg, 61.9 μmol, 0.20 eq), KPO (131 mg, 619 μmol, 2.00 eq) under N. The mixture was stirred at 90 °C for 12 h. The mixture was filtered, and the filtrate was collected and analyzed by prep-TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.3) to give the title compound as a yellow solid (50.4 mg, 125 μmol, 20.0% yield, 98.9% purity by HPLC at 220 nm). 1H 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, (ESI + ) m / z: 401.0 (M+H) + , (C 23 H 20 N4O3).

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

[0442] [ka]

[0443] Preparation of 3-(1-oxo-5-(4-phenylthiophen-3-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 (158 mg, 418 μmol, 97.8% purity, 1.00 eq), 3-bromo-4-phenyl-thiophene (100 mg, 418.18 μmol, 1.00 eq), KPO (176 mg, 836 μmol, 2.00 eq) in dioxane (3.00 mL) and HO (0.10 mL). Ru-Phos-Pd-G3 (70.0 mg, 83.6 μmol, 0.20 eq) was added to the reaction mixture under N2. The mixture was stirred at 100 °C under N2 for 2 h. The mixture was filtered, and the filtrate was collected and purified by preparative HPLC using a Phenomenex luna C18 (150 mm x 25 mm 10 μm) and a gradient of 38-68% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL / min to give the title compound as a white solid (73.9 mg, 179 μmol, 42.8% yield, 97.3% purity by HPLC at 220 nm). 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).

[0444] Example 5 Synthesis of 3-(1-oxo-5-(3-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0445] [ka]

[0446] A. 3-(1-Oxo-5-(3-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of bromo-3-phenyl-1H-pyrazole (100 mg, 448 μmol, 1.00 eq), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (174 mg, 471 μmol, 1.05 eq), (A-taphos)PdCl (63.5 mg, 90.0 μmol, 63.5 μL, 0.20 eq) in dioxane (4.00 mL) and HO (0.40 mL) was added KPO (190 mg, 897 μmol, 2.00 eq) under N. The mixture was stirred under N for 12 h at 100° C. The mixture was filtered, and the filtrate was collected and purified by preparative HPLC using a Phenomenex luna C18 (150 mm×25 mm 10 μm) and a gradient of 15–45% acetonitrile in water containing 0.05% FA over 18 min at a flow rate of 25 mL / min to give the title compound as a yellow solid (5.91 mg, 15.2 μmol, 3.39% yield, 99.4% purity by HPLC at 220 nm). 1H 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), (ESI + ) m / z: 387.0 (M+H) + , (C 22 H 18 N4O3).

[0447] Example 6 Synthesis of 3-(1-oxo-5-(1-phenyl-1H-pyrazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0448] [ka]

[0449] A. 3-(1-oxo-5-(1-phenyl-1H-pyrazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione: 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (50.0 mg, 154 μmol, 1.00 eq) in dioxane (1.00 mL) and HO (0.05 mL) under N To a solution of 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54.3 mg, 201 μmol, 1.30 eq) was added (A-taphos)PdCl (25.8 mg, 30.9 μmol, 0.20 eq) and KPO (65.6 mg, 309 μmol, 2.00 eq) under N. The reaction mixture was stirred at 100 °C under N for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC using a Phenomenex Luna C18 (150 mm x 25 mm 10 μm) and a gradient of 22-42% acetonitrile in water containing 0.05% FA over 63 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (15.0 mg, 38.5 μmol, 24.8% yield, 99.2% purity by HPLC at 220 nm). 1 H 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, 1 H), 7.55 (s, 1H), 7.37-7.46 (m, 3H), 7.26-7.30 (m, 3H), 6.76 (d, J = 2.0 Hz, 1 H), 5.11 (dd, J = 13.6 Hz, 5.2 Hz, 1 H), 4.26-4.44 (m, 2 H), 2.85-2.95 (m, 1 H), 2.56-2.61 (m, 1 H), 2.36-2.44 (m, 1 H), 1.96-2.03 (m, 1 H). (ESI + ) m / z: 387.2 (M+H) + , (C 22 H 18 N4O3).

[0450] Example 7 Synthesis of 3-(1-oxo-5-(1-phenyl-1H-imidazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0451] [ka]

[0452] A. 2-Iodo-1-phenyl-1H-imidazole: A solution of 1-phenylimidazole (1.90 g, 13.1 mmol, 1.00 eq) in THF (95.0 mL) was cooled to -65 to -60 °C. n-BuLi (2.50 M, 7.04 mL, 1.33 eq) was added dropwise at -65 to -60 °C under N. The mixture was then stirred at -60 °C for 1.5 h. A solution of iodine (10.0 g, 39.5 mmol, 7.96 mL, 3.00 eq) in THF (100 mL) was added to the mixture at -65 to -60 °C. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 200 mL), and the organic layer was collected. The organic layer was washed with saturated aqueous NaSO (2x100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, 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 as a yellow solid (2.20 g, 8.15 mmol, 61.8% yield). 1 H 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).

[0453] B. 3-(1-Oxo-5-(1-phenyl-1H-imidazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 2-iodo-1-phenyl-imidazole (100 mg, 370 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 (137 mg, 370 μmol, 1.00 eq) in dioxane (3.00 mL) and HO (0.15 mL) was added (A-taphos)PdCl (61.9 mg, 74.0 μmol, 0.20 eq) and KPO (157 mg, 740 μmol, 2.00 eq) under N. The mixture was stirred at 100 °C for 1 h. The mixture was poured into HO (20.0 mL) and extracted with EtOAc (3 × 20.0 mL), and the organic layer was collected. The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150 × 25 mm × 10 μm) and a gradient of 42.0% to 72.0% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 25 mL / min to give the title compound as a white solid (6.84 mg, 17.3 μmol, 4.68% yield, 97.8% purity by HPLC at 220 nm). 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 H18 N4O3).

[0454] Example 8 Synthesis of 3-(5-(5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0455] [ka]

[0456] A. 3-(5-(5-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-[5-(5-bromo-1-methyl-pyrazol-4-yl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (39.8 mg, 90 mL) in dioxane (1.00 mL). To a solution of 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) were added. The reaction mixture was stirred at 100 °C for 4 h under N2. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate (C18 150x25mmx5μm) and a gradient of 15-45% acetonitrile in water containing 0.05% HCl over 15 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (5.65 mg, 13.5 μmol, 14.8% yield, >99% purity by HPLC at 220 nm). 1H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.90 (s, 1H), 7.60 - 7.55 (m, 1 H), 7.49 - 7.43 (m, 2 H), 7.40 - 7.33 (m, 3 H), 7.25 - 7.20 (m, 1 H), 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).

[0457] Example 9 Synthesis of 3-(1-oxo-5-(1-phenyl-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0458] [ka]

[0459] 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 eq) and 4-bromo-1-phenyl-pyrazole (72.3 mg, 324 μmol, 1.20 eq) in dioxane (2.00 mL) and HO (0.10 mL) was added KPO (114 mg, 540 μmol, 2.00 eq) and Ru-Phos-Pd-G (22.6 mg, 27.0 μmol, 0.10 eq). The reaction mixture was stirred at 100 °C for 2 hours under N2. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give the crude product. The crude product was analyzed by preparative TLC (SiO2, dichloromethane:methanol = 10:1, R f =0.40) and preparative HPLC (Welch Xtimate C 18 Purification using a 150 mm x 25 mm x 5 μm column and a gradient of 21%-51% acetonitrile in water containing HCl (0.10 mol / L, 9 min) gave the title compound as a white solid (15.2 mg, 39.1 μmol, 14.4% yield, 99.4% purity by HPLC at 220 nm). 1 H 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).

[0460] Example 10 Synthesis of 3-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0461] [ka]

[0462] A. 3-(5-(1-Methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: A microwave vial was charged with 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.24 mmol, 1.00 eq), 1-methyl-4-(tributylstannyl)-1H-imidazole (597 mg, 1.61 mmol, 1.30 eq) in DMF (4.00 mL) under N. After degassing with N for 10 minutes, Pd(dppf)Cl.CHCl (202 mg, 247 μmol, 0.20 eq) was added to the mixture. The reaction mixture was stirred at 130 °C for 1.5 h in a microwave under N. The mixture was filtered, the liquid collected, and the liquid was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (dichloromethane / methanol = 10 / 1, R f =0.30) to give the title compound as a brown solid (60.0 mg, 181 μmol, yield 7.30%, purity by LCMS 220 nm 98.0%). (ESI + ) m / z: 324.0 (M+H) + , (C 17 H 16 N4O3).

[0463] B. 3-(5-(5-Bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To 3-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 1.51 mmol, 1.00 eq) in MeOH (3.00 mL) was added NBS (296 mg, 1.66 mmol, 1.10 eq) at 0° C. The mixture was stirred at 25° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (dichloromethane:methanol=10:1, R f =0.32) to give the title compound as a brown solid (40.0 mg, 98.9 μmol, yield 50.1%, purity by LCMS 220 nm 99.7%). (ESI + ) m / z: 403.2 (M+H) + , (C 17 H 15 BrN4O3).

[0464] C. 3-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39.2 mg) in dioxane (3.00 mL) and HO (0.15 mL). To a solution of 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 484 μmol, 5.00 eq) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (96.9 μmol, 99.7% purity, 1.00 eq) was added K2CO3 (40.2 mg, 290 μmol, 3.00 eq) and Pd(dppf)Cl2.CHCl2 (15.8 mg, 19.4 μmol, 0.20 eq) under N2. The mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered, the filtrate was collected, and the liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 3.00%-33.0% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (1.28mg, 2.93µmol, 3.00% yield, 95.7% purity by HPLC at 220nm). 1 H 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).

[0465] Example 11 Synthesis of (3-(5-(5-methyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0466] [ka]

[0467] 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 eq) in THF (0.80 mL) and HO (0.80 mL) was added NaI (189 mg, 1.26 mmol, 2.00 eq), I (802 mg, 3.16 mmol, 637 μL, 5.00 eq), and KCO (174 mg, 1.26 mmol, 2.00 eq). The mixture was stirred at 100 °C for 48 h. The combined mixture was quenched with NaSO (10.0%, 35.0 mL). The mixture was extracted with ethyl acetate (3 × 15.0 mL), dried over NaSO, filtered, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was then analyzed by preparative TLC (petroleum ether / ethyl acetate = 3 / 1, R f =0.30) to give the title compound as a white solid (114 mg, 399 μmol, yield 63.2%, purity by LCMS 220 nm 99.6%). 1 H 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).

[0468] B. 3-(5-(5-methyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-iodo-5-methyl-4-phenyl-1H-pyrazole (80.0 mg, 281 μmol, 1.00 eq), 3-(1-oxo-5-(4, To a solution of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (114 mg, 309 μmol, 1.10 eq) and KPO (119 mg, 563 μmol, 2.00 eq) was added Ru-Phos-Pd-G (47.1 mg, 56.3 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C under N for 60 h. The reaction mixture was then filtered, the filtrate was collected, and the liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 29.0%-49.0% acetonitrile in water containing 0.05% FA over 58 minutes at a flow rate of 25mL / min to give the title compound as a white solid (3.97mg, 9.71µmol, 3.45% yield, 97.9% purity by HPLC at 220nm). 1 H 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).

[0469] Example 12 Synthesis of 3-(5-(2-cyclopropyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0470] [ka]

[0471] AN-(2,2-Dimethoxyethyl)-N-methylcyclopropanecarboximidamide: To a solution of 2,2-dimethoxy-N-methylethan-1-amine (3.00 g, 25.2 mmol, 3.24 mL, 1.00 eq) and cyclopropanecarbonitrile (2.11 g, 31.5 mmol, 2.32 mL, 1.25 eq) was added CuCl (3.12 g, 31.5 mmol, 752 μL, 1.25 eq). The mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (5.00 g, crude). (ESI + ) m / z:186 ​​(C9H 18 N2O2)

[0472] B. 2-Cyclopropyl-1-methyl-1H-imidazole: To a solution of N-(2,2-dimethoxyethyl)-N-methylcyclopropanecarboximidamide (5.00 g, 26.9 mmol, 1.00 eq) in MeOH (15.0 mL) was added concentrated HCl (12.0 M, 2.24 mL, 1.00 eq). 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 as a yellow oil (2.00 g, 16.4 μmol, 60.9% yield). 1 H 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).

[0473] C. 2-Cyclopropyl-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-cyclopropyl-1-methyl-1H-imidazole (1.00 g, 8.19 mmol, 1.00 eq), PCy3 (229 mg, 819 μmol, 265 μL, 0.10 eq), and NaOtBu (2.36 g, 24.5 mmol, 3.00 eq) in o-xylene (40.0 mL) was added chlorobenzene (2.76 g, 24.5 mmol, 2.49 mL, 3.00 eq), and Pd(OAc)2 (91.9 mg, 409 μmol, 0.05 eq) under N2. The mixture was stirred at 130 °C for 17 h under N2. The mixture was then diluted with petroleum ether (100 mL), and the organic layer was filtered and concentrated under reduced pressure to give a residue. The 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 as a yellow oil (1.33 g, 6.35 mmol, yield 77.5%, purity by LCMS 220 nm 95.0%). (ESI + ) m / z: 199.0 (M+H) + , (C 13 H 14 N2).

[0474] D. 4-Bromo-2-cyclopropyl-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-cyclopropyl-1-methyl-5-phenyl-1H-imidazole (300 mg, 1.51 mmol, 1.00 eq) in MeOH (3.00 mL) was added NBS (296 mg, 1.66 mmol, 1.10 eq) at 0° C. The mixture was stirred at 25° C. for 3 h. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=3:1, R f =0.30) to give the title compound as a yellow oil (380 mg, 1.05 mmol, yield 69.7%, purity by LCMS 220 nm 76.9%). (ESI + ) m / z: 277.0 (M+H) + , (C 13 H13 BrN2).

[0475] E. 3-(5-(2-cyclopropyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-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 in dioxane (3.00 mL) and HO (0.15 mL). To a solution of 1,6-dione (701 mg, 1.89 mmol, 1.50 eq), 4-bromo-2-cyclopropyl-1-methyl-5-phenyl-1H-imidazole (350 mg, 1.26 mmol, 1.00 eq), and KPO (536 mg, 2.53 mmol, 2.00 eq) was added Ru-Phos-Pd-G (211 mg, 253 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The mixture was filtered, the filtrate was collected, and the liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 2.00%-32.0% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (33.1mg, 72.2µmol, 5.70% yield, 96.2% purity by HPLC at 220nm). 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 H24 N4O3).

[0476] Example 13 Synthesis of 3-(1-oxo-5-(5-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0477] [ka]

[0478] A. 4-Bromo-5-phenyl-1H-imidazole: To a solution of 5-phenyl-1H-imidazole (200 mg, 1.39 mmol, 1.00 eq) in MeOH (3.00 mL) was added NBS (259 mg, 1.46 mmol, 1.05 eq). The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into HO (15.0 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (3 × 10.0 mL), dried over NaSO, filtered, and concentrated to give the title compound as a pale yellow solid (98.0 mg, 431 μmol, 31.1% yield, 98.3% purity by LCMS 220 nm). 1 (ESI + ) m / z: 224.7 (M+H) + , (C9H7BrN2).

[0479] B. 3-(1-oxo-5-(5-phenyl-1H-imidazol-4-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 in dioxane (3.00 mL) and HO (0.15 mL). To a solution of 4-bromo-5-phenyl-1H-imidazole (50.0 mg, 224 μmol, 1.00 eq) and KPO (142 mg, 672 μmol, 3.00 eq) and Ru-Phos-Pd-G (18.7 mg, 22.4 μmol, 0.10 eq) were added at 25 °C under N. The mixture was then stirred at 100 °C for 2 h under N. The reaction mixture was poured into HO (15.0 mL) and extracted with ethyl acetate (3 × 10.0 mL). The combined organic layers were washed with brine (3 × 10.0 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 1.00%-26.0% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (21.8mg, 54.9µmol, 24.5% yield, 97.0% purity by HPLC at 220nm). 1 H 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).

[0480] Example 14 Synthesis of 3-(5-(1,2-dimethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0481] [ka]

[0482] A. 1,2-Dimethyl-5-phenyl-1H-imidazole: A mixture of 1,2-dimethylimidazole (100 mg, 1.04 mmol, 1.00 eq), Pd(OAc) (11.6 mg, 52.0 μmol, 0.05 eq), PCy (29.1 mg, 104 μmol, 33.7 μL, 0.10 eq), and NaOBu-t (299 mg, 3.12 mmol, 3.00 eq) in o-xylene (5.00 mL) and chlorobenzene (351 mg, 3.12 mmol, 316 μL, 3.00 eq) was degassed and purged with N three times. The mixture was then stirred at 130 °C for 12 h under a N atmosphere. After completion of the reaction, the reaction mixture was cooled to 25 °C and filtered. The filtrate was collected and dried under vacuum to give the title compound as a white solid (170 mg, 977 μmol, 50.0% yield). (ESI + ) m / z: 172.1 (M+H) + , (C 11 H 12 N2).

[0483] 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 eq) in MeCN (8.00 mL) was added NBS (144 mg, 812 μmol, 1.00 eq) and stirred for 20 h at 25° C. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (150 mg, 597 μmol, 73.4% yield). 1H 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).

[0484] C. 3-(5-(1,2-dimethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidin-2,6-dione in dioxane (2.00 mL) and HO (0.10 mL). To a solution of 1,2-dione-2,6-dione (0.20 g, 540 μmol, 1.00 eq) and 4-bromo-1,2-dimethyl-5-phenyl-imidazole (108 mg, 432 μmol, 0.80 eq) was added Ru-Phos-Pd-G3 (45.1 mg, 54.0 μmol, 0.10 eq) and K3PO4 (229 mg, 1.08 mmol, 2.00 eq) under N2. 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 residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 3-33% acetonitrile in water containing 0.05% FA run at a flow rate of 20 mL / min over 58 min to give the title compound as a white solid (53.0 mg, 249 μmol, 25.0% yield, 97.8% purity by HPLC at 220 nm). 1H 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, (ESI + ) m / z: 415.2 (M+H) + , (C 24 H 22 N4O3).

[0485] Example 15 Synthesis of 3-(1-oxo-5-(5-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0486] [ka]

[0487] A. 3-(1-Oxo-5-(5-phenyloxazol-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 (248 mg, 670 μmol, 1.50 eq), 4-bromo-5-phenyloxazole (100 mg, 446 μmol, 1.00 eq) and KPO (189 mg, 893 μmol, 2.00 eq) in dioxane (3.00 mL) and HO (0.15 mL) was added Ru-Phos-Pd-G (74.7 mg, 893 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C for 48 h under N2. The reaction mixture was then filtered, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 x 25 mm x 5 μm) column and a gradient of 24.0% to 54.0% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL / min to give the title compound as a white solid (111 mg, 287 μmol, 64.0% yield, 99.7% purity by HPLC at 220 nm). 1 H 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).

[0488] Example 16 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

[0489] [ka]

[0490] 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-piperidyl)amino)methyl)thiophene-2-carboxylate (2.00 g, 4.96 mmol, 1.00 eq) in DCM (80.0 mL) was added TFA (28.2 g, 247 mmol, 18.3 mL, 50.0 eq). The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuo to afford the title compound as a black oil (3.20 g, crude). (ESI + ) m / z: 348.9 (M+H) + , (C 11 H 11 BrN2O4S).

[0491] 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-dioxo-3-piperidyl)amino]methyl]thiophene-2-carboxylic acid (3.20 g, 9.22 mmol, 1.00 eq) in DMF (120 mL) was added HATU (4.38 g, 11.5 mmol, 1.25 eq) and DIEA (2.98 g, 23.0 mmol, 4.01 mL, 2.50 eq). The reaction mixture was stirred at 25 °C for 3 h. The reaction solvent was removed in vacuo to give a residue. The residue was diluted with HO (100 mL) and extracted with DCM (2 x 150 mL). The organic layer was dried over NaSO and concentrated in vacuo to give a residue. The residue was triturated with ethyl acetate (10.0 mL) at 0° C. for 2 hours to give the title compound as a white solid (1.10 g, 3.32 mmol, 36.4% yield, 99.4% purity by HPLC at 220 nm). (ESI + ) m / z: 328.9 (M+H) + , (C 11 H9BrN2O3S).

[0492] C. (5-(2,6-Dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)boronic acid: 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 eq) in dioxane (4.00 mL) was added BPD (308 mg, 1.22 mmol, 2.00 eq), Pd(dppf)Cl (111 mg, 151 μmol, 0.25 eq), and KOAc (119 mg, 1.22 mmol, 2.00 eq) under N. The reaction mixture was stirred at 90 °C for 16 h under N. The reaction mixture was concentrated in vacuo to give the title compound as a white solid (0.50 g, crude). (ESI + ) m / z: 295.0 (M+H) + , (C 11 H 11 BN2O5S).

[0493] D. 1-Methyl-5-phenyl-1H-imidazole: To a solution of 5-phenyl-1H-imidazole (2.50 g, 17.3 mmol, 1.00 eq) in THF (50.0 mL) at 0 °C was added NaH (832 mg, 20.8 mmol, 60.0% purity, 1.20 eq) (5 batches) under N. The mixture was stirred at 0 °C for 30 min under N, after which MeI (3.45 g, 24.3 mmol, 1.51 mL, 1.40 eq) was added dropwise to the mixture. The reaction mixture was stirred at 25 °C for 2 h under N. The reaction mixture was poured into 100 mL of HO under N, extracted with ethyl acetate (3 x 100 mL), washed with brine (50.0 mL), dried over NaSO, and concentrated to give a residue. The 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 as a yellow solid (0.78 g, 4.93 mmol, 32.0% yield). (ESI + ) m / z: 159.0 (M+H) + , (C 10 H 10 N2).

[0494] 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 eq) in ACN (7.00 mL) was added NBS (874 mg, 4.91 mmol, 1.05 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1; TLC, petroleum ether:ethyl acetate = 1:1, R f =0.25) to give the title compound as a colorless oil (0.73 g, 3.08 mmol, 65.0% yield). 1 H 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).

[0495] 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: 3-[6-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[2,3 To a solution of [-c]pyrrol-5-yl]piperidine-2,6-dione (0.20 g, 531 μmol, 1.00 eq) and 4-bromo-1-methyl-5-phenyl-imidazole (151 mg, 637 μmol, 1.20 eq) was added Ru-Phos-Pd-G3 (88.9 mg, 106 μmol, 0.20 eq) and K3PO4 (225 mg, 1.06 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 40-70% acetonitrile in water containing 0.05% FA over 58 min at a flow rate of 25 mL / min to give the title compound as a white solid (16.9 mg, 41.2 μmol, 14.0% yield, 99.1% purity by HPLC at 220 nm). 1 H 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).

[0496] Example 17 Synthesis of 3-(5-(1,5-dimethyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0497] [ka]

[0498] 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 eq) in DMF (3.00 mL) was added K2CO3 (292 mg, 2.11 mmol, 2.00 eq) and stirred at 0 °C for 30 min under N2. CHI (180 mg, 1.27 mmol, 78.9 μL, 1.20 eq) was then added to the reaction mixture. The reaction mixture was stirred at 25 °C for 3 h under N2. The reaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (3 x 15.0 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, R f =0.30) to give the title compound as a white solid (100 mg, 328 μmol, yield 31.1%, purity by LCMS 220 nm 97.8%). (ESI + ) m / z: 299.3 (M+H) + , (C 11 H 11 IN2).

[0499] B. 3-(5-(1,5-dimethyl-4-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-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 in dioxane (1.00 mL) and HO (0.05 mL) To a solution of 1,4-diisopropyl-2,6-dione (102 mg, 276 μmol, 1.20 eq) and 3-iodo-1,5-dimethyl-4-phenyl-1H-pyrazole (70.0 mg, 229 μmol, 1.00 eq) was added KPO (146 mg, 688 μmol, 3.00 eq) and Ru-Phos-Pd-G (19.2 mg, 22.9 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 10 h under N. Concentration under reduced pressure gave a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 25.0%-55.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25mL / min to give the title compound as a white solid (9.40mg, 22.7µmol, 9.00% yield, 98.7% purity by HPLC at 220nm). 1 H 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).

[0500] Example 18 Synthesis of 3-(5-(1,3-dimethyl-4-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0501] [ka]

[0502] 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 eq) in DMF (3.00 mL) was added K2CO3 (292 mg, 2.11 mmol, 2.00 eq) and stirred at 0 °C for 30 min under N2. CHI (180 mg, 1.27 mmol, 78.9 μL, 1.20 eq) was then added to the reaction mixture. The reaction mixture was stirred at 25 °C for 3 h under N2. 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 residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, R f =0.40) to give the title compound as a white solid (80.0 mg, 258 μmol, yield 24.4%, purity by LCMS 220 nm 96.1%). (ESI + ) m / z: 299.3 (M+H) + , (C 11 H 11 IN2).

[0503] B. 3-(5-(1,3-dimethyl-4-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-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 in dioxane (1.00 mL) and HO (0.05 mL) To a solution of 5-iodo-2,6-dione (104 mg, 282 μmol, 1.20 eq) and 5-iodo-1,3-dimethyl-4-phenyl-1H-pyrazole (73.0 mg, 235 μmol, 1.00 eq) was added KPO (150 mg, 704 μmol, 3.00 eq) and Ru-Phos-Pd-G (19.6 mg, 23.5 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 2 h under N. Concentration under reduced pressure gave a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 24.0%-54.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25mL / min to give the title compound as a white solid (1.14mg, 2.75µmol, 1.00% yield, 97.1% purity by HPLC at 220nm). 1 HNMR: (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).

[0504] Example 19 Synthesis of 3-(5-(2-methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0505] [ka]

[0506] AN-(2-Oxo-2-phenylethyl)acetamide: To a solution of 2-amino-1-phenylethanone (10.0 g, 58.2 mmol, 1.00 eq, HCl) in THF (300 mL) was added acetyl acetate (16.1 g, 158 mmol, 14.8 mL, 2.71 eq) and TEA (11.7 g, 116 mmol, 16.2 mL, 2.00 eq). 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 as a brown oil (10.0 g, crude). 1 H NMR: (400 MHz, DMSO-d6) δ8.27 (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 No. 2).

[0507] B. 2-Methyl-5-phenyloxazole: Compound N-phenacylacetamide (10.0 g, 56.0 mmol, 1.00 eq) 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-cold 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 as a yellow solid (0.30 g, crude). (ESI +) m / z: 160.0 (M+H) + , (C 10 H9NO).

[0508] C. 4-Bromo-2-methyl-5-phenyloxazole: To a solution of 2-methyl-5-phenyl-oxazole (0.30 g, 1.90 mmol, 1.00 eq) in ACN (10.0 mL) was added NBS (1.40 g, 8.17 mmol, 1.30 eq) at 0 °C. The reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1; TLC, petroleum ether:ethyl acetate = 3:1, R f =0.50) to give the title compound as a yellow solid (0.30 g, 1.28 mmol, 66.0% yield). 1 H 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).

[0509] D. 3-(5-(2-Methyl-5-phenyloxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (0.20 g, 540 μmol, 1.00 eq) and 4-bromo-2-methyl-5-phenyl-oxazole (154 mg, 648 μmol, 1.20 eq) in dioxane (2.00 mL) and HO (0.10 mL) was added Ru-Phos-Pd-G3 (90.3 mg, 108 μmol, 0.20 eq), K3PO4 (229 mg, 1.08 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100° C. for 2 hours under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm×25 mm 10 μm) and a gradient of 27-57% acetonitrile in water containing 0.05% FA over 58 minutes at a flow rate of 20 mL / min to give the title compound as a white solid (75.3 mg, 170 μmol, 30.0% yield, 90.7% purity by HPLC at 220 nm). 1 H 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, 3 H), 5.14 - 5.09 (m, (ESI + ) m / z: 402.1 (M+H) + , (C 23 H 19 N3O4).

[0510] Example 20 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

[0511] [ka]

[0512] 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: 3-(3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3 To a solution of [-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 KPO (136 mg, 644 μmol, 2.00 eq) was added Ru-Phos-Pd-G (26.9 mg, 32.2 μmol, 0.10 eq) under N. The reaction mixture was stirred at 100 °C for 2 h under N. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by reverse-phase HPLC (0.1% HCl condition) to give the title compound as a yellow solid (12.8 mg, 31.8 μmol, 7.69% yield, >99% purity by HPLC at 220 nm). 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).

[0513] Example 21 Synthesis of 3-(5-(1-methyl-4-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0514] [ka]

[0515] A. 3-(5-(1-methyl-4-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidin-2,6-dione in dioxane (3.00 mL) and HO (0.15 mL). To a solution of 1,2,6-dione (0.10 g, 270 μmol, 1.00 eq) and 5-bromo-1-methyl-4-phenyl-imidazole (76.5 mg, 324 μmol, 1.20 eq) was added Ru-Phos-Pd-G3 (22.5 mg, 17.0 μmol, 0.10 eq) and K3PO4 (114 mg, 540 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 1-31% acetonitrile in water containing 0.05% FA over 58 min at a flow rate of 25 mL / min to give the title compound as a white solid (65.0 mg, 81.0 μmol, 60.0% yield, 100% purity by HPLC at 220 nm). 1 H 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).

[0516] Example 22 Synthesis of 3-(5-(1-isobutyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0517] [ka]

[0518] A. 1-Isobutyl-5-phenyl-1H-imidazole: To a solution of (E)-N-(2-phenyl-1-tosylvinyl)formamide (2.00 g, 6.63 mmol, 1.00 eq) in DME (20.0 mL) was added TEA (3.35 g, 33.1 mmol, 4.61 mL, 5.00 eq) at −5 °C. POCl3 (0.81 g, 5.30 mmol, 492 μL, 0.80 eq) was then added dropwise at −5 °C. 2-Methylpropan-1-amine (1.03 g, 14.1 mmol, 1.40 mL, 2.00 eq) was then added to the mixture. The mixture was then stirred at 25 °C for 5 h. The mixture was poured into water (100 mL) at 0 °C and extracted with DCM (3 × 80.0 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=10:1, TLC: dichloromethane:methanol=10:1, R f =0.2) to give the title compound as a brown oil (400 mg, 2.00 mmol, 30.1% yield). (ESI + ) m / z: 201.0 (M+H) + , (C 13 H 16 N2).

[0519] B. 4-Bromo-1-isobutyl-5-phenyl-1H-imidazole: To a solution of 1-isobutyl-5-phenyl-1H-imidazole (400 mg, 2.00 mmol, 1.00 eq) in ACN (20.0 mL) was slowly added NBS (249 mg, 1.40 mmol, 0.70 eq) at 0 °C. The mixture was then stirred at 25 °C for 2 h. The mixture was then 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 (3 x 15.0 mL), dried over Na2SO4, filtered, and the filtrate was collected. The liquid was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (DCM:MeOH = 10:1, R f =0.55) to give the title compound as a white solid (500 mg, 1.69 mmol, yield 84.3%, purity by LCMS 220 nm 94.1%). 1 H 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).

[0520] C. 3-(5-(1-isobutyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-Bromo-1-isobutyl-5-phenyl-1H-imidazole (300 mg, 1.07 mmol, 1.00 eq), 3-(1-oxo-5- To a solution of (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 eq) and KPO (456 mg, 2.15 mmol, 2.00 eq) was added Ru-Phos-Pd-G (89.9 mg, 107 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 4 h under N. The mixture was poured into H2O (20.0 mL) and extracted with DCM (3 × 15.0 mL). The combined organic layers were washed with saturated aqueous NaCl (3 × 15.0 mL), dried over Na2SO4, and filtered to obtain the filtrate. The liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150x25mmx5µm) column and a gradient of 11.0%-41.0% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (125mg, 279µmol, 25.9% yield, 98.7% purity by HPLC at 220nm). 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 H26 N4

[0521] Example 23 Synthesis of 3-(1-oxo-5-(5-phenylthiazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0522] [ka]

[0523] A. 4-Bromo-5-phenylthiazole: To a solution of 5-phenylthiazole (0.50 g, 3.10 mmol, 1.00 eq) in ACN (5.00 mL) was added NBS (607 mg, 3.41 mmol, 1.10 eq) at 25 °C under N. The mixture was stirred at 50 °C for 1 h. The reaction mixture was poured into H0 (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 NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1, TLC: petroleum ether:ethyl acetate = 3:1, R f =0.30) to give the title compound as a pale yellow solid (563 mg, 2.34 mmol, yield 75.6%, purity by LCMS 220 nm 100%). 1 H 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).

[0524] B. 3-(1-Oxo-5-(5-phenylthiazol-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 (185 mg, 499 μmol, 1.20 eq) and 4-bromo-5-phenylthiazole (100 mg, 416 μmol, 1.00 eq) in dioxane (2.00 mL) and HO (0.10 mL) was added Ru-Phos-Pd-G3 (34.8 mg, 41.6 μmol, 0.10 eq) and K3PO4 (176.8 mg, 832 μmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 100° C. for 2 h under N. The reaction mixture was concentrated under reduced pressure at 45° C. to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150×25 mm×7 μm) and a gradient of 26.0%-56.0% acetonitrile in water containing 0.05% FA over 20 min at a flow rate of 25 mL / min to give the title compound as a white solid (102.1 mg, 205 mmol, 60.1% yield, 98.9% purity by HPLC at 220 nm). 1 H 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).

[0525] Example 24 Synthesis of (R)-3-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0526] [ka]

[0527] A. (S)-tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a suspension of tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate (14.5 g, 60.6 mmol, 1.00 eq, HCl) in MeCN (231 mL) was added DIEA (28.0 g, 2171 mmol, 37.7 mL, 3.57 eq) at 0 °C. After stirring for 15 min, methyl 4-bromo-2-(bromoethyl)benzoate (22.0 g, 71.4 mmol, 1.18 eq) was added portionwise over 15 min to the mixture. The reaction mixture was stirred at 0 °C for 30 min and then warmed to 25 °C for 3 h. The reaction mixture was warmed to 60 °C for 12 h. 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 under vacuum and filtered to give the title compound as a yellow solid (18.0 g, 45.3 mmol, 74.8% yield). 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).

[0528] 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: (S)-tert-Butyl in dioxane (100 mL) To a solution of 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 eq), BPD (7.67 g, 30.2 mmol, 1.20 eq), AcOK (7.41 g, 75.52 mmol, 3.00 eq), and Pd(dppf)Cl (1.01 g, 1.38 mmol, 0.05 eq) were added. The mixture was stirred at 60 °C for 2 h under N. The reaction mixture was diluted with EtOAc (50.0 mL) and filtered through a plug of Celite, washing with additional EtOAc (30.0 mL). The filtrate was dried under vacuum to give the title compound as an off-white solid (8.74 g, 14.5 mmol, 57% yield, 73.8% purity by LCMS 220 nm). (ESI + ) m / z: 445.1 (M+H) + , (C 22 H 33 BN2O6).

[0529] C. tert-Butyl (S)-5-amino-4-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (117 mg, 264 μmol, 1.10 eq) and 4-iodo-1-methyl-1H-imidazole (50.0 mg, 240 μmol, 1.00 eq) in dioxane (1.00 mL) and HO (0.10 mL) was added KPO (153 mg, 721 μmol, 3.00 eq) and cataCXium A Pd G3 (17.5 mg, 24.0 μmol, 0.1 eq) was added at 25° C. under N2. The mixture was stirred at 80° C. for 10 h under N2. The mixture was concentrated under reduced pressure to give a residue. The residue was poured into H2O (5.0 mL) and extracted with DCM (3×10 mL) and the organic layer was collected. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum at 40° C. to give a residue. The residue was analyzed by prep-TLC (dichloromethane:methanol=10:1, R f =0.20) to give the title compound as a brown solid (40.0 mg, 72.8 μmol, yield 32.0%, purity by LCMS 220 nm 85.0%). (ESI + ) m / z: 399.1 (M+H) + , (C 21 H 26 N4O4).

[0530] D. tert-Butyl (S)-5-amino-4-(5-(5-bromo-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: To a solution of tert-butyl (S)-5-amino-4-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (40.0 mg, 72.1 μmol, 1.00 eq) in MeCN (1.00 mL) was added NBS (12.8 mg, 72.0 μmol, 1.00 eq) at 0° C. The mixture was then stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was analyzed by prep-TLC (dichloromethane:methanol=10:1, R f =0.25) to give the title compound as a brown solid (15.0 mg, 30.9 μmol, yield 53.0%, purity as measured by LCMS at 220 nm 98.6%). 1 H 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, (ESI) + ) m / z: 476.1 (M+H) + , (C 21 H 25 BrN4O4).

[0531] E. tert-Butyl (S)-5-amino-4-(5-(5-(4-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate: tert-Butyl in dioxane (1.00 mL) To a solution of (S)-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 eq), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.67 mg, 61.9 μmol, 2.00 eq), and KCO (8.56 mg, 61.9 μmol, 2.00 eq) was added Pd(dppf)Cl (7.16 mg, 6.20 μmol, 0.20 eq) under N. The reaction mixture was then stirred at 100 °C for 2 h under N. The mixture was poured into HO (6.0 mL), extracted with DCM (3 × 10.0 mL), and the organic layer was collected. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum at 40 °C to give a residue. The residue was analyzed by prep-TLC (dichloromethane:methanol = 10:1, R f =0.15) to give the title compound as a white solid (10.0 mg, 19.8 μmol, yield 60.0%, purity by LCMS 220 nm 97.5%). (ESI + ) m / z: 493.3 (M+H) + , (C 27 H 29 FN4O4).

[0532] 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 eq) in MeCN (1.00 mL) was added TsOH (17.0 mg, 98.9 μmol, 5.00 eq). The mixture was stirred at 80° C. for 4 h. The mixture was poured into HO (10.0 mL) and extracted with DCM (3×10.0 mL). The combined organic layers were washed with brine (2 x 15.0 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150 x 25 mm x 5 μm) and a gradient of 4-34% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (2.57 mg, 5.96 μmol, 29.4% yield, 97.1% purity by HPLC at 220 nm). 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).

[0533] Example 25 Synthesis of 3-(5-(1-methyl-2-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0534] [ka]

[0535] A. 4,5-Dibromo-2-phenyl-1H-imidazole: To a solution of 2-phenyl-1H-imidazole (10.0 g, 69.3 mmol, 1.00 eq) in DMF (100 mL) was added NBS (24.6 g, 138 mmol, 2.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. HO (100 mL) was added to the residue, extracted with ethyl acetate (3 × 100 mL), and the combined organic layers were washed with saturated aqueous NaSO (2 × 100 mL) and dried over anhydrous NaSO. The organic layer was concentrated in vacuo to give the title compound as a yellow solid (6.00 g, crude). (ESI + ) m / z: 300.8 (M+H) + , (C9H6Br2N2).

[0536] B. 4-Bromo-2-phenyl-1H-imidazole: To a solution of 4,5-dibromo-2-phenyl-1H-imidazole (5.00 g, 16.5 mmol, 1.00 eq) in EtOH (50.0 mL) and HO (50.0 mL) was added NaSO (10.4 g, 66.2 mmol, 4.00 eq) under N. The reaction mixture was stirred at 110 °C for 96 h under N. The mixture was cooled to 25 °C, and the solvent was removed under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, 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 as a yellow solid (1.10 g, 4.88 mmol, 25.0% yield, 98.9% purity by HPLC at 220 nm). 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).

[0537] C. 4-Bromo-1-methyl-2-phenyl-1H-imidazole: To a solution of 4-bromo-2-phenyl-1H-imidazole (0.50 g, 2.24 mmol, 1.00 eq) in THF (10.0 mL) at 0 °C was added NaH (117 mg, 2.91 mmol, 60.0% purity, 1.30 eq) (5 batches) under N. The mixture was stirred at 0 °C for 30 min under N, after which CHI (636 mg, 4.48 mmol, 279 μL, 2.00 eq) was added dropwise to the mixture. The reaction mixture was stirred at 25 °C for 2 h under N. The reaction mixture was poured into 100 mL of HO under N, extracted with ethyl acetate (3 × 100 mL), washed with brine (50.0 mL), dried over NaSO, and concentrated to give a residue. The crude product was purified by preparative TLC (dichloromethane:methanol = 100:1, R f =0.60) to obtain the title compound (200 mg, 844 μmol, yield 37.6%). (ESI + ) m / z: 236.9 (M+H) + , (C 10 H9BrN2).

[0538] D. 3-(5-(1-methyl-2-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidin-2,6-dione in dioxane (2.00 mL) and HO (0.10 mL). To a solution of 1,3-dione-2,6-dione (131 mg, 354 μmol, 1.20 eq) and 4-bromo-1-methyl-2-phenyl-imidazole (70.0 mg, 295 μmol, 1.00 eq) was added KPO (125 mg, 590 μmol, 2.00 eq) and Ru-Phos-Pd-G (49.3 mg, 59.0 μmol, 0.20 eq) under N. The reaction mixture was stirred at 100 °C for 2 h under N. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 3-33% acetonitrile in water containing 0.05% FA over 58 min at a flow rate of 25 mL / min to give the title compound as a white solid (17.8 mg, 42.1 μmol, 14.2% yield, 94.7% purity by HPLC at 220 nm). 1 H 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, (ESI) + ) m / z: 401.1 (M+H) + , (C 23 H 20 N4O3).

[0539] Example 26 Synthesis of 3-(5-(1-ethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0540] [ka]

[0541] 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. A solution of 2-tosylacetonitrile (10.0 g, 51.2 mmol, 1.00 eq) in THF (20.0 mL) was added dropwise at −40° C. The mixture was stirred at −40° C. for 0.5 h. A solution of benzaldehyde (5.71 g, 53.8 mmol, 5.44 mL, 1.05 eq) in THF (20.0 mL) was added dropwise at −40° C. The mixture was then stirred at −40° C. for 0.5 h. The mixture was poured into ice water (100 mL), neutralized with 1N HCl solution (pH=7), and extracted with DCM (3×100 mL). The organic layer was then dried over NaSO, filtered, and concentrated to give a residue. The residue was triturated with MTBE (2 x 20.0 mL) at 25 °C to give the title compound as a yellow solid (12.0 g, 39.7 mmol, 77.6% yield, 99.8% purity by LCMS 220 nm). (ESI + ) m / z: 302.6 (M+H) + , (C 16 H 15 NO3S).

[0542] B. 1-Ethyl-5-phenyl-1H-imidazole: To a solution of (E)-N-(2-phenyl-1-tosylvinyl)formamide (2.00 g, 6.63 mmol, 1.00 eq) in DME (20.0 mL) was added TEA (3.35 g, 33.1 mmol, 4.61 mL, 5.00 eq) at −5 °C. POCl (0.81 g, 5.30 mmol, 492 μL, 0.80 eq) was then added dropwise at −5 °C. The reaction mixture was then stirred at 0 °C for 1 h. Ethylamine (636 mg, 14.1 mmol, 923 μL, 2.00 eq) was then added to the mixture. The mixture was then stirred at 25 °C for 4 h. The mixture was poured into water (100 mL) at 0 °C and extracted with DCM (3 × 80 mL). The combined organics were dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=10:1, TLC: dichloromethane:methanol=10:1, R f =0.2) to give the title compound as a brown oil (400 mg, 2.29 mmol, yield 35.0%, purity by LCMS 220 nm 98.5%). (ESI + ) m / z: 173.0 (M+H) + , (C 11 H 12 N2).

[0543] C. 4-Bromo-1-ethyl-5-phenyl-1H-imidazole: To a solution of 1-ethyl-5-phenyl-1H-imidazole (386 mg, 2.24 mmol, 1.00 eq) in MeCN (15.0 mL) was added NBS (319 mg, 1.79 mmol, 0.80 eq) at 25 °C under N. The mixture was stirred at 25 °C for 1 h under N. The reaction mixture was poured into H0 (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 NaSO, filtered, and concentrated. The residue was analyzed by preparative TLC (dichloromethane:methanol = 10:1, R f =0.30) to give the title compound as a brown oil (250 mg, 995 μmol, 44.4% yield). 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 H 11 BrN2).

[0544] D. 3-(5-(1-ethyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-Bromo-1-ethyl-5-phenyl-1H-imidazole (200 mg, 796 μmol, 1.00 eq) and 3-(1-oxo-5-(4, To a solution of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (383 mg, 1.04 mmol, 1.30 eq) was added Ru-Phos-Pd-G3 (99.9 mg, 119 μmol, 0.15 eq) and K3PO4 (507 mg, 2.39 mmol, 3.00 eq) under N2 at 25 °C. The mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was poured into HO (15.0 mL) and extracted with ethyl acetate (3 × 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 HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 5.00%-35.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25mL / min to give the title compound as a white solid (10.5mg, 24.9µmol, 3.14% yield, 98.6% purity by HPLC at 220nm). 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).

[0545] Example 27 Synthesis of 3-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0546] [ka]

[0547] A. 4-Bromo-1-(difluoromethyl)-5-phenyl-1H-pyrazole: To a solution of 4-bromo-5-phenyl-1H-pyrazole (1.00 g, 4.48 mmol, 1.00 eq) and 18-crown-6 (646 mg, 1.79 mmol, 0.40 eq) in ACN (25.0 mL). The reagents were stirred until a colorless solution was formed, after which (2-chloro-2,2-difluoroacetyl)oxysodium (1.37 g, 8.97 mmol, 2.00 eq) was added to the reaction mixture, which was then heated to 80 °C 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 as a white solid (0.40 g, 1.26 mmol, 28.0% yield). (ESI + ) m / z: 272.9 (M+H) + , (C10 H7BrF2N2).

[0548] B. 3-(5-(1-(difluoromethyl)-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-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 in dioxane (3.00 mL) and HO (0.15 mL). To a solution of zinzine-2,6-dione (418 mg, 1.13 mmol, 1.20 eq) and 4-bromo-1-(difluoromethyl)-5-phenyl-pyrazole (300 mg, 941 μmol, 1.00 eq) was added Ru-Phos-Pd-G3 (157 mg, 188 μmol, 0.20 eq) and K3PO4 (399 mg, 1.88 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 29-59% acetonitrile in water containing 0.05% FA over 58 min at a flow rate of 20 mL / min to give the title compound as a yellow solid (122 mg, 278 μmol, 29.6% yield, 99.7% purity by HPLC at 220 nm). 1 H 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 - (ESI + ) m / z: 437.2 (M+H) + , (C 23 H 18 F2N4O3).

[0549] Example 28 Synthesis of 3-(5-(1-methyl-2-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0550] [ka]

[0551] A. 3-(5-(1-methyl-2-phenyl-1H-imidazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidin-2,6-dione in dioxane (1.00 mL) and HO (0.05 mL). To a solution of 1,6-dione (168 mg, 455 μmol, 1.20 eq) and 5-bromo-1-methyl-2-phenyl-imidazole (90.0 mg, 379 μmol, 1.00 eq) was added Ru-Phos-Pd-G3 (63.5 mg, 75.9 μmol, 0.20 eq) and K3PO4 (161 mg, 759 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 10 μm) and a gradient of 1-31% acetonitrile in water containing 0.05% FA over 58 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (21.2 mg, 52.4 μmol, 13.8% yield, 99.0% purity by HPLC at 220 nm). 1H 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).

[0552] Example 29 Synthesis of 3-(5-(3-methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0553] [ka]

[0554] A. 3-(5-(3-methyl-5-phenylisoxazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-iodo-3-methyl-5-phenylisoxazole (100 mg, 350 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4, To a solution of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (168 mg, 456 μmol, 1.30 eq) was added KPO (223 mg, 1.05 mmol, 3.00 eq) and Ru-Phos-Pd-G (58.6 mg, 70.1 μmol, 0.20 eq) under N at 25 °C. The mixture was stirred at 100 °C for 4 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 26.0%-56.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25mL / min to give the title compound as a white solid (17.7mg, 43.1µmol, 12.3% yield, 97.5% purity by HPLC at 220nm). 1 H 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 - (ESI + ) m / z: 402.0 (M+H) + , (C 23 H 19 N3O4).

[0555] Example 30 Synthesis of 3-(5-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0556] [ka]

[0557] 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 eq) and (diacetoxyiodo)benzene (1.63 g, 5.06 mmol, 1.00 eq) in DCM (15.0 mL) was added 3-methyl-5-phenyl-1H-pyrazole (800 mg, 5.06 mmol, 1.00 eq). 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 residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx7µm) and a gradient of 34.0%-64.0% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a pale yellow solid (548mg, 1.93mmol, 38.2% yield, 100% purity by LCMS 220nm). 1 H 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).

[0558] B. 3-(5-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-iodo-3-methyl-5-phenyl-1H-pyrazole (100 mg, 351 μmol, 1.00 eq) and 3-(1-oxo-5-(4,4, To a solution of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (390 mg, 1.06 mmol, 3.00 eq) was added KPO (224 mg, 1.06 mmol, 3.00 eq) and Ru-Phos-Pd-G (29.4 mg, 35.2 μmol, 0.10 eq) at 25 °C under N. The mixture was stirred at 100 °C for 3 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 14.0%-44.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25mL / min to give the title compound as a white solid (33.2mg, 82.4µmol, 23.4% yield, 99.5% purity by HPLC at 220nm). 1 H 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 - (ESI + ) m / z: 400.1 (M+H) + , (C 23 H 20 N4O3).

[0559] Example 31 Synthesis of 3-(1-oxo-5-(4-phenylisothiazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0560] [ka]

[0561] A. 5-Bromo-4-iodoisothiazole: To a solution of 5-bromoisothiazole (1.00 g, 6.10 mmol, 1.00 eq) in TFA (10.0 mL) was added NIS (1.37 g, 6.10 mmol, 1.00 eq) at 25 °C under N. The mixture was stirred at 80 °C for 12 h under N. The reaction mixture was poured into H0 (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 NaSO, filtered, and concentrated. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 10:1, R f =0.30) to give the title compound as a pale yellow solid (1.42 g, 4.90 mmol, yield 80.3%, purity by LCMS 220 nm 97.9%). 1 H NMR: (400 MHz, CDCl3) δ 8.29 (s, 1H). (ESI + ) m / z: 291.7 (M+H) + , (C3HBrINS).

[0562] B. 5-Bromo-4-phenylisothiazole: To a solution of 5-bromo-4-iodoisothiazole (300 mg, 1.03 mmol, 1.00 eq) and phenylboronic acid (113 mg, 931 μmol, 0.90 eq) in dioxane (6.00 mL) and HO (0.30 mL) was added Pd(PPh)Cl (72.6 mg, 103 μmol, 0.10 eq) and NaHCO (330 mg, 3.93 mmol, 153 μL, 3.80 eq) under N at 25 °C. The mixture was stirred at 60 °C for 24 h under N. The reaction mixture was poured into HO (10.0 mL) and extracted with dichloromethane (3 × 10.0 mL). The combined organic layers were washed with brine (3 × 10.0 mL), dried over NaSO, filtered, and concentrated. The residue was analyzed by preparative TLC (dichloromethane:methanol=10:1, R f =0.70) to give the title compound as a pale yellow oil (70.0 mg, 291 μmol, 28.1% yield). (ESI + ) m / z: 238.9 (M+H) + , (C9H6BrNS).

[0563] C. 3-(1-Oxo-5-(4-phenylisothiazol-5-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 (501 mg, 1.35 mmol, 2.50 eq) and 5-bromo-4-phenylisothiazole (130 mg, 541 μmol, 1.00 eq) in dioxane (5.00 mL) and HO (0.25 mL) was added KPO (344 mg, 1.62 mmol, 3.00 eq) and Ru-Phos-Pd-G (45.3 mg, 54.1 μmol, 0.10 eq) at 25 °C under N. The mixture was stirred at 100°C for 4 hours under N2. The reaction mixture was concentrated under reduced pressure at 45°C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 28.0%-58.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (30.0 mg, 73.4 µmol, 13.5% yield, 98.7% purity by HPLC at 220 nm). 1 H 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, (ESI + ) m / z: 403.9 (M+H) + , (C 22 H 17 N3O3S).

[0564] Example 32 Synthesis of 3-(1-oxo-5-(1-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0565] [ka]

[0566] A. 4-Bromo-1-phenyl-1H-imidazole: To a solution of 1-phenyl-1H-imidazole (800 mg, 5.55 mmol, 1.00 eq) in ACN (8.00 mL) was added NBS (790 mg, 4.44 mmol, 0.80 eq) at 0 °C under N. The mixture was stirred at 25 °C for 2 h under N. 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 as a yellow solid (330 mg, 1.48 mmol, 26.6% yield). 1 H 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).

[0567] B. 3-(1-oxo-5-(1-phenyl-1H-imidazol-4-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- in dioxane (5.00 mL) and HO (0.25 mL) To a solution of 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 KPO (285 mg, 1.34 mmol, 3.00 eq) was added Ru-Phos-Pd-G (37.5 mg, 44.8 μmol, 0.10 eq) under N at 25 °C. The mixture was stirred at 100 °C for 4 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 1.00%-31.0% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (51.0mg, 127µmol, 28.4% yield, 96.6% purity by HPLC at 220nm). 1 H 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).

[0568] Example 33 Synthesis of 3-(1-oxo-5-(5-phenyl-1H-pyrazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0569] [ka]

[0570] A. 3-(5-Nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of methyl 2-(bromoethyl)-4-nitrobenzoate (1.00 g, 3.65 mmol, 1.00 eq) and 3-aminopiperidine-2,6-dione (660 mg, 4.01 mmol, 1.10 eq, HCl) in DMF (10.0 mL) was added K2CO3 (1.51 g, 10.9 mmol, 3.00 eq). The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was concentrated to give a residue. Water (10.0 mL) was added to the resulting residue, and the mixture was stirred at 25 °C for 30 minutes. The resulting solid was filtered, washed with EtOAc (2×10.0 mL), and concentrated under reduced pressure to give the title compound as a white solid (0.80 g, 2.77 mmol, 75.0% yield, 100% purity by HPLC at 220 nm). 1 H 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).

[0571] B. 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.80 g, 2.77 mmol, 1.00 eq) in THF (8.00 mL) and MeOH (8.00 mL) was added Pd / C (0.30 g, 10% purity) under N. The reaction mixture was stirred at 25 °C for 12 h under H (15 psi). The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title compound as a white solid (0.20 g, 771 μmol, 27.8% yield). 1 H 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).

[0572] C. 3-(5-Hydrazineyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50.0 mg, 192 μmol, 1.00 eq) in conc. HCl (1.00 mL) was added a solution of NaNO (13.3 mg, 192 μmol, 1.00 eq) in HO (0.50 mL) at 0 °C. After 0.5 h, a solution of SnCl.2HO (87.0 mg, 385 μmol, 2.00 eq) in conc. 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 as a yellow solid (0.19 g, crude). (ESI + ) m / z: 275.1 (M+H) +, (C 13 H 14 N4O3).

[0573] 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-oxo-isoindolin-2-yl)piperidine-2,6-dione (151 mg, 553 μmol, 1.20 eq) and 3-phenylprop-2-ynal (60.0 mg, 461 μmol, 56.2 μL, 1.00 eq) in ACN (1.00 mL) was stirred at 25° C. for 1 h. To the reaction mixture was then added Cu(OAc) (8.37 mg, 46.1 μmol, 0.10 eq). The reaction mixture was stirred at 80° C. for 8 h. The reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm x 25 mm 5 μm) and a gradient of 20-50% acetonitrile in water containing 0.05% FA run at a flow rate of 20 mL / min over 63 min to give the title compound as a yellow solid (13.4 mg, 32.6 μmol, 7.00% yield, 94.0% purity by HPLC at 220 nm). 1 H 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).

[0574] Example 34 Synthesis of 3-(1-oxo-5-(1-phenyl-1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione

[0575] [ka]

[0576] A. 3-(1-Oxo-5-(1-phenyl-1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione: 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 eq), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (179 mg, 555 μmol, 1.50 eq) and KPO (235 mg, 1.11 mmol, 3.00 eq) in dioxane (5.00 mL) and HO (0.25 mL) was added Ru-Phos-Pd-G (30.9 mg, 37.0 μmol, 0.100 eq) under N. The mixture was stirred at 70 °C for 2 h under N2. The mixture was filtered to collect the liquid, and the liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 x 25 mm x 5 μm) column and a gradient of 30.0% to 60.0% acetonitrile in water containing 0.05% TFA over 15 min at a flow rate of 25 mL / min to give the title compound as a white solid (15.7 mg, 39.5 μmol, 11.0% yield, 97.2% purity by HPLC at 220 nm). 1H 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).

[0577] Example 35 Synthesis of 3-(5-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0578] [ka]

[0579] A. 3-(5-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 5-Bromo-1-methyl-3-phenyl-1H-pyrazole (100 mg, 421 μmol, 1.00 eq), 3-(1-oxo-5-(4, To a solution of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (312 mg, 843 μmol, 2.00 eq) and KPO (268 mg, 1.27 mmol, 3.00 eq) was added Ru-Phos-Pd-G (35.3 mg, 42.2 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The mixture was filtered, and the liquid was collected and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150x25mmx5µm) column and a gradient of 27%-57.0% acetonitrile in water containing 0.05% TFA over 15 minutes at a flow rate of 25mL / min to give the title compound as an off-white solid (14.4mg, 34.4µmol, 8.40% yield, 95.6% purity by HPLC at 220nm). 1 H 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).

[0580] Example 36 Synthesis of 3-(5-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0581] [ka]

[0582] A. 3-(5-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-Bromo-1-methyl-5-phenyl-1H-pyrazole (100 mg, 421 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5 To a solution of 1,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (546 mg, 1.48 mmol, 3.50 eq) and KPO (268 mg, 1.27 mmol, 3.00 eq) was added Ru-Phos-Pd-G (52.9 mg, 63.2 μmol, 0.15 eq) at 25 °C under N. The mixture was stirred at 100 °C for 7 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 26.0%-56.0% acetonitrile in water containing 0.05% FA over 13 minutes at a flow rate of 25mL / min to give the title compound as a white solid (51.3mg, 125µmol, 29.6% yield, 97.6% purity by HPLC at 220nm). 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, (ESI) + ) m / z: 400.9 (M+H) + , (C 23 H 20 N4O3).

[0583] Example 37 Synthesis of 3-(1-oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0584] [ka]

[0585] A. 3-(1-Oxo-5-(2-phenyloxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-phenyloxazole (100 mg, 446 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (495 mg, 1.34 mmol, 3.00 eq) and KPO (284 mg, 1.34 mmol, 3.00 eq) in dioxane (5.00 mL) and HO (0.25 mL) was added Ru-Phos-Pd-G (37.3 mg, 44.6 μmol, 0.10 eq) at 25 °C under N. 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 residue was purified by prep-HPLC using a Phenomenex luna C18 (150 x 25 mm x 10 μm) and a gradient of 30.0% to 60.0% acetonitrile in water containing 0.05% FA over 13 min at a flow rate of 25 mL / min to give the title compound as a white solid (50.4 mg, 133 μmol, 29.9% yield, 99.1% purity by HPLC at 220 nm). 1 H 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 - (ESI + ) m / z: 388.1 (M+H) + , (C 22 H 17 N3O4).

[0586] Example 38 Synthesis of 3-(1-oxo-5-(3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0587] [ka]

[0588] A. 3-(1-oxo-5-(3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: A solution of 4-(4-bromo-1H-pyrazol-3-yl)pyridine (100 mg, 446 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (330 mg, 892 μmol, 2.00 eq), and KPO (284 mg, 1.34 mmol, 3.00 eq) in dioxane (5.00 mL) and HO (0.25 mL) was treated with cataCXium A Pd G3 (65.0 mg, 89.2 μmol, 0.20 eq) was added under N. The mixture was stirred at 100° C. for 18 h. The reaction mixture was concentrated under reduced pressure at 45° C. to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150×25 mm×10 μm) and a gradient of 0.00% to 24.0% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL / min to give the title compound as an off-white solid (13.8 mg, 34.1 μmol, 7.63% yield, 95.7% purity by HPLC at 220 nm). 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).

[0589] Example 39 Synthesis of 3-(1-oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0590] [ka]

[0591] A. 4-Bromo-5-phenylisoxazole: To a solution of 5-phenylisoxazole (150 mg, 1.03 mmol, 1.00 eq) and NBS (183 mg, 1.03 mmol, 1.00 eq) 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 residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f =0.80) to give the title compound as a pale yellow solid (130 mg, 393 μmol, yield 79.5%, purity as determined by LCMS at 220 nm 88.0%). 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).

[0592] B. 3-(1-Oxo-5-(5-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-5-phenylisoxazole (175 mg, 781 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (722 mg, 1.95 mmol, 2.50 eq) and KPO (497 mg, 2.34 mmol, 3.00 eq) in dioxane (6.00 mL) and HO (0.30 mL) was added Ru-Phos-Pd-G (65.3 mg, 78.1 μmol, 0.10 eq) under N. 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 residue was purified by preparative HPLC using a Phenomenex luna C18 (150 x 25 mm x 5 μm) and a gradient of 28.0%-48.0% acetonitrile in water containing 0.05% FA over 10 min at a flow rate of 25 mL / min to give the title compound as an off-white solid (22.5 mg, 57.2 μmol, 7.34% yield, 98.5% purity by HPLC at 220 nm). 1H 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).

[0593] Example 40 Synthesis of 3-(5-(1-methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0594] [ka]

[0595] A. 2-Bromo-1-methyl-5-phenyl-1H-imidazole: To a solution of phenylboronic acid (213 mg, 1.75 mmol, 1.40 eq), 2,5-dibromo-1-methyl-1H-imidazole (300 mg, 1.25 mmol, 1.00 eq), and KPO (796 mg, 3.75 mmol, 3.00 eq) in THF (10.0 mL) was added Pd(OAc) (28.0 mg, 125 μmol, 0.10 eq). The mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into HO (15.0 mL) and extracted with ethyl acetate (3 × 15.0 mL). The combined organic layers were washed with brine (3 × 15.0 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f=0.30) to give the title compound as a pale yellow solid (75.0 mg, 309 μmol, yield 24.7%, purity by LCMS 220 nm 97.7%). 1 H 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).

[0596] B. 3-(5-(1-methyl-5-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 2-Bromo-1-methyl-5-phenyl-1H-imidazole (65.0 mg, 274 μmol, 1.00 eq), 3-(1-oxo-5-( To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (253 mg, 685 μmol, 2.50 eq) and KPO (174 mg, 822 μmol, 3.00 eq) was added Ru-Phos-Pd-G (22.9 mg, 27.4 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 3 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 0.00%-30.0% acetonitrile in water containing 0.05% FA over 10 minutes at a flow rate of 25mL / min to give the title compound as an off-white solid (7.85mg, 18.6µmol, 6.79% yield, 95.0% purity by HPLC at 220nm). 1H 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).

[0597] Example 41 Synthesis of 3-(5-(1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0598] [ka]

[0599] A. 1-Methyl-4-phenyl-1H-imidazole: To a solution of 4-phenyl-1H-imidazole (2.00 g, 13.8 mmol, 1.00 eq), CsCO (6.78 g, 20.8 mmol, 1.50 eq) in DMF (30.0 mL) was added MeI (3.94 g, 27.7 mmol, 1.73 mL, 2.00 eq) at 20 °C. The mixture was stirred at 25 °C for 8 h under N. 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 (3 x 30.0 mL), dried over Na2SO4, filtered, and the filtrate was collected. The liquid was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (dichloromethane:methanol = 10:1 R f=0.30) to give the title compound as a yellow solid (270 mg, 1.69 mmol, yield 12.3%, purity by LCMS 220 nm 99.1%). 1 H 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).

[0600] B. 2-Iodo-1-methyl-4-phenyl-1H-imidazole: To a solution of 1-methyl-4-phenyl-1H-imidazole (150 mg, 948 μmol, 1.00 eq) in THF (1.00 mL) was added n-BuLi (2.50 M, 758 μL, 2.00 eq) at −70 °C under a N atmosphere and stirred at −70 °C for 1 h. I (481 mg, 1.90 mmol, 382 μL, 2.00 eq) in THF (3.00 mL) was then added via syringe, maintaining the reaction temperature below −50 °C. The reaction was then brought to 0 °C and stirred for 1 h under N. The reaction mixture was poured into saturated aqueous NH Cl (30.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with Na2SO3 (10.0%, 3x30.0 mL), dried over Na2SO4, filtered, and the liquid collected was concentrated under reduced pressure to give the title compound as a yellow solid (188 mg, 633 μmol, 66.7% yield, 95.7% purity by LCMS 220 nm). 1 H 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).

[0601] C. 3-(5-(1-methyl-4-phenyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 2-iodo-1-methyl-4-phenyl-1H-imidazole (150 mg, 528 μmol, 1.00 eq), 3-(1-oxo-5-(4, To a solution of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (489 mg, 1.32 mmol, 2.50 eq) and KPO (336 mg, 1.58 mmol, 3.00 eq) was added Ru-Phos-Pd-G (44.2 mg, 52.8 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 3 h under N. The reaction mixture was then filtered, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x2 5mmx5µm) and a gradient of 4-34% acetonitrile in water containing 0.5% TFA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (37.4mg, 91.9µmol, 17.4% yield, 98.4% purity by HPLC at 220nm). 1 H 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 20 N4O3).

[0602] Example 42 Synthesis of 3-(1-oxo-5-(4-phenyloxazol-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0603] [ka]

[0604] A. 4-Phenyloxazole: A mixture of 2-bromo-1-phenyl-ethanone (10.0 g, 50.2 mmol, 1.00 eq) and HCOONH4 (11.0 g, 175 mmol, 3.50 eq) 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 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 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 as a yellow oil (2.00 g, 12.9 mmol, 25.7% yield, 93.7% purity by LCMS 220 nm). (ESI + ) m / z: 146.3 (M+H) + , (C9H7NO).

[0605] B. 2-Bromo-4-phenyloxazole: To a solution of 4-phenyloxazole (200 mg, 1.29 mmol, 1.00 eq) in THF (2.00 mL) was added n-BuLi (2.50 M, 568 μL, 1.10 eq) dropwise at −78 °C under N2. The reaction mixture was stirred for an additional 0.5 h, after which 1,2-dibromo-1,1,2,2-tetrafluoroethane (352 mg, 1.36 mmol, 1.05 eq) was added dropwise at −78 °C. The reaction mixture was then stirred at 25 °C for 12 h. Upon completion of the reaction, the reaction mixture was quenched with 10.0 mL of saturated NH4Cl solution at 0 °C under N2. The mixture was then extracted with EtOAc (3 × 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 residue was purified by preparative TLC (SiO2, petroleum ether: EtOAc = 5:1, R f =0.80) to give the title compound as a white solid (150 mg, 669 μmol, yield 51.8%, purity by LCMS 220 nm 100%). 1 H 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).

[0606] 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 eq) 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 eq) in dioxane (6.00 mL) and HO (0.30 mL) was added Ru-Phos-Pd-G3 (44.7 mg, 53.5 μmol, 0.10 eq) and K3PO4 (341 mg, 1.61 mmol, 3.00 eq). 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, which was purified by preparative HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) column and a gradient of 32-62% acetonitrile in water containing 0.5% FA over 8 min at a flow rate of 25 mL / min to give the title compound as a gray solid (16.2 mg, 41.8 μmol, 7.81% yield, 100% purity by HPLC at 220 nm). 1 H 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).

[0607] Example 43 Synthesis of 3-(1-oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0608] [ka]

[0609] A. (2,2-Dibromocyclopropyl)benzene: To a solution of styrene (5.00 g, 48.0 mmol, 1.00 eq) in DCM (25.0 mL) was added TEBA (349 mg, 1.54 mmol, 0.032 eq) and KOH (4.04 g, 72.0 mmol, 1.50 eq) at 40 °C under N2. To the mixture was added CHBr3 (15.5 g, 61.4 mmol, 5.38 mL, 1.28 eq) at 40 °C under N2 over 2 h. The mixture was stirred at 25 °C for 20 h under N2. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The 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 as a yellow oil (5.00 g, 18.1 mmol, 37.7% yield). 1 H 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).

[0610] B. 5-Bromo-3-phenylisoxazole: To a solution of nitridooxonium tetrafluoroborate (2.54 g, 21.7 mmol, 1.20 eq) in dry ACN (15.0 mL) was added a solution of (2,2-dibromocyclopropyl)benzene (5.00 g, 18.1 mmol, 1.00 eq) in dry ACN (10.0 mL) dropwise at 25 °C under N2. The reaction mixture was then stirred at 25 °C for 5 h. After completion of the reaction, the reaction mixture was quenched with 30.0 mL of water and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 10:1, R f =0.20 (petroleum ether:ethyl acetate=10:1)) to give the title compound as a yellow solid (500 mg, 1.94 mmol, yield 12.3%, purity by LCMS 220 nm 86.9%). 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).

[0611] C. 3-(1-Oxo-5-(3-phenylisoxazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 5-bromo-3-phenyl-isoxazole (100 mg, 446 μmol, 1.00 eq) in dioxane (1.00 mL) and HO (0.05 mL) was added 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (330 mg, 892 μmol, 2.00 eq), KPO (189 mg, 892 μmol, 2.00 eq) and Ru-Phos-Pd-G (37.3 mg, 44.6 μmol, 0.10 eq) under N. 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 under vacuum to give a residue. The residue was purified by preparative HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and a gradient of 5-35% acetonitrile in water containing 0.5% TFA over 10 min at a flow rate of 25 mL / min to give the title compound as a white solid (19.8 mg, 50.5 μmol, 11.3% yield, 98.8% purity by HPLC at 220 nm). 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 H 17 N3O4).

[0612] Example 44 Synthesis of 3-(5-(2-cyclopropyl-1-methyl-5-(pyridin-3-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0613] [ka]

[0614] A. 3-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: To a solution of 2-cyclopropyl-1-methyl-imidazole (600 mg, 4.91 mmol, 1.00 eq), PCy3 (138 mg, 491 μmol, 159 μL, 0.10 eq), and NaOtBu (1.42 g, 14.7 mmol, 3.00 eq) in o-xylene (30.0 mL) was added 3-bromopyridine (2.33 g, 14.7 mmol, 1.42 mL, 3.00 eq) and Pd(OAc)2 (221 mg, 982 μmol, 0.20 eq) under N2. The mixture was stirred at 130 °C for 12 h under N2. The mixture was then filtered, the collected liquid collected, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using Welch Ultimate XB-SiOH (250x50x10 μm) and a gradient of 15-45% EtOH+MeOH in water over 25 min at a flow rate of 25 mL / min to give the title compound as a yellow oil (360 mg, 1.79 mmol, 39.6% yield, 99.1% purity by LCMS 220 nm). 1 H 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).

[0615] B. 3-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: To a solution of 3-(2-cyclopropyl-3-methyl-imidazol-4-yl)pyridine (360 mg, 1.81 mmol, 1.00 eq) in ACN (4.50 mL) was added NBS (354 mg, 1.99 mmol, 1.10 eq) at 0 °C. The mixture was then stirred at 20 °C for 2 h. The reaction mixture was poured into HO (30.0 mL) and extracted with DCM (3 x 20.0 mL). The combined organic layers were washed with saturated aqueous NaCl (3 x 15.0 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was then purified by preparative TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.25) to give the title compound as a yellow oil (450 mg, 1.61 mmol, yield 89.0%, purity by LCMS 220 nm 99.4%). 1 H 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).

[0616] C. 3-(5-(2-cyclopropyl-1-methyl-5-(pyridin-3-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 3-(4-bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine (300 mg, 1.08 mmol, 1.00 eq) in dioxane (6.00 mL) and HO (0.30 mL). 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 (799 mg, 2.16 mmol, 2.00 eq) and KPO (458 mg, 2.16 mmol, 2.00 eq) was added Ru-Phos-Pd-G, KPO (180 mg, 216 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C for 2.5 h under N. The mixture was then filtered, the filtrate was collected, and the liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 0-21% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (113mg, 255µmol, 23.6% yield, 100% purity by HPLC at 220nm). 1 H 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).

[0617] Example 45 Synthesis of 3-(5-(2-cyclopropyl-1-methyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0618] [ka]

[0619] A. 4-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: To a solution of 2-cyclopropyl-1-methyl-imidazole (600 mg, 4.91 mmol, 1.00 eq), PCy3 (138 mg, 491 μmol, 159 μL, 0.10 eq), and NaOtBu (1.42 g, 14.7 mmol, 3.00 eq) in o-xylene (30.0 mL) was added 4-bromopyridine (2.33 g, 14.7 mmol, 3.00 eq) and Pd(OAc)2 (221 mg, 982 μmol, 0.20 eq) under N2. The mixture was stirred at 130 °C for 12 h under N2. The mixture was then filtered, the liquid collected, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, M:MeOH = 10:1, R f =0.35) to give the title compound as a yellow oil (856 mg, 3.83 mmol, yield 78.0%, purity by LCMS 220 nm 89.2%). 1 H 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).

[0620] B. 4-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine: To a solution of 4-(2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine (300 mg, 1.43 mmol, 1.00 eq) in MeOH (3.0 mL) was added NBS (255 mg, 1.43 mmol, 1.00 eq) to the reaction mixture. The mixture was stirred at 25 °C for 8 h. The reaction mixture was poured into HO (30.0 mL) and extracted with DCM (3 x 20.0 mL). The combined organic layers were washed with saturated aqueous NaCl (3 x 15.0 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was then analyzed by preparative TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.25) to give the title compound as a yellow oil (450 mg, 1.61 mmol, yield 72.8%, purity by LCMS 220 nm 99.4%). 1 H 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).

[0621] C. 3-(5-(2-cyclopropyl-1-methyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-(4-bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyridine (270 mg, 970 μmol, 1.00 mL) in dioxane (5.40 mL) and HO (0.27 mL). To a solution of 1,3,2-dioxaborolan-2-yl (719 mg, 1.94 mmol, 2.00 eq), 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 eq), and KPO (412 mg, 1.94 mmol, 2.00 eq) was added Ru-Phos-Pd-G (162 mg, 194 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The mixture was then filtered, the filtrate was collected, and the liquid was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 0-21% acetonitrile in water containing 0.05% FA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (242mg, 548µmol, 56.5% yield, 100% purity by HPLC at 220nm). 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).

[0622] Example 46 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

[0623] [ka]

[0624] A. 4-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-pyrazole: To a solution of 2-cyclopropyl-1-methyl-imidazole (0.30 g, 2.46 mmol, 1.00 eq) and 4-bromo-1-methyl-pyrazole (1.19 g, 7.37 mmol, 3.00 eq) in o-xylene (15.0 mL) was added PCy (68.8 mg, 245 μmol, 79.6 μL, 0.10 eq), Pd(OAc) (27.5 mg, 122 μmol, 0.05 eq), and tBuONa (707 mg, 7.37 mmol, 3.00 eq) under N. The reaction mixture was stirred at 130 °C for 12 h under N. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 to 20:1; TLC, dichloromethane:methanol = 20:1, R f =0.60) to give the title compound as a colorless oil (0.40 g, 1.98 mmol, 80.5% yield). (ESI + ) m / z: 203.1 (M+H) + , (C 11 H 14 N4).

[0625] B. 4-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-pyrazole: To a solution of 2-cyclopropyl-1-methyl-5-(1-methylpyrazol-4-yl)imidazole (0.30 g, 1.48 mmol, 1.00 eq) in ACN (2.00 mL) was added a solution of NBS (158 mg, 889 μmol, 0.60 eq) in ACN (1.00 mL) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, dichloromethane:methanol=20:1, R f =0.40) to give the title compound as a yellow oil (120 mg, 426 μmol, 28.7% yield). (ESI + ) m / z: 281.0 (M+H) + , (C 11 H 13 BrN4).

[0626] 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: 4-Bromo-2-cyclopropyl-1-methyl-5-(1-methylpyrazol-4-yl)imidazole (120 mg, 426 μmol) in dioxane (1.00 mL) and HO (0.05 mL). To a solution of KPO (181 mg, 853 μmol, 2.00 eq) and 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (189 mg, 512 μmol, 1.20 eq) was added KPO (181 mg, 853 μmol, 2.00 eq) and Ru-Phos-Pd-G (35.7 mg, 42.6 μmol, 0.10 eq) under N. The reaction mixture was stirred at 100 °C for 2 h under N. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Phenomenex Luna (200 mm x 40 mm x 10 μm) and a gradient of 1-25% acetonitrile in water containing 0.05% TFA over 10 minutes at a flow rate of 25 mL / min to give the title compound as an off-white solid (40.3 mg, 86.4 μmol, 20.2% yield, 95.3% purity by HPLC at 220 nm). 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).

[0627] Example 47 Synthesis of 3-(5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0628] [ka]

[0629] A. 3-(5-(3-cyclopropyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: A solution of 4-bromo-3-cyclopropyl-1H-pyrazole (100 mg, 534 μmol, 1.00 eq) in dioxane (5.00 mL) and HO (0.20 mL) was treated with 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 eq), Ru-Phos-Pd-G3 (151 mg, 213 μmol, 151 μL, 0.40 eq), and K3PO4 (340 mg, 1.60 mmol, 3.00 eq) were added under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f =0:1, R f =0.40) and preparative HPLC using a Phenomenex Luna C18 (150 mm x 25 mm x 10 μm) and a gradient of 10-40% acetonitrile in water containing 0.1% TFA over 15 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (12.6 mg, 35.3 μmol, 3.36% yield, 98.3% purity by HPLC at 220 nm). 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 18 N4O3).

[0630] Example 48 Synthesis of 3-(5-(1-cyclohexyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0631] [ka]

[0632] 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 eq) and 1-cyclohexyl-1H-imidazole (212 mg, 1.41 mmol, 1.40 eq) in dioxane (16.0 mL) was added CuI (384 mg, 2.01 mmol, 2.00 eq), PPh (26.4 mg, 101 μmol, 0.10 eq), and DBU (307 mg, 2.01 mmol, 304 μL, 2.00 eq). To the mixture was then added Pd(OAc) (56.5 mg, 252 μmol, 0.25 eq) under N. The mixture was then stirred at 140°C for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, dichloromethane:methanol = 100 / 1 to 15 / 1, TLC: dichloromethane:methanol = 10 / 1, R f =0.40) to give the title compound as a yellow solid (220 mg, 380 μmol, yield 37.7%, purity by LCMS 220 nm 80.6%). (ESI + ) m / z: 467.1 (M+H) + , (C 26 H 34 N4O4).

[0633] B. 3-(5-(1-Cyclohexyl-1H-imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 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). The mixture was then stirred at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 10.0%-40.0% acetonitrile in water containing 0.50% acetonitrile over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (47.6mg, 121µmol, 22.7% yield, 100% purity by HPLC at 220nm). 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).

[0634] Example 49 Synthesis of 3-(5-(2-cyclohexyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0635] [ka]

[0636] AN-(2,2-Dimethoxyethyl)-N-methylcyclohexanecarboximidamide: 2,2-Dimethoxy-N-methyl-ethanamine (3.00 g, 25.1 mmol, 3.24 mL, 1.00 eq) was charged to a round-bottom flask, followed by cyclohexanecarbonitrile (3.44 g, 31.4 mmol, 3.74 mL, 1.25 eq) and CuCl (3.12 g, 31.4 mmol, 1.25 eq). The reaction mixture was stirred at 85 °C for 12 h to give the title compound as a brown oil (3.00 g, crude). (ESI + ) m / z: 229.1 (M+H) + , (C 12 H 24 N2O2).

[0637] B. 2-Cyclohexyl-1-methyl-1H-imidazole: To a solution of N-(2,2-dimethoxyethyl)-N-methyl-cyclohexanecarboxamidine (3.00 g, 13.1 mmol, 1.00 eq) in MeOH (15.0 mL) was added conc. HCl (3.00 mL, 2.74 eq). The reaction mixture was concentrated in vacuo to give a residue. 50% aq. NaOH (5.00 g) was added to the reaction mixture at 0 °C, followed by TMBE (30.0 mL) and stirring at 20 °C for 5 min. The reaction mixture was filtered to give a solid. The solid was washed with TMBE (2 × 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 as a yellow oil (120 mg, 730 μmol, 5.56% yield). 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).

[0638] C. 2-Cyclohexyl-1-methyl-5-phenyl-1H-imidazole: To a solution of 2-cyclohexyl-1-methyl-imidazole (120 mg, 730 μmol, 1.00 eq) and bromobenzene (344 mg, 2.19 mmol, 230 μL, 3.00 eq) in DMF (1.00 mL) was added Pd(OAc) (16.4 mg, 73.0 μmol, 0.10 eq), P(oxole) (33.9 mg, 146 μmol, 0.20 eq), and KCO (201 mg, 1.46 mmol, 2.00 eq) under N. The reaction mixture was stirred at 100 °C for 12 h under N. The reaction mixture was concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, dichloromethane:methanol = 20:1, R f =0.25) to give the title compound as a yellow solid (55.0 mg, 228 μmol, 31.3% yield). 1 H 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, (ESI + ) m / z: 201.1 (M+H) + , (C 16 H20 N2).

[0639] D. 4-Bromo-2-cyclohexyl-1-methyl-5-phenyl-1H-imidazole: A solution of NBS (42.7 mg, 240 μmol, 1.05 eq) 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 eq) 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 HO (5.00 mL), extracted with EtOAc (3 × 5.00 mL), dried over NaSO, and concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, dichloromethane:methanol = 20:1; TLC, dichloromethane:methanol = 20:1, R f =0.50) to give the title compound as a colorless oil (52.0 mg, 162 μmol, yield 71.1%). 1 H NMR: (400 MHz, DMSO-d6) δ7.51 - 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).

[0640] E. 3-(5-(2-cyclohexyl-1-methyl-5-phenyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-Bromo-2-cyclohexyl-1-methyl-5-phenyl-imidazole (50.0 mg, 156 μmol, 1.00 eq), 3-[1 To a solution of 5-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 eq) was added Ru-Phos-Pd-G3 (13.1 mg, 15.6 μmol, 0.10 eq) and K3PO4 (66.4 mg, 313 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and a gradient of 10-40% acetonitrile in water (TFA) over 10 min at a flow rate of 25 mL / min to give the title compound as a white solid (30.3 mg, 62.7 μmol, 40.0% yield, 100% purity by HPLC at 220 nm). 1 H 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).

[0641] Example 50 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

[0642] [ka]

[0643] AN-(2,2-Dimethoxyethyl)-N-methylcyclohexanecarboximidamide: 2,2-Dimethoxy-N-methylethan-1-amine (3.00 g, 25.1 mmol, 3.24 mL, 1.00 eq) was charged to a round-bottom flask, followed by tetrahydro-2H-pyran-4-carbonitrile (3.50 g, 31.4 mmol, 1.25 eq) and CuCl (3.12 g, 31.4 mmol, 1.25 eq). The reaction mixture was stirred at 85 °C for 12 h to give the title compound as a brown oil (3.00 g, crude). (ESI + ) m / z: 229.1 (M+H) + , (C 11 H 22 N2O3).

[0644] B. 1-Methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of N-(2,2-dimethoxyethyl)-N-methylcyclohexanecarboximidamide (3.00 g, 13.1 mmol, 1.00 eq) in MeOH (15.0 mL) was added conc. HCl (3.00 mL, 2.74 eq). The reaction mixture was concentrated in vacuo to give a residue. 50% aq. NaOH (5.00 g) was added to the reaction mixture at 0 °C, followed by TMBE (30.0 mL) and stirring at 20 °C for 5 min. The reaction mixture was filtered to give a solid. The solid was washed with TMBE (2 × 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, Rf =0.25) to give the title compound as a yellow oil (400 mg, 2.41 mmol, 18.4% yield). 1 H 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).

[0645] C. 1-Methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: To a solution of 1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (400 mg, 2.41 mmol, 1.00 eq) and bromobenzene (1.13 g, 7.22 mmol, 3.00 eq) in DMF (4.00 mL) was added Pd(OAc) (54.3 mg, 240 μmol, 0.10 eq), P(oxole) (111 mg, 481 μmol, 0.20 eq), and KCO (665 mg, 4.81 mmol, 2.00 eq) under N. The reaction mixture was stirred at 100 °C for 12 h under N. The reaction mixture was concentrated in vacuo to give a residue. The 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 as a yellow solid (200 mg, 825 μmol, 34.3% yield). 1 H 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).

[0646] D. 4-Bromo-1-methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole: A solution of NBS (115 mg, 649 μmol, 1.05 eq) 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 eq) 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 HO (5.00 mL), extracted with EtOAc (3 × 5.00 mL), dried over NaSO, and concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, dichloromethane:methanol = 20:1; TLC, dichloromethane:methanol = 20:1, R f =0.50) to give the title compound as a colorless oil (150 mg, 466 μmol, yield 75.4%). 1 H NMR: (400 MHz, DMSO-d6) δ7.50 - 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 BrNO).

[0647] 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: 4-Bromo-1-methyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (150 mg, 466 μm) in dioxane (2.00 mL) and HO (0.10 mL). To a solution of Ru-Phos-Pd-G3 (39.1 mg, 46.6 μmol, 0.10 eq) and 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 eq) was added Ru-Phos-Pd-G3 (39.1 mg, 46.6 μmol, 0.10 eq) and K3PO4 (198 mg, 933 μmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 5 μm) and a gradient of 10-40% acetonitrile in water (TFA) over 10 min at a flow rate of 25 mL / min to give the title compound as a white solid (88.2 mg, 182 μmol, 39.0% yield, 100% purity by HPLC at 220 nm). 1 H 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).

[0648] Example 51 Synthesis of 3-(5-(2-ethyl-5-phenyl-2H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0649] [ka]

[0650] A. 4-Iodo-5-phenyl-2H-1,2,3-triazole: To a solution of 4-phenyl-2H-1,2,3-triazole (600 mg, 4.13 mmol, 1.00 eq) in MeCN (20.0 mL) was added NIS (1.21 g, 5.37 mmol, 1.30 eq) at 0 °C. The mixture was stirred at 50 °C for 72 h. The reaction mixture was poured into HO (25.0 mL) and extracted with ethyl acetate (3 × 30.0 mL). The combined organic layers were washed with brine (3 × 20.0 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, dichloromethane:methanol = 15:1, TLC: dichloromethane:methanol = 15:1, R f =0.40) to give the title compound as a pale yellow solid (500 mg, 1.82 mmol, yield 44.0%, purity by LCMS 220 nm 98.7%). (ESI + ) m / z: 271.7 (M+H) + , (C8H6IN3).

[0651] B. 2-Ethyl-4-iodo-5-phenyl-2H-1,2,3-triazole: To a solution of 4-iodo-5-phenyl-2H-1,2,3-triazole (440 mg, 1.62 mmol, 1.00 eq), K2CO3 (112 mg, 811 μmol, 0.50 eq), and bromoethane (194 mg, 1.79 mmol, 133 μL, 1.10 eq) in DMF (10.0 mL). The mixture was stirred at 25 °C for 30 h. The reaction mixture was poured into HO (20.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (3 × 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 give the title compound as a yellow solid (280 mg, 928 μmol, yield 57.2%, purity by LCMS 220 nm 99.2%). (ESI + ) m / z: 299.8 (M+H) + , (C 10 H 10 IN3).

[0652] C. 3-(5-(2-ethyl-5-phenyl-2H-1,2,3-triazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 2-Ethyl-4-iodo-5-phenyl-2H-1,2,3-triazole (200 mg, 660 μmol, 1.00 eq), 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione in dioxane (5.00 mL) and HO (0.25 mL). To a solution of 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 eq) and KPO (425 mg, 2.01 mmol, 3.00 eq) was added Ru-Phos-Pd-G (55.9 mg, 66.8 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 30.0%-60.0% acetonitrile in water containing 0.50% TFA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (106mg, 255µmol, 38.1% yield, 100% purity by HPLC at 220nm). 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).

[0653] Example 52 Synthesis of 3-(5-(1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0654] [ka]

[0655] 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 eq) in DCE (1.50 mL) was added TFAA (180 mg, 861 μmol, 119 μL, 2.50 eq). The mixture was then stirred at 50° C. for 15 hours. MeNH (69.7 mg, 1.03 mmol, 3.00 eq) was then added to the mixture. The mixture was then stirred at 140° C. for 3 hours. The reaction mixture was concentrated under reduced pressure at 45° C. to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=5:1, R f =0.50) to give the title compound as a yellow solid (86.0 mg, 356 μmol, yield 25.8%, purity by LCMS 220 nm 93.8%). (ESI + ) m / z: 227.0 (M+H) + , (C 11 H9F3N2).

[0656] B. 4-Bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (110 mg, 486 μmol, 1.00 eq) in ACN (3.00 mL) was added NBS (95.2 mg, 534 μmol, 1.10 eq) at 0° C. 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 residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=5:1, R f =0.60) to give the title compound as a pale yellow solid (86.0 mg, 356 μmol, yield 70.1%, purity by LCMS 220 nm 93.8%). 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).

[0657] C. 3-(5-(1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 4-Bromo-1-methyl-5-phenyl-2-(trifluoromethyl)-1H-imidazole (90.0 mg, 294 μmol, 1.00 eq) in dioxane (5.00 mL) and HO (0.25 mL). To a solution of 2,4-dioxaborolan-2-yl, 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 eq), and KPO (187 mg, 884 μmol, 3.00 eq) was added Ru-Phos-Pd-G (24.6 mg, 29.5 μmol, 0.10 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 34.0%-64.0% acetonitrile in water containing 0.50% TFA over 10 minutes at a flow rate of 25mL / min to give the title compound as a white solid (59.3mg, 126µmol, 42.7% yield, 98.4% purity by HPLC at 220nm). 1H 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).

[0658] Example 53 Synthesis of 3-(1-oxo-5-(5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0659] [ka]

[0660] 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 eq) in DCE (7.50 mL) was added TFAA (904 mg, 4.31 mmol, 598 μL, 2.50 eq). The mixture was then stirred at 50° C. for 15 hours. AcONH4 (663 mg, 8.61 mmol, 5.00 eq) was then added to the mixture. The mixture was then stirred at 140° C. for 2 hours. The reaction mixture was concentrated under reduced pressure at 45° C. to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=5:1, R f =0.50) to give the title compound as a pale yellow solid (287 mg, 1.34 mmol, yield 38.8%, purity by LCMS 220 nm 99.0%). (ESI + ) m / z: 212.9 (M+H) + , (C10 H7F3N2).

[0661] B. 4-Bromo-5-phenyl-2-(trifluoromethyl)-1H-imidazole: To a solution of 5-phenyl-2-(trifluoromethyl)-1H-imidazole (280 mg, 1.31 mmol, 1.00 eq) in ACN (5.00 mL) was added NBS (323 mg, 1.31 mmol, 1.00 eq) at 0° C. 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 residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=5:1, R f =0.50) to give the title compound as a pale yellow solid (314 mg, 1.07 mmol, yield 82.4%, purity by LCMS 220 nm 99.6%). 1 H 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).

[0662] C. 3-(1-oxo-5-(5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: 4-Bromo-5-phenyl-2-(trifluoromethyl)-1H-imidazole (150 mg, 513 μmol, 1.00 eq), 3-(1- To a solution of 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 eq) and KPO (326 mg, 1.54 mmol, 3.00 eq) was added Ru-Phos-Pd-G (214 mg, 256 μmol, 0.50 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure at 45 °C to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx5µm) and a gradient of 24.0%-54.0% acetonitrile in water containing 0.50% TFA over 10 minutes at a flow rate of 25mL / min to give the title compound as a white solid (111mg, 244µmol, 47.5% yield, 100% purity by HPLC at 220nm). 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).

[0663] Example 54 Synthesis of 3-(1-oxo-5-(2-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0664] [ka]

[0665] A. 3-(1-Oxo-5-(2-phenyl-1H-imidazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-bromo-2-phenyl-1H-imidazole (150 mg, 672 μmol, 1.00 eq), 3-[1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]piperidine-2,6-dione (497 mg, 1.34 mmol, 2.00 eq) in dioxane (2.00 mL) and HO (0.10 mL) was added Ru-Phos-Pd-G3 (112 mg, 134 μmol, 0.20 eq), K3PO4 (285 mg, 1.34 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100° C. for 2 hours under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 (150 mm×25 mm×10 μm) and a gradient of 6-36% acetonitrile in water containing 0.05% TFA over 10 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (46.3 mg, 118 μmol, 17.5% yield, 98.5% purity by HPLC at 220 nm). 1 H 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), (ESI)+ ) m / z: 386.9 (M+H) + , (C 22 H 18 N4O3).

[0666] Examples 55-116 The compounds of Examples 55-116 were prepared according to Scheme 1 below:

[0667] [ka]

[0668] Process 1 Suzuki Coupling

[0669] [ka]

[0670] Condition 1: To a vial containing a solution of A001 (150 μmol, 1.00 eq) and Bi (180 μmol, 1.20 eq) in dioxane (1.20 mL), KPO (1.5 M in HO, 450 μmol, 3.00 eq) and Pd-118 (15.0 μmol, 0.10 eq) were added under N protection. The mixture was stirred at 65 °C for 16 h. The reaction mixture was diluted with HO (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 NaSO, filtered, and concentrated under reduced pressure to give the crude intermediate used in the next step.

[0671] Condition 2: To a vial containing a solution of A001 (150 μmol, 1.00 eq) and Bi (180 μmol, 1.20 eq) in dioxane (1.20 mL), KPO (1.5 M in HO, 450 μmol, 3.00 eq) and Pd-118 (15.0 μmol, 0.10 eq) were added under N protection. The mixture was stirred at 120 °C for 2 h under microwave irradiation. The reaction mixture was diluted with HO (2.00 mL) and extracted with ethyl acetate (2.00 mL × 3). The combined organic layers were washed with brine (2.00 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude intermediate used in the next step.

[0672] Step 2 Ring closure:

[0673] [ka]

[0674] Conditions: To a vial containing a solution of A001Bi_1 (~150 μmol, 1.00 eq) in CH3CN (1.50 mL) was added TsOH (1.50 mmol, 10.0 eq). The mixture was stirred at 80 °C for 2 h. The residue was concentrated under reduced pressure and purified by prep-HPLC to give the final product.

[0675] According to the above method, the following compounds were synthesized:

[0676] [Table 1-1]

[0677] [Table 1-2]

[0678] [Table 1-3]

[0679] [Table 1-4]

[0680] [Table 1-5]

[0681] [Table 1-6]

[0682] [Table 1-7]

[0683] [Table 1-8]

[0684] [Table 1-9]

[0685] [Table 1-10]

[0686] [Table 1-11]

[0687] [Table 1-12]

[0688] Example 117 Synthesis of 3-(5-(2-cyclopropyl-1-methyl-5-(pyrimidin-5-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0689] [ka]

[0690] 5-(2-Cyclopropyl-1-methyl-1H-imidazol-5-yl)pyrimidine: 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) was added Pd(OAc) (55.1 mg, 245 μmol, 0.10 eq), P(oxole) (114 mg, 491 μmol, 0.20 eq), and KCO (678 mg, 4.91 mmol, 2.00 eq) under N. The reaction mixture was stirred at 100 °C for 12 h under N. The reaction mixture was concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1, R f =0.25) to give the title compound as a yellow solid (0.40 g, 2.00 mmol, 81.3% yield). 1 H 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).

[0691] B. 5-(4-Bromo-2-cyclopropyl-1-methyl-1H-imidazol-5-yl)pyrimidine: 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) was added a solution of NBS (426 mg, 2.40 mmol, 1.20 eq) in ACN (2.00 mL) at 0 °C. 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 NaSO, and concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO, methanol:dichloromethane = 20:1; TLC, methanol:dichloromethane = 20:1, R f =0.40) to give the title compound as a yellow solid (245 mg, 877 μmol, 43.9% yield). (ESI + ) m / z: 279.0 (M+H) + , (C 11 H 11 BrN4).

[0692] C. 3-(5-(2-cyclopropyl-1-methyl-5-(pyrimidin-5-yl)-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: 5-(5-bromo-2-cyclopropyl-3-methyl-imidazol-4-yl)pyrimidine (200 mg, 716 μmol, 1.00 mL) in dioxane (2.00 mL) and HO (0.10 mL). To a solution of Ru-Phos-Pd-G3 (119 mg, 143 μmol, 0.20 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) was added Ru-Phos-Pd-G3 (119 mg, 143 μmol, 0.20 eq) and K3PO4 (304 mg, 1.43 mmol, 2.00 eq) under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and a gradient of 4-34% acetonitrile in water (TFA) over 10 min at a flow rate of 25 mL / min to give the title compound as a white solid (22.2 mg, 49.5 μmol, 6.92% yield, 98.6% purity by HPLC at 220 nm). 1 H 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).

[0693] Example 118 Synthesis of 3-(1-oxo-5-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0694] [ka]

[0695] A. 2-(4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridine: To a solution of 2-(4-bromo-1H-pyrazol-3-yl)pyridine (400 mg, 1.79 mmol, 1.00 eq), TFA (81.4 mg, 714 μmol, 53.1 μL, 0.40 eq) in Toluene (2.00 mL) and ACN (2.00 mL) was added DHP (1.40 g, 16.6 mmol, 1.52 mL, 9.30 eq) slowly in several portions at 25 °C. The mixture was stirred at 100 °C for 8 h. The mixture was poured into HO (20.0 mL) and extracted with ethyl acetate (3 × 30.0 mL). The combined organic layers were washed with saturated aqueous NaCl (3 × 20.0 mL), dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 15:1 to 8:1; petroleum ether:ethyl acetate = 1 / 1, R f =0.35) to give the title compound as a yellow oil (530 mg, 1.49 mmol, 83.2% yield, 86.4% purity by LCMS 220 nm). (ESI + ) m / z: 309.9 (M+H) + , (C 13 H 14 BrNO).

[0696] B. 3-(1-oxo-5-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: 2-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) in dioxane (2.50 mL) and HO (0.13 mL) To a solution of pyridine (200 mg, 649 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (480 mg, 1.30 mmol, 2.00 eq), and KPO (275 mg, 1.30 mmol, 2.00 eq) was added cataCXium A Pd G (108.6 mg, 130 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C for 2 h under N. The combined mixture was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f =0.10) to give the title compound as a brown solid (25.0 mg, 41.9 μmol, yield 6.46%, purity by LCMS 220 nm 79.1%). (ESI + ) m / z: 472.2 (M+H) + , (C 26 H 25 N5O4).

[0697] C. 3-(1-oxo-5-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(1-oxo-5-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione (21.0 mg, 44.5 μmol, 1.00 eq) in DCM (1.00 mL) was added HCl / dioxane (4.00 M, 100 μL, 9.00 eq) at 0° C. The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150x25mmx10µm) and a gradient of 0%-30.0% acetonitrile in water containing 0.50% TFA over 15 minutes at a flow rate of 25mL / min to give the title compound as a white solid (6.00mg, 14.9µmol, 33.4% yield, 96.1% purity by HPLC at 220nm). 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.59 -8.51 (m, 1H), 7.85 - 7.79 (m, 3H), 7.65 - 7.63 (m, 2H), 7.47 - 7.44 (m, 1H),7.35 (s, 1H), 5.14 - 5.09 (m, 1H), 4.45 - 4.24 (m, 2H), 2.93 - 2.87 (m, 1H), 2.63 - 2.52 (m, 1H), 2.47 - 2.42 (m, 1H), 2.02 - 1.99 (m, 1H). (ESI+) m / z: 388.2 (M+H) + , (C 21 H 17 N5O3).

[0698] Examples 119-160 The compounds of Examples 119-160 were prepared according to the method of Scheme 1 shown for Examples 55-116.

[0699] [Table 2-1]

[0700] [Table 2-2]

[0701] [Table 2-3]

[0702] [Table 2-4]

[0703] [Table 2-5]

[0704] [Table 2-6]

[0705] [Table 2-7]

[0706] [Table 2-8]

[0707] Examples 161-204 The compounds of Examples 161-204 were prepared according to Scheme 2 below:

[0708] [ka]

[0709] Step 1 Suzuki Coupling

[0710] [ka]

[0711] Conditions: To a vial containing a solution of A002 (100 μmol, 1.00 eq) and Bi (120 μmol, 1.20 eq) in dioxane (0.80 mL), KPO (1.5 M in HO, 300 μmol, 3.00 eq) and Pd-118 (10.0 μmol, 0.10 eq) were added under N protection. The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with HO (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 NaSO, filtered, and concentrated under reduced pressure to give the crude intermediate used in the next step.

[0712] Step 2 Ring closure

[0713] [ka]

[0714] Conditions: To a vial containing a solution of A002Bi_1 (~100 μmol, 1.00 eq) in CH3CN (1.00 mL) was added H2SO4 (100 μL). The mixture was stirred at 65 °C for 1 h. The residue was concentrated under reduced pressure and purified by prep-HPLC to give the final product.

[0715] [Table 3-1]

[0716] [Table 3-2]

[0717] [Table 3-3]

[0718] [Table 3-4]

[0719] [Table 3-5]

[0720] [Table 3-6]

[0721] [Table 3-7]

[0722] [Table 3-8]

[0723] Example 205 Synthesis of 3-(1-oxo-5-(1-phenyl-1H-imidazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione

[0724] [ka]

[0725] A. (1H-Imidazol-4-yl)(phenyl)-13-iodanyl acetate: To a solution of PhI(OAc)2 (1.18 g, 3.67 mmol, 0.50 eq) in MeOH (5.00 mL). The mixture was stirred at 25 °C. 1H-Imidazole (500 mg, 7.34 mmol, 1.00 eq) was then added to the mixture. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with DCM (5.00 mL) and MTBE (5.00 mL) at 25 °C for 20 min to give the title compound as a white solid (1.00 g, 3.03 mmol, 41.2% yield, 96.5% purity by LCMS 220 nm). 1H NMR: (400 MHz, MeOD) δ 8.07 - 8.05 (m, 2H), 8.05 - 8.04 (m, 1H), 7.84 - 7.84 (m, 1H), 7.66 - 7.63 (m, 1H), 7.52 - 7.48 (m, 2H), 1.89 (s, 3H). (ESI + ) m / z: 330.1 (M+H) + , (C 11 H 11 IN2O2).

[0726] B. 5-Iodo-1-phenyl-1H-imidazole: To a solution of Cu(OTf)2 (33.6 mg, 254 μmol, 0.20 eq) and Cs2CO3 (621 mg, 1.91 mmol, 1.50 eq) in HFIP (4.00 mL) was added N-methylbenzimidazole (23.0 mg, 63.6 μmol, 0.05 eq). The mixture was stirred at 25 °C for 30 min. Then, (1H-imidazol-4-yl)(phenyl)-13-iodaneyl acetate (420 mg, 1.27 mmol, 1.00 eq) was added to the mixture. The mixture was then stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f =0.30) to give the title compound as a yellow solid (200 mg, 621 μmol, yield 48.8%, purity by LCMS 220 nm 89.3.0%). (ESI + ) m / z: 270.9 (M+H) + , (C9H7IN2).

[0727] C. 3-(1-Oxo-5-(1-phenyl-1H-imidazol-5-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 5-iodo-1-phenyl-1H-imidazole (200 mg, 740 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (822 mg, 2.21 mmol, 3.00 eq) and KPO (471 mg, 2.21 mmol, 3.00 eq) in dioxane (5.00 mL) and HO (0.25 mL) was added Ru-Phos-Pd-G (123 mg, 147 μmol, 0.20 eq) under N. The mixture was stirred at 100° C. for 6 hours under N2. The reaction mixture was concentrated under reduced pressure at 43° C. to give a residue. The residue was purified by preparative HPLC using a Phenomenex luna C18 (150×25 mm×5 μm) and a gradient of 5.00% to 35.0% acetonitrile in water containing 0.50% FA over 10 minutes at a flow rate of 25 mL / min to give the title compound as a white solid (23.6 mg, 61.1 μmol, 7.19% yield, 100% purity by HPLC at 220 nm). 1 H NMR: (400 MHz, DMSO-d6) δ 11.0 - 10.9 (m, 1H), 8.99 - 8.96 (m, 1H), 7.92 - 7.89 (m, 1H), 7.68 - 7.66 (m, 1H), 7.53 - 7.42 (m, 6H), 7.28 - 7.23 (m, 1H), 5.11 - 5.07 (m, 1H), 4.45 - 4.29 (m, 2H), 2.96 - 2.85 (m, 1H), 2.60 - 2.53 (m, 1H), 2.40 - 2.39 (m, 1H), 2.00 - 1.97 (m, 1H). (ESI + ) m / z: 387.2 (M+H) + , (C 22 H 18 N4O3).

[0728] Example 206 Synthesis of 3-(1-oxo-5-(3-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0729] [ka]

[0730] A. 3-Phenylisoxazole: To a solution of (E)-N-hydroxybenzimidoyl chloride (2.00 g, 12.8 mmol, 1.00 eq) and ethynyltrimethylsilane (1.39 g, 14.1 mmol, 1.96 mL, 1.10 eq) in DCM (24.0 mL) was added TEA (3.25 g, 32.1 mmol, 4.47 mL, 2.50 eq) at 0 °C under N2. After stirring at 50 °C for 1.5 h, the reaction mixture was diluted with DCM (3 x 30.0 mL) and the organic phase was washed with water (30.0 mL) and brine (2 x 30.0 mL) and concentrated with Na2. The mixture was dried over SO4 and concentrated under reduced pressure to give a residue. The residue was dissolved in EtOH (50.0 mL) and CsF (11.7 g, 77.1 mmol, 2.85 mL, 6.00 eq) was added under N2. The mixture was then stirred at 20 °C for 1.5 h under N2. The reaction mixture was poured into H2O (50.0 mL) and extracted with DCM (3 x 60.0 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 50.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1, R f =0.40) to give the title compound as a colorless oil (1.20 g, 7.93 mmol, 61.7% yield, 95.9% purity by LCMS 220 nm). (ESI + ) m / z: 146.0 (M+H) + , (C9H7NO).

[0731] B. 4-Iodo-3-phenylisoxazole: To a solution of 3-phenylisoxazole (350 mg, 2.41 mmol, 1.00 eq) in TFA (4.00 mL) was added NIS (488 mg, 2.17 mmol, 0.90 eq) under N2. The reaction mixture was stirred at 50 °C for 8 h under N2. The mixture was poured into saturated aqueous NaHCO3 (40.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with 10% Na2S2O3 solution (2 x 30.0 mL) and brine (2 x 20.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (petroleum ether / ethyl acetate = 10 / 1, R f =0.35) to give the title compound as a white solid (340 mg, 1.13 mmol, 46.7% yield, 89.8% purity by LCMS 220 nm). (ESI + ) m / z: 272.0 (M+H) + , (C9H6INO).

[0732] C. 3-(1-Oxo-5-(3-phenylisoxazol-4-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 4-iodo-3-phenylisoxazole (270 mg, 996 μmol, 1.00 eq), 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (553 mg, 1.49 mmol, 1.50 eq) and KPO (422 mg, 1.99 mmol, 2.00 eq) in dioxane (6.00 mL) and HO (0.30 mL) was added Ru-Phos-Pd-G (167 mg, 199 μmol, 0.20 eq) under N. The mixture was stirred at 100 °C for 3 h under N2. The mixture was filtered, and the collected liquid was concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC using a Phenomenex luna C18 (150 mm x 25 mm x 10 μm) and a gradient of 24-54% acetonitrile in water containing 0.05% FA over 15 min at a flow rate of 25 mL / min to give the title compound as a white solid (129 mg, 323 μmol, 32.4% yield, 97.0% purity by HPLC at 220 nm).1 H NMR: (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.36 (s, 1H), 7.73 - 7.71 (m, 1H), 7.54 - 7.51 (m, 1H), 7.49 - 7.45 (m, 5H), 7.38 - 7.36 (m, 1H), 5.14 - 5.09 (m, 1H), 4.45 - 4.28 (m, 2H), 2.94 - 2.87 (m, 1H), 2.60 - 2.57 (m, 1H), 2.41 - 2.38 (m, 1H), 2.02 - 1.99 (m, 1H). (ESI + ) m / z: 388.0 (M+H) + , (C 22 H 17 N3O4).

[0733] Example 207 Synthesis of 3-(5-(1-(ethyl-d3)-5-phenyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0734] [ka]

[0735] A. 4-Bromo-1-(methyl-d3)-1H-pyrazole: A mixture of 4-bromo-1H-pyrazole (6.00 g, 40.8 mmol, 1.00 eq), trideuterio(iodo)methane (9.27 g, 65.3 mmol, 3.98 mL, 1.60 eq), and t-BuOK (9.16 g, 81.7 mmol, 2.00 eq) in THF (60.0 mL) was stirred for 4 h at 25° C. The reaction mixture was poured into 50.0 mL of HO, extracted with EtOAc (3×50.0 mL), and then concentrated to give a residue to afford the title compound as a colorless oil (4.00 g, 24.4 mmol, 59.7% yield). 1 H NMR: (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.51 (s, 1H). (ESI + ) m / z: 162.9 (M+H)+ (C4H2D3BrN2).

[0736] B. 4-Bromo-1-(methyl-d3)-5-phenyl-1H-pyrazole: To a solution of 4-bromo-1-(methyl-d3)-1H-pyrazole (400 mg, 2.03 mmol, 1.00 eq) and bromobenzene (956 mg, 6.09 mmol, 642 μL, 3.00 eq) in DMF (4.00 mL) was added Pd(OAc)2 (45.6 mg, 203 μmol, 0.10 eq), P(oxo...

Claims

1. Compounds of Formula I or II: 【Chemical 1】 (In the formula: Ar is aryl, heteroaryl, C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, 5- to 7-membered heterocyclyl or 5- to 7-membered heterocycloalkenyl; E is the moiety that binds to 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 heterocyclyl; or two R groups at adjacent positions on the ring are joined to form an alkylene; or R and Ar at adjacent positions on a five-membered ring are joined to form a fused ring; however: i) In formula II, X １ If C, then X ２ , X ４ and X ５ is N and X ３ is CH or X １ and X ２ If C, then X ３ is NMe, X ４ is N and X ５ is CH, and then E is not an isoindolinedione moiety; ii) In formula II, X １ and X ２ If C, then X ３ is CH, X ４ is N and X ５ is NMe, and then Ar is not 5-fluoro-2-pyridyl; iii) In formula II, X １ If N, then X ２ is C, X ３ and X ４ is CH and X ５ is N or X １ and X ３ If N, then X ２ is C and X ４ and X ５ is CH, or in that case Ar is not phenyl; iv) In formula II, 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) or a pharmaceutically acceptable derivative thereof.

2. X １ is C and X ２ The compound of claim 1 wherein is N.

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

4. If the compound has the structure: 【Chemistry 2】 2. The compound of claim 1 having the formula:

5. The following formula: 【Chemistry 3】 【Chemistry 4】 2. The compound of claim 1 having one of:

6. structure: 【Chemistry 5】 2. The compound of claim 1 having the formula:

7. structure: 【Chemistry 6】 10. The compound of claim 1 or 6, having the formula:

8. structure: 【Chemistry 7】 8. The compound of any one of claims 1, 6 or 7, having the formula:

9. structure: 【Chemistry 8】 9. The compound of any one of claims 1 or 6-8, having the formula:

10. structure: 【Chemistry 9】 10. The compound of claim 1 or 6, having the formula:

11. structure: 【Chemistry 10】 11. The compound of any one of claims 1, 6 or 10, having the formula:

12. structure: 【Chemistry 11】 12. The compound of any one of claims 1, 6, 10 or 11, having the formula:

13. structure: 【Chemistry 12】 10. The compound of claim 1 or 6, having the formula:

14. structure: 【Chemistry 13】 14. The compound of any one of claims 1, 6 or 13, having the formula:

15. structure: 【Chemistry 14】 10. The compound of claim 1 or 6, having the formula:

16. structure: 【Chemistry 15】 2. The compound of claim 1 having the formula:

17. structure: 【Chemistry 16】 2. The compound of claim 1 having the formula:

18. structure: 【Chemistry 17】 2. The compound of claim 1 having the formula:

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

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

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

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

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

24. 19. The compound of any one of claims 1 to 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, trideuteromethyl, 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. 19. The compound of any one of claims 1 to 18, wherein each R is independently H, methyl, difluoromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoro-1-ethyl, cyclopropyl, trideuteromethyl, ethyl, 2-hydroxy-2-methylpropyl, cyclohexyl, 4-pyranyl, or phenyl; or two R groups at adjacent positions on the ring together form propylene.

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

27. 19. The compound of any one of claims 1 to 18, wherein each R is independently H or methyl.

28. 19. The compound of any one of claims 1 to 18, wherein each R is H.

29. 19. The compound of any one of claims 1 to 18, wherein each R is methyl.

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

31. 31. The compound of any one of claims 1 to 30, wherein E comprises an imide, amide, thioamide, or thioimide-derived moiety.

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

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

34. 34. The compound of any one of claims 1 to 33, wherein E comprises a thalidomide, lenalidomide, or pomalidomide moiety, or an analog or derivative thereof.

35. E is of the following formula: 【Chemistry 18】 (In the formula: 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, heterocyclyl, aryl, or heteroaryl; Y １ and Y ２ One of them is S and the other is CR ３ and R ３ is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Z １ ~Z ４ are each independently N or CR ４ and each R ４ is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

36. E is of the formula: 【Chemistry 19】 (In the formula: 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 and each R ４ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

37. A is of the structure: 【Chemistry 20】 (In the formula: R ５ is H or alkyl; R ６ and R ７ are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl; and m is an integer from 1 to 4.

38. R ５ The compound of any one of claims 1 to 37, wherein is H or lower alkyl.

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

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

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

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

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

44. R ６ and R ７ and R are both H.

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

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

47. 47. The compound of any one of claims 1 to 46, wherein m is 2.

48. 47. The compound of any one of claims 1 to 46, wherein m is 3.

49. A is of the structure: 【Chemical 21】 ． 48. The compound of any one of claims 1 to 47, having the formula:

50. A is of the structure: 【Chemical 22】 50. The compound of any one of claims 1 to 47 and 49, having the formula:

51. A is of the following structure: 【Chemical 23】 51. The compound of any one of claims 1 to 47, 49 and 50, having one of:

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

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

54. R １ and R ２ 54. The compound of any one of claims 1 to 53, wherein each is independently H or methyl.

55. R １ and R ２ The compound of any one of claims 1 to 54, wherein each is H.

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

57. R ３ 57. The compound of any one of claims 1 to 56, wherein is H or alkyl.

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

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

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

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

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

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

64. Y １ is S and Y ２ is CR ３ The compound of any one of claims 33 to 63,

65. Y １ is S and Y ２ The compound of any one of claims 33 to 64, wherein is CH.

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

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

68. Z １ is N and Z ２ ~Z ４ is CR ４ The compound of any one of claims 33 to 63,

69. Z １ is N and Z ２ ~Z ４ 69. The compound of any one of claims 33-63 and 68, wherein is CH.

70. Z ２ is N and Z １ , Z ３ and Z ４ is CR ４ The compound of any one of claims 33 to 63,

71. Z ２ is N and Z １ , Z ３ and Z ４ 71. The compound of any one of claims 33 to 63 and 70, wherein is CH.

72. Z ３ is N and Z １ , Z ２ and Z ４ is CR ４ The compound of any one of claims 33 to 63,

73. Z ３ is N and Z １ , Z ２ and Z ４ 73. The compound of any one of claims 33 to 63 and 72, wherein is CH.

74. Z ４ is N and Z １ ~Z ３ is CR ４ The compound of any one of claims 33 to 63,

75. Z ４ is N and Z １ ~Z ３ 64. The compound of any one of claims 33 to 63, wherein is CH.

76. E: 【Chemistry 24】 76. The compound of any one of claims 1 to 75, selected from:

77. E is of the structure: 【Chemistry 25】 77. The compound of any one of claims 1 to 76, having the formula:

78. E: 【Chemical 26】 78. The compound of any one of claims 1 to 77, selected from:

79. 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 pyridopyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted benzofuryl, optionally substituted imidazopyridyl, optionally substituted benzopyrazolyl, optionally substituted pyrrolopyridyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted thienopyridyl, optionally substituted dihydrobenzofuryl, optionally substituted benzopyridazinyl, optionally substituted benzopyranyl, 79. The compound of any one of claims 1 to 78, wherein the compound is 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 azepinyl, optionally substituted isoquinolinyl, optionally substituted cycloheptenyl, optionally substituted indenyl, optionally substituted dihydronaphthyl, optionally substituted 8-azabicyclooctanyl, optionally substituted adamantanyl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl.

80. 79. The compound of any one of claims 1 to 78, wherein Ar is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted pyridopyrazolyl, optionally substituted isoxazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted thienyl, optionally substituted dihydrobenzofuryl, optionally substituted dihydroindenyl, optionally substituted cyclopropyl, or optionally substituted cyclohexyl.

81. Ar is phenyl, biphenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, pyridopyrazolyl, isoxazolyl, indolyl, isoindolyl, thienyl, dihydrobenzofuryl, dihydroindenyl, cyclopropyl, or cyclohexyl; and Ar is selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ Each may be substituted with one or more substituents independently selected from: R ８ is alkyl, OR １３ or NR １４ R １５ ; R ９ is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or COR １６ ; R １０ and R １１ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or COR １７ ; R １２ is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR １８ or NR １４ R １５ ; Each R １３ , R １４ and R １５ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R １６ is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR １３ or NR １４ R １５ ; R １７ is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR １３ or NR １４ R １５ ; R １８ is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and 79. The compound of any one of claims 1 to 78, wherein n is 0, 1 or 2.

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

83. 82. The compound of any one of claims 1 to 81, wherein Ar is unsubstituted.

84. Ar is phenyl and is selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

85. Ar is phenyl and is selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

86. Ar is phenyl and is selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR １４ R １５ , OR ９ , N.R. １０ R １１ and S(O) ２ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

87. Ar is phenyl and chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

88. Ar is phenyl and chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

89. Ar is phenyl and chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

90. Ar is phenyl and chloro, fluoro, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridinyl, hydroxy, methoxy, CONH ２ , CONHMe, CONMe ２ , N.H. ２ and NMe ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

91. 82. The compound of any one of claims 1 to 81, wherein Ar is unsubstituted phenyl, unsubstituted 4-biphenyl, or unsubstituted 1-naphthyl.

92. 82. The compound of any one of claims 1 to 81, wherein Ar is unsubstituted phenyl.

93. Ar is thienyl, and halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

94. Ar is thienyl, and halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

95. Ar is thienyl, and halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR １４ R １５ , OR ９ , N.R. １０ R １１ and S(O) ２ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

96. Ar is thienyl and chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

97. Ar is thienyl and chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

98. Ar is thienyl and chloro, fluoro, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridinyl, hydroxy, methoxy, CONH ２ , CONHMe, CONMe ２ , N.H. ２ and NMe ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

99. 82. The compound of any one of claims 1 to 81, wherein Ar is unsubstituted thienyl.

100. Ar is pyrazolyl, and is selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

101. Ar is pyrazolyl, and is selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

102. Ar is pyrazolyl, and is selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR １４ R １５ , OR ９ , N.R. １０ R １１ and S(O) ２ R １２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

103. Ar is pyrazolyl and the alkyl groups selected from the group consisting of chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

104. Ar is pyrazolyl and the alkyl groups selected from the group consisting of chloro, fluoro, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, difluoromethyl, methoxymethyl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-tert-butyloxycarbonyl-1-piperazinyl, morpholin-4-ylmethyl, pyrrolidinyl, phenyl, 1-pyrazolyl, 4-pyridinyl, hydroxy, methoxy, benzyloxy, 3-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me and SO ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

105. Ar is pyrazolyl and is selected from the group consisting of chloro, fluoro, cyano, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, dimethylaminomethyl, cyclopropyl, 1-cyano-1-cyclopropyl, 1-pyrrolidinyl, 1-pyrazolyl, 3-pyridinyl, hydroxy, methoxy, CONH ２ , CONHMe, CONMe ２ , N.H. ２ and NMe ２ 82. The compound of any one of claims 1 to 81, optionally substituted with one or more substituents each independently selected from:

106. 82. The compound of any one of claims 1 to 81, wherein Ar is unsubstituted pyrazolyl.

107. structure: ​ (R ５ is H or alkyl.

108. structure: ​ (R ５ is H or alkyl.

109. structure: ​ (R ５ is H or alkyl.

110. structure: 【Chemistry 30】 (R ５ is H or alkyl.

111. structure: 【Chemical 31】 (R ５ is H or alkyl.

112. structure: 【Chemical 32】 (R ５ is H or alkyl.

113. structure: 【Chemical 33】 113. The compound of claim 1 or claim 112, having the formula:

114. structure: 【Chemical 34】 114. The compound of any one of claims 1, 112 and 113, having the formula:

115. structure: 【Chemistry 35】 107. The compound of claim 1 or claim 106, having the formula:

116. structure: 【Chemical 36】 116. The compound of any one of claims 1, 106 and 115, having the formula:

117. structure: 【Chemical 37】 116. The compound of any one of claims 1, 106, 114 and 115, having the formula:

118. structure: 【Chemical 38】 107. The compound of claim 1 or claim 106, having the formula:

119. structure: 【Chemical Formula 39】 119. The compound of any one of claims 1, 106 and 118, having the formula:

120. structure: 【Chemistry 40】 120. The compound of any one of claims 1, 106, 118 and 119, having the formula:

121. structure: 【Chemistry 41】 107. The compound of claim 1 or claim 106, having the formula:

122. structure: 【Chemistry 42】 122. The compound of any one of claims 1, 106 and 121, having the formula:

123. structure: 【Chemistry 43】 123. The compound of any one of claims 1, 106, 121 and 122, having the formula:

124. structure: 【Chemical 44】 124. The compound of any one of claims 1, 106 and 121-123, having the formula:

125. structure: 【Chemistry 45】 107. The compound of claim 1 or claim 106, having the formula:

126. structure: 【Chemistry 46】 126. The compound of any one of claims 1, 106 and 125, having the formula:

127. structure: 【Chemistry 47】 127. The compound of any one of claims 1, 106, 125 and 126, having the formula:

128. structure: 【Chemistry 48】 128. The compound of any one of claims 1, 106 and 125-127, having the formula:

129. structure: 【Chemistry 49】 2. The compound of claim 1 having the formula:

130. structure: 【Chemistry 50】 2. The compound of claim 1 having the formula:

131. structure: 【Chemistry 51】 2. The compound of claim 1 having the formula:

132. structure: 【Chemistry 52】 2. The compound of claim 1 having the formula:

133. Ar is phenyl and is selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from:

134. Ar is phenyl and is selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, CONR １４ R １５ , OR ９ , N.R. １０ R １１ and S(O) ２ R １２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from:

135. Ar is phenyl and chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

136. Ar is thienyl, and halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from:

137. Ar is thienyl and chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

138. Ar is pyrazolyl, and is selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, COR ８ , OR ９ , N.R. １０ R １１ and S(O) ｎ R １２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from:

139. Ar is pyrazolyl and the alkyl groups selected from the group consisting of chloro, fluoro, 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-butyloxycarbonyl-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-pyridinyloxy, 3-(4-morpholinyl)propoxy, CONH ２ , CONHMe, CONMe ２ , CONH-cyclopentyl, CONH-cyclohexyl, CONH-benzyl, CO-(4-morpholinyl), CO-(4-methylpiperazin-1-yl), NH ２ , NMe ２ ,NHCOPh,S.O. ２ Me, SO ２ NH-cyclohexyl and SO ２ 133. The compound of any one of claims 106 to 132, optionally substituted with one or more substituents each independently selected from: -(1-pyrrolidinyl).

140. 2. The compound of claim 1, wherein the compound is any of Examples 1 to 735.

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

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

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

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

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

146. 140. A method of treating a subject having a proliferative disorder, comprising administering to the subject a compound of any one of claims 1-140 or a composition of claim 128.

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

148. 148. The method of claim 147, wherein the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) (such as 5q-MDS), colorectal cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), B-cell lymphoma, or mantle cell lymphoma (MCL).

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

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

151. 151. The method of claim 150, wherein the DLBCL is ABC DLBCL.

152. 148. The method of claim 147, wherein the cancer is a BTK inhibitor-resistant cancer.

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

154. 154. The method of claim 153, wherein the ibrutinib-resistant cancer is ABC DLBCL.

155. 153. The method of claim 152, wherein the BTK inhibitor-resistant cancer is resistant to one or more of acalabrutinib, zanubrutinib, pirtobrutinib, spebrutinib, evobrutinib, olmutinib, tirabrutinib, elsbrutinib (ABBV-105), trebrutinib (SAR 442168), fenebrutinib, bakabrutinib, rilzabrutinib, M7583, BMS-986142, CT-1530, TG-1701, AC0058, SHR1459, RN-486, BIIB068, or DTRMWXHA-12.

156. 153. The method of 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's macroglobulinemia, or chronic graft-versus-host disease.

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

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

159. 142. 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 adenocarcinoma in a subject, comprising administering to the subject a compound of any one of claims 1-140 or a composition of claim 141.

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

161. 161. The method of claim 160, wherein the autoimmune disorder is Addison's disease, celiac-sprue (gluten-sensitive enteropathy), dermatomyositis, Graves' disease, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, or type 1 diabetes.

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

163. 163. The method of 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. 164. The method of claim 162 or 163, wherein the second active agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tramelimumab, or a combination thereof.

165. 165. The method of any one of claims 162 to 164, wherein the proliferative disease being treated is melanoma, including unresectable or metastatic melanoma, BRAF 600 mutation positive, and melanoma with lymph node metastasis; 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. 142. A method of treating a RAS-driven cancer in a subject, comprising administering to the subject a compound of any one of claims 1-140 or a composition of claim 141.

167. 167. The method of claim 166, wherein the RAS-driven cancer is a RAS-mutated cancer.

168. RAS-driven cancer is KRAS Ｇ１２Ｄ The method of claim 166, wherein the cancer is a driving force.

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

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

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