Compounds, pharmaceutical compositions thereof, and methods of using the same

Abstract

The present disclosure provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Description

COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME BACKGROUND

[0001] Treatment of cancer remains a considerable challenge despite significant research into the underpinnings of various cancers and a variety of existing cancer therapeutics. Currently available cancer therapeutics and treatment methods using said therapeutics largely focus on the inhibition of key cellular pathways which support, e.g., growth, proliferation, and metastasis of neoplastic cells. However, many cancers may not comprise, e.g., targeted mutations or may be resistant to currently available inhibition-based strategies. Moreover, such resistance may be developed during the course of treatment with available inhibitory cancer therapeutics. Accordingly, there is an ongoing and unmet need for novel cancer therapeutics. SUMMARY

[0002] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, Ring C, and L is as defined and described herein.

[0003] In some embodiments, the present disclosure also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0004] In some embodiments, the present disclosure also provides a method of treating a cancer, the method comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the cancer is a CK1α-mediated cancer. In some embodiments, the cancer is a Wnt-mediated cancer. In some embodiments, the cancer is a p53-mediated cancer. In some embodiments, the cancer is an adenomatous polyposis coli (APC)-mediated cancer. In some embodiments, the cancer is selected from colorectal cancer (CRC) (e.g., APC colorectal cancer), small intestine (small bowel) cancer, thyroid cancer,brain cancer, pancreatic cancer, bile duct cancer, hepatoblastoma, primary effusion lymphoma (PEL), myelodysplastic syndrome (MDS), and acute myeloid lymphoma (AML).

[0005] In some embodiments, the present disclosure provides a method of modulating an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some embodiments, the oncogenic pathway is a WNT-mediated pathway or a p53- mediated pathway. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Provided Compounds

[0006] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is substituted with m instances of Rx; each Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CX2)zY, or: two instances of Rx, together with the atoms to which they are attached, form a 5- to 6- membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each X is independently selected from hydrogen, C1-4 alkyl, and halogen; Y is selected from -N(R)2, -OR, -O(CH2)2OR, -C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, - N(R)C(O)R, -N(R)C(O)OR, -SO2R, -SO2N(R)2, and -N(R)SO2R;L is selected from a covalent bond or a C1-2aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-; Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry; each Ryis selected from halogen, C1-3 alkyl, and lower haloalkyl; Ring C is a bivalent group comprisingor , wherein Ring C is substitutedwith 0-3 instances of Rx; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; n is 0-2; y is 0-2; and z is 0-1. 2. Compounds and Definitions

[0007] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. andMarch, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0008] Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0009] Alkylene: The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0010] Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish and / or worms. In some embodiments, an animal may be a transgenic animal, a genetically-engineered animal and / or a clone.

[0011] Aryl: The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like, wherein the point of attachment is on the aryl ring.

[0012] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and / or form of one is correlated with that of the other. For example, a particular biological phenomenon (e.g., expression of a specific biomarker) is considered to be associated with a disease, disorder, and / or condition (e.g., a cancer, a specific type of cancer), if its presence correlates with incidence of and / or susceptibility of the disease, disorder, and / or condition (e.g., across a relevant population).

[0013] Biological sample: The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal, e.g., a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0014] Cancer: The term “cancer” is used herein to generally refer to a disease or condition in which cells of a tissue of interest exhibit relatively abnormal, uncontrolled, and / or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, cancer may comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic.

[0015] Combination: As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unitdosage form comprising a provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0016] Halogen: The term “halogen” means F, Cl, Br, or I.

[0017] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0018] Heteroatom: The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N- substituted pyrrolidinyl)).

[0019] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more,preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl).

[0020] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0021] In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within an organism (e.g., animal, plant and / or microbe).

[0022] In vivo: As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant and / or microbe).

[0023] Lower haloalkyl: The term “lower haloalkyl” refers to a C1-3straight or branched alkyl group that is substituted with one or more halogen atoms.

[0024] Optionally substituted: As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0025] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0–4R°; –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0– 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4 straight or branched alkylene)O– N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0026] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independentlyhalogen, –(CH2)0–2Rl, –(haloRl), –(CH2)0–2OH, –(CH2)0–2ORl, –(CH2)0–2CH(ORl)2; -O(haloRl), –CN, –N3, –(CH2)0–2C(O)Rl, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)ORl, – (CH ) SRl, –(CH ) SH, –(CH ) NH , –(CH )0–2Nll l 2 0–2 2 0–2 2 0–2 2 2 HR , –(CH2)0–2NR 2, –NO2, –SiR 3, – OSiRl3,-C(O)SRl, –(C1–4straight or branched alkylene)C(O)ORl, or –SSRlwherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0027] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Suitable substituents on the aliphatic group of R* include halogen, – Rl, -(haloRl), -OH, –ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or –NO2, wherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] Suitable substituents on the aliphatic group of R† are independently halogen, – Rl, -(haloRl), –OH, –ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or -NO2, wherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0032] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0033] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0034] Pharmaceutically acceptable derivative: A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound disclosed herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound disclosed herein or an active metabolite or residue thereof.

[0035] Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0036] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0037] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject is a mouse. In some embodiments, subject is a rat. In some embodiments, a subject is a non-human primate. In some embodiments, a subject is a human. In some embodiments, a subject is a patient. In some embodiments, a subject may be suffering from and / or susceptible to a disease, disorder, and / or condition. In some embodiments, a subject may be suffering from and / or susceptible to a cancer.

[0038] Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0039] Susceptible to: An individual who is “susceptible to” a condition, disorder, and / or disease is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition is predisposed to have that disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0040] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0041] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0042] Unsaturated: The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

[0043] Wild-type: As used herein, the term “wild-type” has its art-understood meaning that refers to an entity having a structure and / or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc.) state or context. Those of ordinary skill in the art will appreciate that wild type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0044] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. 3. Description of Exemplary Compounds

[0045] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is substituted with m instances of Rx; each Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CH2)zY, or:two instances of Rx, together with the atoms to which they are attached, form a 5- to 6- membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Y is selected from -C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -SO2R, -SO2N(R)2, and -N(R)SO2R; L is selected from a covalent bond or a C1-2 aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-; Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry; each Ryis selected from halogen, C1-3 alkyl, and lower haloalkyl; Ring C is a bivalent group comprisingor; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; n is 0-2; y is 0-2; and z is 0-1.

[0046] In some embodiments, the present disclosure provides a compound of formula I’:or a pharmaceutically acceptable salt thereof, wherein:Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is substituted with m instances of Rx; each Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CH2)zY, or: two instances of Rx, together with the atoms to which they are attached, form a 5- to 6- membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Y is selected from -C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -SO2R, -SO2N(R)2, and -N(R)SO2R; L is selected from a covalent bond or a C1-2 aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-; Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry; each Ryis selected from halogen, C1-3 alkyl, and lower haloalkyl; Ring C is a bivalent group comprisingorwherein Ring C is substituted with 0-3 instances of Rx; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; n is 0-2; y is 0-2; and z is 0-1.

[0047] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is substituted with m instances of Rx; each Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CX2)zY, or: two instances of Rx, together with the atoms to which they are attached, form a 5- to 6- membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each X is independently selected from hydrogen, C1-4 alkyl, and halogen; Y is selected from -N(R)2, -OR, -O(CH2)2OR, -C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, - N(R)C(O)R, -N(R)C(O)OR, -SO2R, -SO2N(R)2, and -N(R)SO2R; L is selected from a covalent bond or a C1-2aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-; Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry; each Ryis selected from halogen, C1-3 alkyl, and lower haloalkyl; Ring C is a bivalent group comprisingor , wherein Ring C is substitutedwith 0-3 instances of Rx; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; n is 0-2; y is 0-2; and z is 0-1.

[0048] As defined generally above for any one of Formula I, I’, and I’’, Ring C is a bivalent group comprisingorIn some embodiments, Ring C is a bivalent group comprising. In some embodiments, Ring C is a bivalent group comprisingIn some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure. In some embodiments, the present disclosure provides a compound of formula II:or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula II-a:or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the present disclosure provides a compound of formula III:or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present disclosure provides a compound of formula III-a:or a pharmaceutically acceptable salt thereof.

[0051] As defined generally above for any one of Formula I, I’, and I’’, Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 7-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 4-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 4- to 5-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5- to 6-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5- to 7-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0052] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is phenyl.

[0053] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10- membered bicyclic aryl ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a naphthyl ring. In some such embodiments, Ring A is 2-naphthyl.

[0054] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx.

[0055] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 7- membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5- to 6-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 6-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 6-membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a piperidinyl ring optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx.

[0056] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3- to 7- membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5- to 6-membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5- to 6-membered partially unsaturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring,wherein the bicyclic ring formed thereby is substituted with m instances of Rx. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 3,6-dihydro-2H-pyranyl ring optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of Rx.

[0057] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10- membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10-membered saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10-membered saturated bicyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a tetrahydroisoquinolinyl ring.

[0058] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10- membered partially unsaturated bicyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 2H-chromenyl ring or a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl ring.

[0059] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 5-membered monocyclic heteroaryl ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a furanyl ring, a pyrazolyl ring, or a thiazolyl ring.

[0060] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 6- membered monocyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 6-membered monocyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a pyridyl ring or a pyrimidinyl ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III- a, Ring A is a pyridyl ring, a pyrimidinyl ring, or a pyrazinyl ring.

[0061] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III- a, Ring A is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a benzo[d]thiazolyl ring, a benzo[d]isoxazolyl ring, or a 1H-benzo[d]imidazolyl ring.

[0062] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9- membered bicyclic heteroaryl ring having 1-4 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9- membered bicyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 2-3 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is selected from an indolyl ring, a 1H-indazolyl ring, or a 4,5,6,7-tetrahydro-2H-indazolyl ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is selected from an indolylring, a 1H-indazolyl ring, a benzimidazolyl ring, a benzofuranyl ring, a benzothiazolyl ring, or a 4,5,6,7-tetrahydro-2H-indazolyl ring.

[0063] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10- membered bicyclic heteroaryl ring having 1-4 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10-membered bicyclic heteroaryl ring having 1-2 nitrogen atoms. In some such embodiments, a 1,5-naphthyridinyl ring, a 1,6-naphthyridinyl ring, or a 2,6-naphthyridinyl ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a 10-membered bicyclic heteroaryl ring having 1 nitrogen atom. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is a quinolinyl ring or an isoquinolinyl ring.

[0064] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is selected from:

[0065] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is selected from:

[0066] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In someembodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is

[0067] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is.

[0068] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A isIn someembodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is.

[0069] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is. In some embodiments, of Formula I, I’, I’’, II, II-a, III, or III-a Ring A isIn someembodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring A is.

[0070] As defined generally above for Formula I and Formula I’, each Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and - (CH2)zY, or two instances of Rx, together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis oxo. In some embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis halogen. In some embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis –CN. In some embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis –OR. In some embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis -N(R)2. In some embodiments of Formula I, I’, II, II-a, III, or III- a, Rxis –SR. In some embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis -(CH2)yR. Insome embodiments of Formula I, I’, II, II-a, III, or III-a, Rxis -(CH2)zY. It will be appreciated that a Rxgroup on Ring A can be independent of a Rxgroup on Ring C. In some embodiments, a Rxgroup on Ring A is different than a Rxgroup on Ring C. In some embodiments, the Rxgroup of Ring A is selected from any of the embodiments as herein described for Rxgenerally. In some embodiments, the Rxgroup of Ring C is selected from any of the embodiments as herein described for Rxgenerally.

[0071] As defined generally above for Formula I’’, Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CX2)zY, or two instances of Rx, together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0072] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, two instances of Rx, together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, two instances of Rx, together with the atoms to which they are attached, form a 5-membered saturated ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, two instances of Rx, together with the atoms to which they are attached, form a 1,3-dioxolanyl ring.

[0073] As defined generally above for Formula I’’, each X is independently selected from hydrogen, C1-4alkyl, and halogen. In some embodiments, each X is hydrogen. Accordingly, in some embodiments of Formula I’’, Rxis –(CH2)zY. In some embodiments, one X is hydrogen and the other X is C1-4 alkyl. In some embodiments, one X is hydrogen and the other X is -CH3. In some embodiments, each X is C1-4alkyl. In some embodiments, each X is - CH3. Accordingly, in some embodiments of Formula I’’, Rxis -CH(CH3)Y or -C(CH3)2Y.

[0074] As defined generally above for Formula I and Formula I’, Y is selected from - C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -SO2R, -SO2N(R)2, and -N(R)SO2R. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Y is –CO2R.

[0075] As defined generally above for Formula I’’, Y is selected from As definedgenerally above for Formula I’’, Y is selected from -N(R)2, -OR, -O(CH2)2OR, -C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -SO2R, -SO2N(R)2, and -N(R)SO2R.

[0076] In some embodiments of Formula I’’, Y is selected from -N(R)2and -OR. In some embodiments of Formula I’’, Y is -N(R)C(O)OR. In some embodiments of Formula I’’, Y is - Os(CH2)2OR.

[0077] As defined generally above for any one of Formula I, I’, and I’’, L is selected from a covalent bond or a C1-2 aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is a covalent bond. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is a C1-2 aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-.

[0078] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is –C(=O)-.

[0079] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is -CH2O- or – OCH2-.

[0080] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is –CH2-.

[0081] As defined generally above for Formula I, Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry. As defined generally above for Formula I’, Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B iswherein * indicates the point of attachment to Ring A.

[0083] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A. In some embodiments ofFormula I, I’, I’’, II, II-a, III, or III-a, Ring B is , wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is.

[0084] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A.

[0085] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A.

[0086] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A.

[0087] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B iswherein * indicates the point of attachment to Ring A. In some embodimentsof Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is , wherein * indicates the point of attachment to Ring A.

[0088] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B iswherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A.

[0089] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is , wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’,I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A.

[0090] In some embodiments of Formula I’, I’’, II, II-a, III, or III-a, Ring B is a 5- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I’, I’’, II, II-a, III, or III-a, Ring B is a 5-membered partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I’, I’’, II, II-a, III, or III-a, Ring B isIn some embodiments of Formula I’, I’’, or II, Ring B is, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I’, I’’, II, II-a, III, or III-a, Ring B is, wherein * indicates the point of attachment to Ring A.

[0091] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5-membered saturated monocyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0092] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isorIn some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isor, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isor, wherein * indicates the point of attachment to Ring A.

[0093] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isor. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isor, wherein * indicates the point of attachment to Ring A.In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is or, wherein * indicates the point of attachment to Ring A.

[0094] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is a 5- membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isor, wherein * indicates the point of attachment to Ring A. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ring B isor , wherein * indicates the point of attachment to Ring A.

[0095] As defined generally above for any one of Formula I, I’, and I’’, each Ryis selected from halogen, C1-3 alkyl, and lower haloalkyl. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ryis halogen. In some such embodiments, Ryis fluoro or chloro. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ryis C1-3alkyl. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ryis methyl or ethyl. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, Ryis lower haloalkyl. In some such embodiments Ryis -CF3, -CH2F, or CHF2. In some embodiments Formula I, I’, I’’, II, II-a, III, or III-a, when Ryis attached to a nitrogen atom, Ryis selected from C1-3alkyl, and lower haloalkyl. In some such embodiments, Ryis selected from methyl, ethyl, -CF3, -CH2F, or CHF2.

[0096] As defined generally above for any one of Formula I, I’, and I’’, each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is hydrogen. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted group selected from C1-6aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is optionally substituted C1-6aliphatic. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is optionally substituted C1-4 aliphatic. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is optionally substituted C1-2 aliphatic. In some embodiments of Formula I, I’, I’’, II, II- a, III, or III-a, R is C1-2aliphatic optionally substituted with halogen. In some such embodiments, R is –CH3, -CH2CH3, -CH(CH3)2, or –CF3.

[0098] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, or III-a, R is C1-2 aliphatic optionally substituted with –(CH2)0-4ORº, wherein Rº is hydrogen or C1-6aliphatic. In some such embodiments, Rº is substituted with –(CH2)0-2OR●or –(CH2)0-2OH, wherein R●is C1-4aliphatic.

[0099] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 3- to 4-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 5- to 6-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted cyclopropyl or cyclobutyl ring. [000100] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted phenyl. [000101] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 3- to 4- membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 5- to 6-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted azetidinyl ring, a tetraydrofuranyl ring, or a piperidinyl ring. In some embodiments of Formula I, I’, I’’, II, II-a,III, or III-a, R is an optionally substituted azetidinyl ring, a tetraydrofuranyl ring, a piperidinyl ring or a tetrahydropyranyl ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an azetidinyl ring optionally substituted with –(CH2)0-4CO2Rº. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an azetidinyl ring optionally substituted with –(CH2)0-4CO2Rº, wherein Rº is C1-6 aliphatic. [000102] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 5- membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is a furanyl ring. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 nitrogen atom. [000103] As defined generally above for any one of Formula I, I’, and I’’, m is 0-3. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 0. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 1. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 2. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 3. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 2. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 0-1. In some embodiments of Formula I, I’, I’’, II, II- a, III, or III-a, m is 2-3. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, m is 1-2. [000104] As defined generally above for any one of Formula I, I’, and I’’, n is 0-2. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, n is 0. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, n is 1. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, n is 2. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, n is 0-1. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, n is 1-2.[000105] As defined generally above for any one of Formula I, I’, and I’’, y is 0-2. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, y is 0. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, y is 1. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III- a, y is 2. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, y is 0-1. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, y is 1-2. [000106] As defined generally above for any one of Formula I, I’, and I’’, z is 0-1. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, z is 0. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, z is 1. [000107] In some embodiments, the compound of Formula I, I’, I’’, II, II-a, III, or III-a is selected from a compound in Table 1.Table 1.or a pharmaceutically acceptable salt thereof. [000108] In some embodiments, the compound is not a compound in Table 2. Table 2.4. Pharmaceutical Compositions [000109] In some embodiments, the present disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound of this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a composition of this disclosure is formulated for administration to a subject in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a subject. [000110] The compounds and compositions, according to the method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, e.g., a cancer described herein. [000111] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [000112] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [000113] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [000114] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [000115] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.[000116] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [000117] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [000118] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [000119] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. [000120] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. [000121] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a subject receiving these compositions.[000122] It should also be understood that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition. [000123] In some embodiments, the present disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound of this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a composition of this disclosure is formulated for administration to a subject in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a subject. [000124] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [000125] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [000126] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [000127] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [000128] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [000129] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [000130] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [000131] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [000132] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [000133] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [000134] Provided compounds and compositions thereof are effective over a wide dose range. In some embodiments, a dose is from about 0.01 to about 1000 mg, from about 0.5 to about 100 mg, from about 1 to about 50 mg, or from about 5 to about 100 mg. Exact doses may depend upon routes of administration, forms in which compounds are administered, subjects (e.g., body weight, age, body surface area, etc.), conditions, disorders or diseases, and / or preferences and experiences of physicians. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, disorder, or disease, e.g., cancer, the particular agent, its mode of administration, and the like. In some embodiments, a fixed dose is administered. In some embodiments, two or more doses are about the same amount. In some embodiments, one or more doses are independently more than one or more other doses. For example, in some embodiments, one or more loading doses each independently of a higher amount are administered before one or more maintenance doses each independently of a lower amount. In some embodiments, two or more or all loading doses are about the same amount. In some embodiments, a loading dose is of a higher amount than another loading dose. In some embodiments, two or more or all maintenancedoses are about the same amount. In some embodiments, a maintenance dose is of a higher amount than another maintenance dose. [000135] Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. [000136] Among other things, the present disclosure provides kits comprising any of the compounds and compositions described herein. In some embodiments, a kit comprises a solid composition. In some embodiments, a kit comprises a tablet, capsule, or pill. In some embodiments, a kit comprises a liquid composition. In some embodiments, a kit comprises instructions for performing any of the methods described herein. 5. Characterization and Assessment [000137] As appreciated by those skilled in the art, various technologies may be utilized to characterize and / or assess provided technologies in accordance with the present disclosure. Certain useful technologies are described in the Examples. As demonstrated, among other things, the present disclosure describes various in vitro technologies suitable for assessing and characterizing provided technologies. In some embodiments, provided technologies are characterized and / or assessed, e.g., in in vitro systems, e.g., in cells. [000138] In some embodiments, provided technologies (e.g., compounds, compositions) are characterized and / or assessed using various in vitro assays known in the art. For example, in some embodiments, compounds are assessed using a HiBiT assay. The HiBiT assay reportedly can be used to provide quantitative measurement of proteins in a system, e.g., an in vitro system,e.g., a cell or population of cells. A HiBiT assay can be conducted in a high-throughput manner. By tagging a target protein with a Small BiT (HiBiT tag), the protein levels can reportedly be measured through the addition of the LgBiT component to form an active nanoluciferase enzyme. Luminescence generated by the nanoluciferase enzyme under assay conditions can then reportedly be quantitatively measured to provide quantitation of Small BiT-tagged protein levels. The HiBiT system is described in, e.g., Schwinn et al. ACS Chem Biol.2018 Feb 16;13(2):467- 474. In some embodiments, Small BiT-tagged CK1α is used in a HiBiT assay. In some embodiments, a HiBiT assay is used to assess level of targeted protein in a system, e.g., an in vitro system. In some embodiments, a HiBit assay is used to assess level of CK1α protein in a system, e.g., an in vitro system. In some embodiments, a HiBiT assay is used to assess level of targeted protein degradation in a system, e.g., an in vitro system, by a provided compound or composition. In some embodiments, a HiBit assay is used to assess level of CK1α protein degradation in a system, e.g., an in vitro system, by a provided compound or composition. In some embodiments, a HiBiT assay is conducted as described herein, e.g., in an example. [000139] In some embodiments, compounds are assessed using an assay to assess level of CK1α protein or level of CK1α activity in a system. In some embodiments, level of CK1α protein is assessed by an immunoassay. In some embodiments, level of CK1α protein is assessed by Western blot. In some embodiments, level of CK1α protein is assessed by capillary-based immunoassay. Various additional methods for assessing levels of CK1α protein or activity are described in the art, including those described in WO 2021 / 222542. [000140] In some embodiments, compounds are assessed using a TOPflash assay. The TOPflash assay reportedly utilizes a reporter plasmid comprising multiple (e.g., two sets of three) copies of a wild-type TCF binding site upstream of a thymidine kinase minimal promoter and luciferase open reading frame (ORF). The TOPflash reporter plasmid is described in, e.g., Korinek et al. Science.1997 Mar 21;275(5307):1784-7. Using the TOPflash plasmid, an assay can reportedly be performed to provide quantitative measurement (through measurement of luciferase-driven luminescence) of β-catenin / TCF activity in a system (e.g., an in vitro system, e.g., a cell), which activates the expression from the luciferase ORF. This quantitative measurement may reportedly be used to assess Wnt signaling pathway activation in a system. In some embodiments, a TOPflash assay is used to assess level of Wnt signaling pathway activation in a system, e.g., an in vitro system, by a provided compound or composition. In someembodiments, a TOPflash assay is used to assess level of β-catenin activity in a system, e.g., an in vitro system, by a provided compound or composition. In some embodiments, a TOPflash assay is conducted as described herein, e.g., in an example. [000141] In some embodiments, compounds are assessed using an assay to assess level of p53 protein or level of p53 activity in a system. In some embodiments, level of p53 protein is assessed by an immunoassay. In some embodiments, level of p53 protein is assessed by Western blot. In some embodiments, level of p53 protein is assessed by capillary-based immunoassay. Various additional methods for assessing levels of p53 protein or activity are described in the art, including those described in WO 2021 / 222542. [000142] In some embodiments, a provided compound or composition is characterized or assessed in an in vivo system. In some embodiments, a provided compound or composition is characterized or assessed in an animal, e.g., a mouse, rat, pig, dog, non-human primate, e.g., a monkey. In some embodiments, a provided compound or composition is characterized or assessed in a human. In some embodiments, a provided compound or composition is characterized in xenograft model, e.g., a xenograft mouse model. Various xenograft models for assessment of anti-cancer and / or anti-tumor properties of compounds and compositions thereof are known in the art. [000143] Those skilled in the art reading the present disclosure will readily appreciate that other technologies, e.g., in vitro models (e.g., cell lines) for various conditions, disorders, or diseases, animals models for various conditions, disorders, or diseases, clinical trials, etc. may be designed and / or utilized to assess provided technologies (e.g., compounds, compositions, methods, etc.) in accordance with the present disclosure. 6. Uses and Applications [000144] As appreciated by those skilled in the art, compounds described herein are useful for many purposes. In some embodiments, provided technologies (e.g., compounds, compositions, methods, etc.) are useful for treating conditions, disorders, or diseases, e.g., various cancers as described herein. In some embodiments, provided technologies (e.g., compounds, compositions, methods, etc.) are useful for modulating cellular pathways, e.g., Wnt signaling pathway in a system. In some embodiments, provided technologies (e.g., compounds,compositions, methods, etc.) are useful for decreasing level of target proteins, e.g., CK1α and / or level of activity of target proteins, e.g., CK1α in a system. [000145] The Wnt signaling pathway, which may also be referred to the Wnt / β-catenin signaling pathway, reportedly involves a variety of proteins and modulates gene expression in cells (Komiya, Y. and Habas, R. Organogenesis.2008 Apr;4(2):68-75). Wnt proteins are reportedly secreted glycoproteins which bind to receptors belonging to the Frizzled (Fz) family of receptors on the outside of cells. Further, the interaction of a Wnt protein with a co-receptor may also be necessary; reported co-receptors include lipoprotein receptor-related protein (LRP) 5 / 6 and various receptor tyrosine kinases (RTKs). Wnt binding with these receptors has been reported as leading to modulation of the protein Axin, which may be translocated to membrane, bound to LRP 5 / 6, destabilized, and degraded. Additionally, upon Wnt binding to Fz, a cytoplasmically located Dishevelled (Dsh) protein may reportedly interact with Fz, become phosphorylated, and inhibit activity of glycogen synthase kinase 3 (GSK3). These actions have been reported to disrupt a destruction complex, which comprises Axin, GSK3, adenomatosis polyposis coli (APC), β-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP), and casein kinase 1α (CK1α). [000146] In the absence of Wnt signaling pathway activation, the destruction complex described above has been reported to target β-catenin for destruction. Such targeting reportedly involves phosphorylation of β-catenin by the proteins of the destruction complex, e.g., GSK3 and CK1α, and ensuing ubiquitination and proteasomal degradation. Accordingly, β-catenin levels are decreased and β-catenin is not translocated to the nucleus to effect gene transcription through interactions with TCF / LEF transcription factors, which reportedly repress target gene transcription in the absence of β-catenin. Whereas, with Wnt signaling pathway activation, the destruction complex is reportedly disrupted, β-catenin degradation is reduced, and an increased level of β-catenin can be translocated to the nucleus to modulate transcription of target genes. [000147] Various genes have been reported as being regulated by Wnt signaling pathway activation, including genes related to cancer cell functioning, growth, and proliferation (Zhang, Y. and Wang, X. J Hematol Oncol.2020 Dec 4;13(1):165). In some embodiments, Wnt signaling pathway modulates expression of genes involved in any of the following non-limited functions: cellular proliferation, cellular differentiation, stem cell renewal, tissue homeostasis, apoptosis, migration, and / or invasion. In some embodiments, Wnt signaling pathway modulatesexpression of genes over-expressed or under-expressed in tumor cells. In some embodiments, Wnt signaling pathway modulates expression of genes over-expressed or under-expressed in cancer cells. [000148] Accordingly, without wishing to be bound by any particular theory, modulation of one or more proteins of a Wnt signaling pathway may be conducted to increase or decrease level of Wnt signaling pathway activation and / or downstream gene expression. In some embodiments, modulation of one or more proteins may modulate level of Wnt signaling pathway activation in a system, e.g., a cell. In some embodiments, modulation of a level of Wnt signaling pathway activation may involve increasing or decreasing Wnt signaling pathway activation. In some embodiments, modulation of a level of Wnt signaling pathway activation may involve increasing Wnt signaling pathway activation. In some embodiments, modulation of one or more proteins may modulate level of β-catenin in a system, e.g., a cell. In some embodiments, modulation of a level of β-catenin may involve increasing or decreasing the level of β-catenin. In some embodiments, modulation of one or more proteins may modulate level of expression of one or more genes in a system, e.g., a cell. In some embodiments, modulation of a level of expression of one or more genes may involve increasing or decreasing the level of expression of one or more genes. In some embodiments, modulation of one or more proteins may involve increasing or decreasing a level of one or more proteins. In some embodiments, modulation of one or more proteins may involve increasing or decreasing a level of activity of one or more proteins. In some embodiments, modulation of one or more proteins may involve degradation of the one or more proteins. In some embodiments, the present disclosure provides a method of modulating an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some embodiments, a method of modulating an oncogenic pathway results in the activation of the pathway. In some embodiments, a method of modulating an oncogenic pathway results in the inhibition of the pathway. In some embodiments, the present disclosure provides a method of activating an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some such embodiments, the oncogenic pathway is a WNT- mediated pathway.[000149] The tumor suppressor gene, p53 reportedly regulates transcription of a variety of genes, including those involved in, e.g., DNA damage repair, cell cycle progression, and apoptosis. Further, p53 has been reported as the most frequently mutated gene in human cancers, and even in cancers without a p53 mutation, reduced levels of p53 activity have been reported. Accordingly, increasing and / or restoring levels of wild-type and / or functional p53 and p53 activity remains a potential route of action for cancer therapeutic agents. Levels of p53 protein and activity has been found to be regulated by a p53 / MDM2 / MDMX pathway. MDM2 is reportedly an E3 ubiquitin ligase that binds to and ubiquitinates p53 – leading to inhibition of p53 and degradation of p53 by the proteasome. MDMX reportedly acts a modulator of p53 activity by binding to p53 and inhibiting p53 transcriptional activity. Studies have shown that CK1α is able to interact with MDM2 and MDMX. CK1α has been reported to interact with MDM2 and thusly promote the binding of MDM2 to p53 and the subsequent ubiquitination, inhibition, and degradation of p53 (Huart, A. et al. J Biol Chem.2009 Nov 20;284(47):32384- 94). Additionally, CK1α has been reported to phosphorylate MDMX, which allows MDMX to interact with and inhibit p53 (Chen, L. et al. Mol Cell Biol.2005 Aug;25(15):6509-20). Thus, CK1α may act a positive regulator of MDM2 and / or MDMX activity, which in turn acts to decrease levels of p53 protein and activity. Potential CK1α involvement in p53 / MDM2 / MDMX pathways is discussed in, e.g., Jiang, S. et al. Cell Commun Signal.2018 May 24;16(1):23. Potential downregulation of p53 through the p53 / MDM2 / MDMX pathway has been reported in some cancers, including, e.g., acute myeloid leukemia (AML), wherein high levels of CK1α is associated with suppression of p53 and decreased overall survival (Xu, W. et al. Oncol Rep. 2020 Nov;44(5):1895-1904). [000150] Accordingly, without wishing to be bound by any particular theory, modulation of one or more proteins in a p53 / MDM2 / MDMX pathway may be conducted to increase or decrease level of p53 protein and / or activity and / or downstream gene expression. In some embodiments, modulation of one or more proteins may modulate level of p53 protein in a system, e.g. a cell. In some embodiments, modulation of one or more proteins may modulate level of p53 activity in a system, e.g. a cell. In some embodiments, modulation of one or more proteins may modulate level of p53 binding activity in a system, e.g., a cell. In some embodiments, modulation of one or more proteins may modulate level of degradation of p53 protein in a system, e.g., a cell. In some embodiments, modulation of one or more proteins maymodulate level of MDM2 activity in a system, e.g. a cell. In some embodiments, modulation of one or more proteins may modulate level of expression of one or more genes in a system, e.g., a cell. In some embodiments, modulation of one or more proteins may modulate level of expression of one or more p53-regulated genes in a system, e.g., a cell. In some embodiments, modulation of a level of expression of one or more genes may involve increasing or decreasing the level of expression of one or more genes. In some embodiments, modulation of one or more proteins may involve increasing or decreasing a level of one or more proteins. In some embodiments, modulation of one or more proteins may involve increasing or decreasing a level of activity of one or more proteins. In some embodiments, modulation of one or more proteins may involve degradation of the one or more proteins. In some embodiments, the present disclosure provides a method of inhibiting an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some such embodiments, the oncogenic pathway is a p53-mediated pathway. [000151] Casein kinase 1α (CK1α) refers to a protein encoded by, in humans, the CSNK1A1 gene. CK1α may also be known as casein kinase 1 isoform alpha, CKI-alpha, or CK1. Various CK1α sequences are readily available to those of skill in the art, including NCBI Reference Protein Sequences Accession Nos. NP_001020276.1, NP_001883.4, NP_001258670.1, and NP_001258671.1. Various technologies, e.g., assays, cells, etc., associated with CK1α have also been reported and can be utilized for characterization and / or assessment of provided technologies (e.g., compounds, compositions, methods, etc.) in accordance with the present disclosure. [000152] CK1α reportedly belongs to a family of proteins that act as serine / threonine kinases. As part of a destruction complex, CK1α phosphorylates β-catenin, which acts as a signal transduction protein in the Wnt signaling pathway. The phosphorylation of β-catenin by CK1α has been reported to contribute to the subsequent ubiquitination and degradation of β- catenin. Other components which have been indicated to be part of the β-catenin destruction complex include, e.g., APC, GSK3, and Axin. CK1α reportedly also phosphorylates APC, which in turn assists in the association of APC with β-catenin (Ferrarese, A. et al. Biochemistry. 2007 Oct 23;46(42):11902-10). In addition to functioning as a component of the β-catenin destruction complex, studies have suggested potential additional roles for CK1α in cellularfunctioning due to widespread localization in the cell and ubiquitous expression of the protein in different types of cells and tissues (Jiang, S. et al. Cell Commun Signal.2018 May 24;16(1):23). [000153] In some embodiments, a provided compound interacts with a CK1α polypeptide or protein. In some embodiments, a provided compound binds a CK1α polypeptide or protein. In some embodiments, a provided compound binds a CK1α polypeptide or protein and binds an additional polypeptide or protein. In some embodiments, a provided compound binds a CK1α polypeptide or protein and binds a CRBN polypeptide or protein. [000154] Cereblon (CRBN) refers to a protein encoded by, in humans, the CRBN gene. Various CRBN sequences are readily available to those of skill in the art, including NCBI Reference Protein Sequences Accession Nos. NP_057386.2 and NP_001166953.1. Various technologies, e.g., assays, cells, etc., associated with CRBN have also been reported and can be utilized for characterization and / or assessment of provided technologies (e.g., compounds, compositions, methods, etc.) in accordance with the present disclosure. [000155] CRBN reportedly acts a substrate receptor as part of the E3 ubiquitin ligase complex, which also includes CUL4, RBX1, and DDB1. As the substrate receptor for the complex, CRBN directly binds to proteins targeted for ubiquitin-mediated degradation. Through degradation of target proteins, CRBN may reportedly play a role in regulation of various cellular processes or pathways, including, e.g., the TLR4 signaling pathway and ATP metabolism. Studies have further shown that CRBN can be facilitated to bind to specific target proteins through the usage of immune modulatory drugs, therein leading to targeted degradation of the target proteins (Petzold et al. Nature.2016 Apr 7;532(7597):127-30). [000156] In some embodiments, a provided compound interacts with an E3 ubiquitin ligase protein. In some embodiments, a provided compound binds an E3 ubiquitin ligase protein. In some embodiments, a provided compound binds an E3 ubiquitin ligase protein and an additional polypeptide or protein. In some embodiments, a provided compound binds an E3 ubiquitin ligase protein and a CK1α polypeptide or protein. In some embodiments, a provided compound interacts with a CRBN polypeptide or protein. In some embodiments, a provided compound binds a CRBN polypeptide or protein. In some embodiments, a provided compound binds a CRBN polypeptide or protein and an additional polypeptide or protein. In some embodiments, a provided compound binds a CRBN polypeptide or protein and a CK1α polypeptide or protein.[000157] In some embodiments, provided technologies (e.g., compounds, compositions) promote or facilitate binding of CRBN to target polypeptides or proteins. In some embodiments, provided technologies (e.g., compounds, compositions) promote or facilitate binding of CRBN to CK1α polypeptides or proteins. In some embodiments, provided technologies (e.g., compounds, compositions) promote or facilitate CRBN-mediated degradation of target polypeptides or proteins. In some embodiments, provided technologies (e.g., compounds, compositions) promote or facilitate CRBN-mediated degradation of CK1α polypeptides or proteins. In some embodiments, provided technologies (e.g., compounds, compositions) modulate level of CRBN- mediated degradation of CK1α polypeptides or proteins. In some embodiments, provided technologies (e.g., compounds, compositions) increase level of CRBN-mediated degradation of CK1α polypeptides or proteins. [000158] Studies have suggested that level of cellular pathway activity in cancers often follow a “just right” model, wherein inhibition of an oncogenic cellular pathway may prove lethal for cancer cells or wherein further activation (hyperactivation) may also prove lethal for cancer cells. Currently available cancer therapeutic agents are predominantly targeted to provide inhibition of oncogenic pathways to perturb cancer cell growth, proliferation, and division and to kill cancer cells. The Wnt signaling pathway has been previously implicated as an oncogenic in a variety of cancers, including cancers comprising a mutation of APC, e.g., APC mutant colorectal cancer. Mutations of APC in such cancers reportedly provide oncogenic activation of Wnt signaling pathway and oncogenic activation of target genes by increased β-catenin stability and / or activity. In some embodiments, Wnt signaling pathway is an oncogenic pathway. Recent research has indicated that further perturbation of proteins in the destruction complex (e.g., Axin, CK1α) in the Wnt signaling pathway may be used to further activate the Wnt signaling pathway and genes regulated thereby. The further activation of the Wnt signaling pathway reportedly results in lethal hyperactivation and death of cancer cells (Chang et al. Nat Genet.2023 Sep 25). Without wishing to be bound by any particular theory, the present disclosure provides the unique insight that activation of oncogenic pathways, e.g., Wnt signaling pathway, by modulating CRBN-mediated degradation of CK1α using compounds described herein can be used to treat cancers, e.g., APC mutant cancers, e.g., APC mutant colorectal cancer. [000159] Insights contained herein recognize that hyperactivation of cellular pathways provides additional routes for cancer therapeutics to target various cancers. For example, suchhyperactivation may be particularly useful in treatment of cancers comprising certain mutations (e.g., APC-mutant colorectal cancers), which may not be effectively targeted by available cancer therapeutics, or in treatment of subjects comprising cancers which have developed resistance to currently available inhibitory cancer therapeutics. Without wishing to be bound by any particular theory, exemplary compounds, compositions, and methods described herein can, among other things, provide anti-cancer properties and treatment of various cancers through the hyperactivation of cellular pathways, e.g., Wnt signaling pathway. See Chang et al. Nat Genet. 2023 Sep 25. [000160] In some embodiments, the present disclosure provides methods of hyperactivating an cellular pathway in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to a system. In some embodiments, the present disclosure provides methods of hyperactivating an oncogenic pathway in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to a system. In some embodiments, the present disclosure provides methods of hyperactivating a Wnt signaling pathway in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to a system. In some embodiments, the present disclosure provides methods of causing death of a cancer cell, comprising hyperactivating a cellular pathway in the cancer cell. In some embodiments, the present disclosure provides methods of causing death of a cancer cell, comprising hyperactivating an oncogenic pathway in the cancer cell. In some embodiments, the present disclosure provides methods of causing death of a cancer cell, comprising hyperactivating a Wnt signaling pathway in the cancer cell. [000161] In some embodiments, the present disclosure provides the insight that compounds which are able to bind at the interface of an E3 ubiquitin ligase protein, e.g., CRBN, and another protein such as, e.g., CK1α, can activate an oncogenic pathway to the point of lethality. Without wishing to be bound by any particular theory, it is believed that compounds of formula I interact with residues of both CK1α and CRBN. In some such embodiments, themoiety of formula I comprises one or more atoms or groups that interact with the side chains of CK1α Lys18, CK1α Arg21, CRBN Glu377, and / or CRBN His353. In certain embodiments, Ring A or a substituent on Ring A (i.e., an Rx group) comprises at least one atom that interactswith CK1α Arg21. In some embodiments, Ring B comprises at least one atom that interacts with CK1α Lys18, CRBN Glu377, and / or CRBN His353. [000162] In some embodiments, the present disclosure provides a method of activating a cellular pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some embodiments, a cellular pathway is Wnt signaling pathway. In some embodiments, the present disclosure provides a method of activating an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some embodiments, the oncogenic pathway is a Wnt-mediated pathway. In some embodiments, a method described herein comprises administering or delivering to a subject (or contacting a biological sample with) a compound selected from those in Table 1. In some embodiments, a method described herein comprises administering or delivering to a subject (or contacting a biological sample with) a compound selected from those in Tables 1 and 2. [000163] In some embodiments, the present disclosure provides a method of modulating association of CK1α polypeptides and CRBN polypeptides in a system, comprising administering or delivering to the system an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of increasing association of CK1α polypeptides and CRBN polypeptides in a system, comprising administering or delivering to the system an effective amount of a provided compound or composition thereof to the system. [000164] Without wishing to be bound by any theory, the stabilization of interactions between CK1α polypeptides and CRBN polypeptides may increase such interactions and the degradation of CK1α polypeptides. In some embodiments, the present disclosure provides a method of modulating level of CK1α polypeptide in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of decreasing level of CK1α polypeptide in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of modulating level of CK1α activity in a system, comprising administering or delivering to the system an effective amount of a provided compound orcomposition thereof to the system. In some embodiments, the present disclosure provides a method of decreasing level of CK1α activity in a system, comprising administering or delivering to the system an effective amount of a provided compound or composition thereof to the system. [000165] Without wishing to be bound by any particular theory, decreasing level of CK1α polypeptides and / or activity in a system may decrease active destruction complexes, which may increase level of Wnt pathway activation by decreasing β-catenin degradation. In some embodiments, the present disclosure provides a method of modulating level of Wnt pathway activation in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of increasing Wnt pathway activation in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of modulating level of β-catenin degradation in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of decreasing level of β-catenin degradation in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of modulating level of β-catenin in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of increasing level of β-catenin in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of modulating expression of Wnt pathway target genes in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. In some embodiments, the present disclosure provides a method of increasing expression of Wnt pathway target genes in a system, comprising administering or delivering an effective amount of a provided compound or composition thereof to the system. [000166] In some embodiments, the present disclosure provides a method of causing death of a cancer cell. In some embodiments, the present disclosure provides a method of causing death of a cancer cell, comprising contacting the cancer cell with an effective amount of a provided compound. In some embodiments, the present disclosure provides a method of causingdeath of a cancer cell, comprising contacting the cancer cell with an effective amount of a compound of Formula I. In some embodiments, the present disclosure provides a method of causing death of a cancer cell, comprising contacting the cancer cell with an effective amount of a compound of Table 1. In some embodiments, the present disclosure provides a method of causing death of a cancer cell, comprising contacting the cancer cell with an effective amount of a compound of Table 2. In some embodiments, a cancer cell is a cancer cell in a system. In some embodiments, a cancer cell is a cancer cell in a subject. [000167] In some embodiments, a system comprises CK1α polypeptides. In some embodiments, a system comprises CRBN polypeptides. In some embodiments, a system comprises CK1α polypeptides and CRBN polypeptides. In some embodiments, a system expresses CK1α polypeptides. In some embodiments, a system expresses CRBN polypeptides. In some embodiments, a system expresses CK1α polypeptides and CRBN polypeptides. [000168] In some embodiments, a system comprises an in vitro system. In some embodiments, a system is an in vitro system. In some embodiments, a system comprises an in vivo system. In some embodiments, a system is an in vivo system. [000169] In some embodiments, a system comprises a cell. In some embodiments, a system is a cell. In some embodiments, a cell is a tumor cell. In some embodiments, a cell is a cancer cell. In some embodiments, a system comprises a tissue. In some embodiments, a system is a tissue. In some embodiments, a system comprises a tumor. In some embodiments, a system is a tumor. In some embodiments, a system comprises an organ. In some embodiments, a system is an organ. In some embodiments, a system comprises an organism. In some embodiments, a system is an organism. In some embodiments, a system is a subject. In some embodiments, a system is an animal. In some embodiments, a system is a mammal, e.g., a mouse, a rat, a rabbit, a pig, a dog, a non-human primate, e.g., a monkey. In some embodiments, a system is a human. [000170] In some embodiments, a level is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% compared to absence of a provided compound or composition and / or presence of a reference compound or composition. In some embodiments, a level is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%compared to absence of a provided compound or composition and / or presence of a reference compound or composition. In some embodiments, such a reduction is achieved in a system, e.g., using various suitable assays (e.g., in vitro assays (e.g., in vitro cell-based assays), assays described in, e.g., the Examples). In some embodiments, a reference compound associates with CK1α and / or CRBN. In some embodiments, a reference compound binds CK1α and / or CRBN. In some embodiments, a reference compound is a compound disclosed in a Table herein. In some embodiments, a reference compound is a compound disclosed in Table 1. In some embodiments, a reference compound is a compound disclosed in Table 2. [000171] In some embodiments, the present disclosure provides methods using provided technologies (e.g., compounds, compositions). In some embodiments, a method comprises administering or delivering a compound or composition thereof described herein. In some embodiments, a method comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein. In some embodiments, a method comprises administering or delivering a compound or composition thereof described herein and one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. In some embodiments, a method comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein and a therapeutically effective amount of one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. [000172] In some embodiments, the present disclosure provides methods of treating, e.g., a condition, disorder, or disease using provided technologies (e.g., compounds, compositions). In some embodiments, a method of treating a condition, disorder, or disease comprises administering or delivering a compound or composition thereof described herein. In some embodiments, a method of treating a condition, disorder, or disease comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein. In some embodiments, a method of treating a condition, disorder, or disease comprises administering or delivering a compound or composition thereof described herein and one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. In some embodiments, a method of treating a condition, disorder, or disease comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein and a therapeutically effective amount of one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. In some embodiments, a method of treating a cancercomprises administering or delivering a compound or composition thereof described herein. In some embodiments, a method of treating a cancer comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein. In some embodiments, a method of treating a cancer comprises administering or delivering a compound or composition thereof described herein and one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. In some embodiments, a method of treating a cancer comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein and a therapeutically effective amount of one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. [000173] In some embodiments, a condition, disorder, or disease comprises or is a neoplastic disorder. In some embodiments, a condition, disorder, or disease comprises or is a tumor. In some embodiments, a condition, disorder, or disease comprises or is a cancer, e.g., a cancer described herein. [000174] Provided technologies (e.g., compounds, compositions, methods) may be used in treatment of any cancer or tumor described herein. Cancer is a disease marked by the unregulated cellular growth and division. Such uncontrolled growth may result in a tumor, which may then become cancerous through spreading to other tissues and / or locations in the body. Cancers may be described in a variety of terms, including type of cell that formed the cancer, tissue or organ from which the cancer originated, rate of progression, etc. [000175] In some embodiments, a cancer may specifically be of any of the following non- limiting types: acinar cell carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenoid cystic carcinoma, adrenocortical carcinoma, agnogenic myeloid leukemia, anal cancer, ameoblastoma, appendix cancer, astroblastoma, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, blood cancer, bone cancer, bowel cancer, brain cancer, breast cancer, bronchioloalveolar carcinoma, bronchogenic carcinoma, Burkitt lymphoma, cancer of unknown primary, cervical cancer, cholangiocarcinoma, chondroblastoma, chondrosarcoma, chordoma, chromophobe carcinoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, connective tissue cancer, craniopharyngioma, cutaneous lymphoma, cutaneous T-cell lymphoma, cystadenocarcinoma, ductal carcinoma, endocrine cancer, endometrial cancer, ependymoma, erythroleukemia, esophageal cancer, esophageal squamous cell carcinoma, essential thrombocythemia (ET),esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer, follicular adenocarcinoma, gallbladder cancer, gastric cancer, germ cell cancer, giant and spindle cell carcinoma, glomangiosarcoma, granular cell carcinoma, hairy cell leukemia, head and neck cancer, head and neck squamous cell carcinoma, hemangiopericytoma, hepatocellular carcinoma (HCC), Hodgkin lymphoma, hypopharyngeal cancer, infiltrating duct carcinoma, intraocular melanoma, juxtacortical osteosarcoma, Kaposi sarcoma, kidney cancer, large B-cell lymphoma, laryngeal cancer, leukemia, lip and oral cavity cancer, lipid cell tumor, liver cancer, lung cancer, lung squamous cell carcinoma, lymphoepithelial carcinoma, lymphoma, lymphosarcoma cell leukemia, medulloblastoma, melanoma, Merkel cell carcinoma (MCC), mesothelioma, midline tract carcinoma, mouth cancer, multiple myeloma, myelodysplastic syndrome (MDS), myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal carcinoma, neuroblastoma, nonencapsulating sclerosing carcinoma, non-Hodgkin lymphoma, non-small cell lung cancer, ocular cancer, odontosarcoma, oral cancer, osteosarcoma, ovarian cancer, oxyphilic adenocarcinoma, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilomatrix carcinoma, plasmacytoma, primary bone cancer, primary central nervous system lymphoma, primary effusion lymphoma (PEL), primary liver cancer, primary peritoneal cancer, prostate cancer, rectal cancer, renal cancer, renal cell carcinoma (RCC), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, secondary bone cancer, secondary liver cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell skin cancer, stomach cancer, testicular cancer, throat cancer, thymic carcinoma, thymoma, thyroid cancer, trabecular adenocarcinoma, transitional cell cancer, transitional cell carcinoma, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine cancer, uterine sarcoma, urothelial cancer, vaginal cancer, or vulvar cancer. [000176] In some embodiments, a cancer comprises one or more particular mutations. In some embodiments, a cancer comprises one or more mutations of a component (e.g., a gene or protein encoded thereby) of a Wnt signaling pathway. In some embodiments, a cancer comprises one or more activating mutations of a component (e.g., a gene or protein encoded thereby) of a Wnt signaling pathway. In some embodiments, an activating mutation increases Wnt signaling pathway activation. In some embodiments, an activating mutation decreases degradation of β-catenin. In some embodiments, an activating mutation is a mutation in β-catenin or a mutation of a deconstruction complex gene or protein encoded thereby, e.g., APC, GSK3, Axin1, Axin2, CK1α, ZNRF3, or RNF43. In some embodiments, a cancer comprises one or more mutations of APC. In some embodiments, a cancer comprises one or more mutations of a p53 / MDM2 / MDMX pathway. In some embodiments, a cancer comprises one or more mutations of p53. [000177] In some embodiments, a cancer is a Wnt-mediated cancer. In some embodiments, a cancer is an APC-mediated cancer. In some embodiments, a cancer is selected from colorectal cancer (CRC) (e.g., APC colorectal cancer), small intestine (small bowel) cancer, thyroid cancer, brain cancer, pancreatic cancer, bile duct cancer, and hepatoblastoma. [000178] In some embodiments, a cancer is a p53-mediated cancer. In some embodiments, a cancer is a leukemia or a lymphoma. In some embodiments, a cancer is selected from primary effusion lymphoma (PEL), myelodysplastic syndrome (MDS), or acute myeloid lymphoma (AML). [000179] In some embodiments, the present disclosure also provides a method of treating a cancer, the method comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [000180] In some embodiments, a subject is an animal. In some embodiments, a subject is a mammal. In some embodiments, a subject is a mouse. In some embodiments, a subject is a rat. In some embodiments, a subject is a pig. In some embodiments, a subject is a dog. In some embodiments, a subject is a non-human primate, e.g., a monkey. In some embodiments, a subject is a human. In some embodiments, a subject is an adult, e.g., an adult human. In some embodiments, a subject is a child, e.g., a human child. In some embodiments, a subject is susceptible to or suffering from a condition, disorder, or disease described herein. In some embodiments, a subject is susceptible to or suffering from a cancer, e.g., a cancer described herein. [000181] In some embodiments, a provided compound is a compound of Formula I. In some embodiments, a provided compound is a compound of Table 1 or Table 2. In some embodiments, a provided compound is a compound of Table 1. In some embodiments, a compound described herein is a compound of Table 2. In some embodiments, a compound described herein is a compound of Formula I. In some embodiments, a compound describedherein is a compound of Table 1 or Table 2. In some embodiments, a compound described herein is a compound of Table 1. In some embodiments, a compound described herein is a compound of Table 2. [000182] Compounds and compositions described herein may be administered or delivered to a subject by any suitable route known in the art. For example, in some embodiments, a compound or composition described herein is administered by an auricular, buccal, conjunctival, cutaneous, endosinusial, endotracheal, enteral, epidural, inhalational, intraabdominal, intraarterial, intraarticular, intrabiliary, intrabronchial, intrabursal, intracapsular, intracardiac, intracaudal, intracerebral, intracervical, intracisternal, intracorneal, intracoronary, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraorbital, intraosseous, intraovarian, intraparenchymal, intrapericardial, intraperitoneal, intrapleural, intraspinal, intrasternal, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intraventricular, intravesical, intravitreal, laryngeal, nasal, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, peripheral, rectal, subarachnoid, subcapsular, subconjunctival, subcutaneous, subcuticular, sublingual, submucosal, topical, transdermal, transmucosal, transnasal, transtracheal, transtympanic, urethral, or vaginal route, or any combination thereof. [000183] In some embodiments, provided compounds or compositions thereof (e.g., pharmaceutical compositions thereof) may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Implantable devices coated with a compound of this disclosure are another embodiment of the present disclosure. 7. Combination Therapies [000184] In some embodiments, the present disclosure provides technologies (e.g., compositions, methods) for combination therapy, for example with other therapeutic agents and / or medical procedures. In some embodiments, a subject is administered a provided compound or composition and one or more additional treatments (including, e.g., a therapeutic agent or method).[000185] In some embodiments, an additional treatment comprises or is surgery. In some embodiments, an additional treatment comprises or is radiation. [000186] In some embodiments, an additional treatment comprises or is one or more additional therapeutic agents. In some embodiments, an additional therapeutic agent comprises or is one or more cancer therapeutics described herein. In some embodiments, an additional therapeutic agent comprises or is an antibody or antigen binding fragment thereof. In some embodiments, an additional therapeutic agent comprises or is a cell therapy, e.g., a genetically modified cell therapy or an engineered cell therapy. In some embodiments, an additional therapeutic agent comprises or is a chemotherapeutic. In some embodiments, an additional therapeutic agent comprises or is a hormone. In some embodiments, an additional therapeutic agent comprises or is radiation. In some embodiments, an additional therapeutic agent comprises or is a vaccine. In some embodiments, an additional therapeutic agent comprises or is a nucleic acid. In some embodiments, an additional therapeutic agent comprises or is an oligonucleotide. In some embodiments, an additional therapeutic agent comprises or is a RNAi molecule, e.g., a miRNA, a shRNA, a siRNA. In some embodiments, an additional therapeutic agent comprises or is a lipid. In some embodiments, an additional therapeutic agent comprises or is a polypeptide or a portion thereof. In some embodiments, an additional therapeutic agent comprises or is a protein or a portion thereof. In some embodiments, an additional therapeutic agent comprises or is a lipid. [000187] In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a condition, disorder, or disease when administered alone. In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a cancer when administered alone. In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a condition, disorder, or disease when administered in combination with a provided compound or composition. In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a cancer when administered in combination with a provided compound or composition. [000188] Various cancer therapeutics are known in the art and can be used with provided technologies (e.g., compounds, compositions, methods) described herein. In some embodiments, a cancer therapeutic comprises or is an antibody or antigen-binding fragment thereof. In someembodiments, cancer therapeutic comprises or is a chemotherapeutic agent. In some embodiments, a cancer therapeutic comprises or is a hormone. In some embodiments, a cancer therapeutic comprises or is radiation. In some embodiments, a cancer therapeutic comprises or is a vaccine. In some embodiments, a cancer therapeutic is a biologic agent. In some embodiments, a cancer therapeutic comprises or is a cellular therapeutic, e.g., a stem cell, an engineered cell, a genetically modified cell. [000189] In some embodiments, one or more cancer therapeutics are used in combination with a compound or composition described herein. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject in combination with a compound or composition described herein. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject prior to administering or delivering a compound or composition described herein to the subject. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject at the same time as administering or delivering a compound or composition described herein to the subject. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject following administering or delivering a compound or composition described herein to the subject. [000190] Various antibodies known in the art can be used with provided technologies (e.g., compounds, methods) described herein. In some embodiments, a cancer therapeutic comprises or is an antibody or an antigen-binding fragment thereof. In some embodiments, an antibody comprises or is a monoclonal antibody. In some embodiments, an antibody comprises or is a bispecific antibody. In some embodiments, an antibody comprises or is a conjugated antibody. In some embodiments, an antibody comprises or is an antibody-drug conjugate (ADC). In some embodiments, an antibody comprises or is a labeled antibody. In some embodiments, a labeled antibody comprises or is a radiolabeled antibody. [000191] Various targets associated with cancer are known in the art and can be targeted with an antibody or an antigen-binding fragment thereof. In some embodiments, an antibody comprises or is an anti-4-1BB antibody, an anti-5’-nucleotidase antibody, an anti-5T4 antibody, an anti-ALK1 antibody, an anti-AFP antibody, an anti-angiopoietin-2 antibody, an anti-AXL antibody, an anti-BAFF antibody, an anti-BCMA antibody, an anti-c-Met antibody, an anti- CA125 antibody, an anti-CCR4 antibody, an anti-CCR5 antibody, an anti-CD3 antibody, an anti- CD3E antibody, an anti-CD4 antibody, an anti-CD19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD23 antibody, an anti-CD25 antibody, an anti-CD27 antibody, an anti- CD28 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti- CD38 antibody, an anti-CD40 antibody, an anti-CD44 antibody, an anti-CD51 antibody, an anti- CD56 antibody, an anti-CD70 antibody, an anti-CD74 antibody, an anti-CD79B antibody, an anti-CD80 antibody, an anti-CD123 antibody, an anti-CD134 antibody, an anti-CD152 antibody, an anti-CD200 antibody, an anti-CD221 antibody, an anti-CD276 antibody, an anti-CD279 antibody, an anti-CD319 antibody, an anti-CEA antibody, an anti-CEACAM5 antibody, an anti- CLDN18 antibody, an anti-CSF1 antibody, an anti-CSF1R antibody, an anti-CSF2 antibody, an anti-CTGF antibody, an anti-CTLA4 antibody, an anti-CXCR4 antibody, an anti-DLL3 antibody, an anti-DLL4 antibody, an anti-DR5 antibody, an anti-EGFL7 antibody, an anti-EGFR antibody, an anti-ENG antibody, an anti-EpCAM antibody, an anti-FAP antibody, an anti-FGFR2 antibody, an anti-FOLR1 antibody, an anti-GCPII antibody, an anti-GD2 ganglioside antibody, an anti-GPC3 antibody, an anti-GPNMB antibody, an anti-GPRC5D antibody, an anti-GUCY2C antibody, an anti-HER1 antibody, an anti-HER2 antibody, an anti-HER3 antibody, an anti- HGFR antibody, an anti-IGF-2 antibody, an anti-IL-1α antibody, an anti-IL-2 antibody, an anti- IL-6 antibody, an anti-IL-13 antibody, an anti-MIF antibody, an anti-MSLN antibody, an anti- MUC1 antibody, an anti-MUC5AC antibody, an anti-Notch-1 antibody, an anti-PCDC1 antibody, an anti-PCDP1 antibody, an anti-PCSK9 antibody, an anti-PD-1 antibody, an anti-PD- L1 antibody, an anti-PDGFRA antibody, an anti-PTK7 antibody, an anti-ROR1 antibody, an anti-SDC1 antibody, an anti-SLAMF7 antibody, an anti-SLITRK6 antibody, an anti-STEAP1 antibody, an anti-TAG-72 antibody, an anti-TEM antibody, an anti-TGFβ antibody, an anti- TIGIT antibody, an anti-TN-C antibody, an anti-TRAIL-R1 antibody, an anti-TRAIL-R2 antibody, an anti-TWEAKR antibody, an anti-TYRP1 antibody, an anti-VEGF-A antibody, an anti-VEGFR-1 antibody, an anti-VEGFR-2 antibody, or an anti-vimentin antibody. [000192] Various antibodies that may be used as a cancer therapeutic are described in the art. For example, in some embodiments, an antibody comprises or is abagovomab, abituzumab, adalimumab, adecatumumab, alemtuzumab, alirocumab, amatuximab, amivantamab, anatumomab mafentaox, andecaliximab, anetumab ravtansine, apolizumab, arcitumomab, ascrinvacumab, atezolizumab, avelumab, bavituximab, belimumab, bemarituzumab, benralizumab, bermekimab, bevacizumab, bezlotoxumab, bivatuzumab, blinatumomab, brentuximab vedotin, brodalumab, brolucizumab, brontictuzumab, burosumab, cabiralizumab,camidanlumab tesirine, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, capromab, carlumab, carotuximab, catumaxomab, cemiplimab, certolizumab pegol, cetrelimab, cetuximab, cibisatamab, cirmtuzumab, citatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab pelidotin, coltuximab ravtansine, conatumumab, cusatuzumab, dancetuzumab, dalotuzumab, daratumumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, derlotuximab biotin, detumomab, dinutuximab, dinutuximab beta, dostarlimab, drozitumab, duligotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, edrecolomab, elgemtumab, elotuzumab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enoblituzumab, ensituximab, epcoritamab, epratuzumab, erenumab, ertumaxomab, etaracizumab, evolocumab, figitumumab, flanvotumab, flotetuzumab, fremanezumab, fresolimumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gatipotuzumab, gemtuzumab ozogamicin, girentuximab, glembatumumab vedotin, glofitamab, golimumab, guselkumab, ibalizumab, ibritumomab tiuxetan, icrucumab, idarucizumab, igovomab, iladatuzumab vedotin, imalumab, imaprelimab, imgatuzumab, indatuximab ravtansine, indium altumomab pentetate, indusatumab vedotin, inebilizumab, infliximab, inolimomab, inotuzumab ozogamicin, intetumumab, iodine tositumomab, ipilimumab, iratumumab, isatuximab, istiratumab, ixekizumab, labetuzumab, lacnotuzumab, ladiratuzumab vedotin, lanadelumab, lenzilumab, leronlimab, lexatumumab, lifastuzumab vedotin, loncastuximab tesirine, losatuxizumab vedotin, lilotomab satetraxetan, lintuzumab, lirilumab, lorvotuzumab mertansine, lucatumumb, lumretuzumab, mapatumumab, margetuximab, matuzumab, mepolizumab, metelimumab, milatuzumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, mosunetuzumab, moxetumomab pasudodox, nacolomab tafenatox, naptumomab estafenatox, narnatumab, natalizumab, navicixizumab, naxitamab, necitumumab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, ofatumumab, olaratumab, oleclumab, omalizumab, omburtamab, onartuzumab, ontuxizumab, oportuzumab monatox, oregovomab, otlertuzumab, palivizumab, pamrevlumab, panitumumab, pankomab, parsatuzumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, pertuzumab, pidilizumab, pinatuzumab vedotin, pintumumab, polatuzumab vedotin, pritumumab, racotumomab, radretumab, ramucirumab, ranibizumab, ravulizumab,relatlimab, reslizumab, retifanlimab, rilotumumab, risankizumab, rituximab, robatumumab, romosozumab, rosmantuzumab, rovalpituzumab tesirine, sacituzumab govitecan, samalizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, sibrotuzumab, siltuximab, sintilimab, sitratumab vedotin, sofituzumab vedotin, solitomab, spartalizumab, tabalumab, tacatuzumab tetraxetan, tafasitamab, talacotuzumab, talquetamab, taplitumomab paptox, tarextumab, tavolimab, teclistamab, telisotuzumab, telisotuzumab vedotin, tenatumomab, tepoditamab, tetulomab, tigatuzumab, tildrakizumab, timigutuzumab, tiragotumab, tislelizumab, tisotumab vedotin, tocilizumab, tomuzotuximab, tositumomab, tovetumab, trastuzumab, trastuzumab deruxtecan, trastuzumab duocarmazine, trastuzumab emtansine, tremelimumab, tucotuzumab celmoleukin, ublituximab, ulocuplumab, urelumab, ustekinumab, utomilumab, vadastuximab talirine, vandortuzumab vedotin, vantictumab, vanucizumab, varisacumab, varlilumab, vedolizumab, veltuzumab, vesencumab, volociximab, vonlerolizumab, vorsetuzumab mafodotin, votumumab, zalutumumab, zanolimumab, zatuximab, zenocutuzumab, or zolbetuximab, or an antigen-binding fragment thereof, or any combination thereof. [000193] In some embodiments, a cancer therapeutic comprises or is a chemotherapeutic agent. Various chemotherapeutic agents are known in the art and can be used with provided technologies (e.g., compounds, compositions, methods) described herein. For example, in some embodiments, compounds of the present disclosure, or a pharmaceutically acceptable composition thereof, are administered in combination with chemotherapeutic agents to treat proliferative diseases and cancer. [000194] In some embodiments, a chemotherapeutic agent comprises or is an alkylating agent. In some embodiments, a chemotherapeutic agent comprises or is an antimetabolite. In some embodiments, a chemotherapeutic agent comprises or is a cytidine analog. In some embodiments, a chemotherapeutic agent comprises or is an antifolate. In some embodiments, a chemotherapeutic agent comprises or is a nucleoside analogue. In some embodiments, a chemotherapeutic agent comprises or is a purine analog. In some embodiments, a chemotherapeutic agent comprises or is a pyrimidine agent. In some embodiments, a chemotherapeutic agent comprises or is an antimicrotubular agent. In some embodiments, a chemotherapeutic agent comprises or is topoisomerase inhibitor, e.g., a topoisomerase I inhibitor, a topoisomerase II inhibitor. In some embodiments, a chemotherapeutic agent comprises or is an anthracycline. In some embodiments, a chemotherapeutic agent comprises or is a taxane. Insome embodiments, a chemotherapeutic agent comprises or is an antibiotic. In some embodiments, a chemotherapeutic agent comprises or is a proteasome inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a platinum-containing compound. In some embodiments, a chemotherapeutic agent comprises or is a kinase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a tyrosine kinase inhibitor. In some embodiments, a Bcr-Abl kinase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is an EGFR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a HER2 inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a JAK inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a mTOR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a PDGFR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a VEGFR inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a retinoid. In some embodiments, a chemotherapeutic agent comprises or is a histone deacetylase inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a DNA replication inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a DNA synthesis inhibitor. In some embodiments, a chemotherapeutic agent comprises or is an RNA synthesis inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a cytoskeletal disruptor. In some embodiments, a chemotherapeutic agent comprises or is a proteasome inhibitor. In some embodiments, a chemotherapeutic agent comprises or is a plant alkaloid. In some embodiments, a chemotherapeutic agent comprises or is a cell cycle disruptor. [000195] Various chemotherapeutic agents that may be used as a cancer therapeutic are described in the art. For example, in some embodiments, a chemotherapeutic agent is 5- fluorouracil, aclarubicin, actinomycin D, afatinib, aflibercept, alitretinoin, altretamine, anagrelide, arsenic trioxide, asparaginase, axitinib, azacitidine, belotecan, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, camptothecin, capecitabine, carboplatin, carmofur, carmustine, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunomycin, daunorubicin, decitabine, diaziquone, docetaxel, doxorubicin, entionstat, epirubicin, erlotinib, estramustine, etoposide, everolimus, exatecan, floxuridine, fludarabine, fluorouracil, folinic acid, fotemustine, gefitinib, gemcitabine, hexamethylmelamine, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, isotretinoin, ixabepilone, lapatinib, larotaxel,lenalidomide, lomustine, mechlorethamine, melphalan, merbarone, mercaptopurine, methotrexate, mitomycin, mitomycin C, mitoxantrone, mitozolomide, mustine, nedaplatin, nelarabine, nilotinib, N-nitroso-N-methylurea, novobiocin, oxalipatin, paclitaxel (e.g., solvent- based paclitaxel, protein-bound paclitaxel, nanoparticle albumin-bound paclitaxel), panobinostat, pazopanib, pemetrexed, pentostatin, pirarubicin, pomalidomide, ponatinib, prednisolone, prednisone, procarbazine, raltitrexed, regorafenib, romidepsin, ruxolitinib, semustine, sorafenib, streptozotocin, sunitinib, tamibarotene, tegafur, temozolomide, temsirolimus, teniposide, tesetaxel, thalidomide, thioguanine, thiotepa, topotecan, tretinoin, valproate, valrubicin, vandetanib, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, or zabadinostat, or a derivative thereof, or any combination thereof. [000196] Other compounds that may be effective in treating cancer, that are suitable for use with the provided technologies (e.g., compounds, compositions, methods) of the present disclosure, are known in the art and are described, for example, in Anand U., et al. Gene Dis. 2022 Mar 18;10(4):1367-1401; Huang C., et al. Biomedicine (Taipei).2017 Dec;7(4):23; Amjad M. T., et al., StatsPearls, 2023 Feb 27. [000197] In some embodiments, a provided compound and an additional therapeutic agent are administered or delivered in the same composition. In some embodiments, a provided compound and an additional therapeutic are administered or delivered in separate compositions. [000198] In some embodiments, an additional therapeutic agent may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. In some embodiments, an additional therapeutic agent may be administered separately from a provided compound or composition thereof, as part of a multiple dosage regimen. If administered as part of a multiple dosage regime, a provided compound or composition thereof and an additional therapeutic agent may be administered or delivered simultaneously or sequentially. For example, in some embodiments, a provided compound may be administered simultaneously with the additional therapeutic agent. In some embodiments, a provided compound may be administered prior to an additional therapeutic agent (e.g., an inhibitor of a particular cancer pathway). In some embodiments, a provided compound is administered four, six, eight, or twelve hours prior to the additional therapeutic agent. In some embodiments, a provided compound is administered one, two, three, four, five, six, or seven days prior to the additional therapeutic agent. In some embodiments, a provided compound is administered one,two, three, or four weeks prior to the additional therapeutic agent. In some embodiments, a provided compound and an additional therapeutic agent are administered in a multi-dose regimen such as A→(B→A→)nB, wherein A is a provided compound, B is the additional therapeutic agent, n is 0-20 or more, and “” is the time period between each dose of A and B. [000199] Among other things, compounds of formula I and compositions thereof may be administered or delivered to a subject who previously was administered or delivered any of the additional therapeutic agents described herein and whose cancer may exhibit one or more signs of resistance to the previously administered additional therapeutic agent. In some embodiments, a subject comprises a cancer resistant to one or more additional therapeutic agents. In some embodiments, a subject comprises a cancer resistant to one or more cancer therapeutic agents. In some embodiments, a subject comprises a cancer resistant to one or more additional therapeutic agents which were previously administered or delivered to the subject. [000200] The amount of both, a compound of formula I and an additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of a provided compound can be administered. [000201] In some embodiments, in a composition which comprises a provided compound and an additional therapeutic agent, a provided compound and an additional therapeutic agent may act synergistically. Therefore, for example, an amount of additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only the additional therapeutic agent. In some embodiments, in such compositions a dosage of between 0.01 – 100 mg / kg body weight / day of an additional therapeutic agent may be administered. [000202] An amount of additional therapeutic agent present in a composition of this disclosure will be no more than an amount that would normally be administered in a composition comprising that additional therapeutic agent as the only active agent. Preferably, an amount of an additional therapeutic agent in a presently disclosed composition will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.EXAMPLES [000203] Example 1. Synthesis of Exemplary Compounds [000204] Example 1.1. General procedure for the synthesis of compounds of Formula I wherein Ring B is a 1,2,3-triazolyl ring:[000205] In a round-bottom flask, to a stirred solution of alkyne (2.0 equiv) and 3-(5-azido- 1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (1.0 equiv) in water (0.6M) and DMSO (0.3M) were added CuSO4.5H2O (0.2 equiv) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4- dihydroxy-2,5-dihydrofuran-2-one (0.6 equiv) in portions at room temperature under argon atmosphere and stirred for 4 days at room temperature. The resulting mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by Prep-HPLC. [000206] Example 1.2. Synthesis of 3-{5-[1-(6-methoxynaphthalen-2-yl) pyrazol-3-yl]- 1-oxo-3H-isoindol-2-yl} piperidine-2,6-dione (I-19)[000207] Synthesis of 1-[(4-methoxyphenyl) methyl]-3-[1-oxo-5-(1H-pyrazol-3-yl)-3H- isoindol-2-yl]piperidine-2,6-dione[000208] Into a 50 mL round-bottom flask were added 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (750 mg, 3.865 mmol, 1.1 equiv), dioxane (4 mL) and Cs2CO3 (3.43 g, 10.541 mmol, 3.0 equiv) at room temperature under argon atmosphere. To the above mixture was added Pd(dppf)Cl2(1.03 g, 1.405 mmol, 0.4 equiv) and 3-(5-bromo-1-oxo-3H- isoindol-2-yl)-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (1557.66 mg, 3.514 mmol, 1.0 equiv). The resulting mixture was stirred for 24 h at 100°C. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL), then extracted with EA(3x25mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water, 20% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 1-[(4-methoxyphenyl) methyl]-3-[1-oxo-5-(1H-pyrazol-3-yl)-3H- isoindol-2-yl] piperidine-2,6-dione (330 mg, 21.82%) as an off-white solid. [000209] LC-MS: (ES,m / z): [M+H]+:431 [000210]1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.26 – 7.92 (m, 2H), 7.90 – 7.67 (m, 2H), 7.21 (dd, J = 8.4, 3.0 Hz, 2H), 6.94 – 6.78 (m, 2H), 5.25 (dd, J = 13.4, 5.0 Hz, 1H), 4.77 (q, J = 14.3 Hz, 2H), 4.53 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 3.72 (s, 3H), 3.09 (ddd, J = 18.2, 13.7, 5.3 Hz, 1H), 2.88 – 2.73 (m, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.14 – 1.98 (m, 1H). [000211] Synthesis of 3-(5-[1-(6-methoxynaphthalen-2-yl) pyrazol-3-yl]-1-oxo-3H- isoindol-2-yl-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione[000212] Into a 100 mL round-bottom flask were added 1-[(4-methoxyphenyl) methyl]-3- [1-oxo-5-(1H-pyrazol-3-yl)-3H-isoindol-2-yl] piperidine-2,6-dione (330 mg, 0.767 mmol, 1.0 equiv), 2-bromo-6-methoxynaphthalene (727.05 mg, 3.068 mmol, 4.0 equiv) and dioxane (5 mL) at room temperature under argon atmosphere. To the above mixture was added CuI (29.20 mg, 0.153 mmol, 0.2 equiv) and K2CO3 (211.90 mg, 1.534 mmol, 2.0 equiv) and methyl[2- (methylamino)ethyl] amine (54.06 mg, 0.614 mmol, 0.8 equiv) at room temperature. Theresulting mixture was stirred for 18 h at 110 °C. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 20% to 95% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(5-[1-(6-methoxynaphthalen-2-yl) pyrazol-3-yl]-1-oxo-3H-isoindol-2-yl-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (300 mg, 40.02%) as an off-white solid. [000213] LC-MS: (ES,m / z): [M+H]+:587 [000214] Synthesis of 3-{5-[1-(6-methoxynaphthalen-2-yl) pyrazol-3-yl]-1-oxo-3H- isoindol-2-yl} piperidine-2,6-dione[000215] Into a 25 mL 2-necked round-bottom flask were added 3-{5-[1-(6- methoxynaphthalen-2-yl) pyrazol-3-yl]-1-oxo-3H-isoindol-2-yl}-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (300 mg, 0.307 mmol, 1 equiv, 60%) and TFA (2 mL) at room temperature. To the above mixture was added TfOH (0.2 mL) at 0°C under argon atmosphere. The resulting mixture was stirred for 2 h at 70°C. The reaction was monitored by LCMS. The resulting mixture was diluted with EA (10 mL). The reaction was quenched with NaHCO3(aq) at 0°C and neutralized to pH 7. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 32% B to58% B in 10 min; Wave Length: 254nm / 200nm; RT1(min): 8.33) to afford 3-{5-[1-(6-methoxynaphthalen-2-yl) pyrazol-3-yl]-1-oxo-3H-isoindol-2-yl} piperidine-2,6-dione (11.4 mg, 7.78%) as a white solid. [000216] LC-MS: (ES,m / z): [M+H]+:467[000217]1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.22 (s, 1H), 8.18 – 8.08 (m, 2H), 7.97 (dd, J = 20.1, 9.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.32 – 7.17 (m, 2H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.62 – 4.35 (m, 2H), 3.91 (s, 3H), 3.05 – 2.85 (m, 1H), 2.63 (d, J = 17.6 Hz, 1H), 2.48 – 2.37 (m, 1H), 2.12 – 1.98 (m, 1H). [000218] Example 1.3. Synthesis of 3-(5-[3-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]- 1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (I-22)[000219] Synthesis of (E)-3-(dimethylamino)-1-(6-methoxynaphthalen-2-yl)prop-2-en-1- one[000220] Into a 50 mL round-bottom flask were added 1-(6-methoxynaphthalen-2- yl)ethanone (500 mg, 2.497 mmol, 1 equiv), N, N-dimethylformamide dimethyl acetal (892.67 mg, 7.491 mmol, 3.0 equiv) and toluene (10 mL) at room temperature. The resulting mixture was stirred for overnight at 80oC. Desired product could be detected by LCMS, and the resulting mixture was concentrated under reduced pressure, then the reaction was quenched by the addition of Water (10mL) at room temperature. The resulting mixture was extracted with EA (3 x 20mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 550 mg (E)-3-(dimethylamino)-1-(6-methoxynaphthalen-2-yl)prop-2-en-1-one as a white solid. The crude product was used in the next step directly without further purification. [000221] LC-MS: (ES, m / z): [M+1]+=256.15 [000222]1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 1.7 Hz, 1H), 8.02 – 7.92 (m, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 12.2 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 8.9, 2.5 Hz, 1H), 5.99 (d, J = 12.3 Hz, 1H), 3.90 (s, 3H), 3.25 (s, 3H), 2.96 (s, 3H). [000223] Synthesis of 3-(5-hydrazinyl-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione[000224] 3-(5-Amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (500 mg, 1.929 mmol, 1.0 equiv) was initially charged in water (4 ml) in a 50 mL round bottom flask, concentrated hydrochloric acid (8 ml) was added and the mixture is stirred at room temperature for 30 min. The reaction mixture was cooled to 0oC, and a solution of sodium nitrite (199.59 mg, 2.893 mmol, 1.5 equiv) in water (4 ml) was slowly added dropwise. The mixture was stirred at 0oC. for one hour, then tin(II) chloride dihydrate (1.54 g, 6.752 mmol, 3.5 equiv) in concentrated hydrochloric acid (15 ml) was added dropwise at 0oC. The mixture was stirred initially at 0oC. for 30 min and then at room temperature for 1.5 h. The reaction mixture was diluted with water (10 ml). The filtrate was poured into ice-water, adjusted to pH 8-9 using semi-concentrated aqueous sodium hydroxide solution and extracted twice with dichloromethane. The organic phases were combined and dried over sodium sulfate. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (92% / 8%) to afford 3-(5-hydrazinyl-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (51 mg, 9.64%) as a yellow solid. The product was used immediately in the next step. [000225] LC-MS: (ES,m / z): [M+1]+=275.15 [000226] Synthesis of 3-(5-[3-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione[000227] Into a 25mL round-bottom flask were added 3-(5-hydrazinyl-1-oxo-3H-isoindol- 2-yl) piperidine-2,6-dione (50 mg, 0.182 mmol, 1.0 equiv), (2E)-3-(dimethylamino)-1-(6- methoxynaphthalen-2-yl) prop-2-en-1-one (46.54 mg, 0.182 mmol, 1.0 equiv), acetic acid (1.09 mg, 0.018 mmol, 0.1 equiv) and ethanol (2 mL) at room temperature. The resulting mixture was stirred for 3h at 80oC under nitrogen atmosphere.32% product detected. The reaction wasquenched by the addition of water (20mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 15mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Xcelect CSH Phenyl-Hexyl OBD Column 19*250 mm, 5μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 42% B to 47% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 7.25) to afford 3-(5-[3-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (8.6 mg, 9.85%) as a white solid. [000228] LC-MS: (ES,m / z): [M+1]+=465.20 [000229]1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.95 – 7.73 (m, 4H), 7.68 (dd, J = 5.0, 3.1 Hz, 2H), 7.32 (dt, J = 5.0, 2.0 Hz, 2H), 7.24 – 7.14 (m, 2H), 6.78 (d, J = 1.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.44 (d, J = 17.7 Hz, 1H), 4.31 (d, J = 17.7 Hz, 1H), 3.88 (s, 3H), 2.90 (ddd, J = 17.8, 13.3, 5.2 Hz, 1H), 2.59 (d, J = 16.9 Hz, 1H), 2.47 – 2.28 (m, 1H), 2.10 – 1.95 (m, 1H). [000230] Example 1.4. Synthesis of 3-(5-[4-(6-methoxynaphthalen-2-yl) imidazol-1-yl]- 1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (I-20)[000231] Synthesis of 4-(6-methoxynaphthalen-2-yl)-1H-imidazole[000232] To a solution of 6-methoxynaphthalen-2-ylboronic acid (2.0 g, 9.900 mmol, 1.00 equiv) and 4-iodo-1H-imidazole (2.11 g, 10.890 mmol, 1.10 equiv) in water (20 mL) and toluene (20 mL) in a 100 mL round bottom flask were added benzyltriethylammonium chloride (225.50 mg, 0.990 mmol, 0.10 equiv), cesium fluoride (4511.55 mg, 29.700 mmol, 3.00 equiv) and [1,1'- Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (724.39 mg, 0.990 mmol, 0.10 equiv) .After stirring for overnight at 100oC under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure.70% desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 4-(6-methoxynaphthalen-2-yl)-1H-imidazole (870 mg, 39.19%) as an off-white solid. [000233] LC-MS: (ES,m / z):[M+1]+=225.10 [000234] Synthesis of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)-1-[(4- methoxyphenyl)methyl]piperidine-2,6-dione[000235] Into a 25 mL round-bottom flask were added 3-(5-bromo-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (300 mg, 0.928 mmol, 1 equiv) and N, N-dimethylformamide (5 mL) at room temperature. To the above mixture was added 4-methoxybenzylchloride (159.93 mg, 1.021 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2:3) to afford 3-(5-bromo-1-oxo-3H-isoindol-2-yl)-1-[(4- methoxyphenyl) methyl] piperidine-2,6-dione (350 mg, 85.05%) as a white solid. [000236] LC-MS: (ESI): [M+H] + = 442.95 [000237]1H NMR (300 MHz, DMSO-d6) δ 7.89 (dd, J = 1.7, 0.8 Hz, 1H), 7.70 (m, J = 8.1, 1.2 Hz, 2H), 7.24 – 7.13 (m, 2H), 6.90 – 6.79 (m, 2H), 5.24 (dd, J = 13.4, 5.0 Hz, 1H), 4.85 – 4.67 (m, 2H), 4.49 (d, J = 17.6 Hz, 1H), 4.31 (d, J = 17.6 Hz, 1H), 3.72 (s, 3H), 3.08 (m, J = 18.0, 13.5, 5.4 Hz, 1H), 2.86 – 2.73 (m, 1H), 2.47 – 2.31 (m, 1H), 2.11 – 1.99 (m, 1H). [000238] Synthesis of 3-{5-[4-(6-methoxynaphthalen-2-yl) imidazol-1-yl]-1-oxo-3H- isoindol-2-yl}-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione[000239] To a solution of 4-(6-methoxynaphthalen-2-yl)-1H-imidazole (379.42 mg, 1.692 mmol, 1.50 equiv) in DMSO (6 mL) were added 3-(5-bromo-1-oxo-3H-isoindol-2-yl)-1-[(4- methoxyphenyl) methyl]piperidine-2,6-dione (500 mg, 1.128 mmol, 1.00 equiv), copper iodide (64.44 mg, 0.338 mmol, 0.3 equiv), cesium fluoride (428.34 mg, 2.820 mmol, 2.5 equiv), (1S,2S)-N1, N2-dimethylcyclohexane-1,2-diamine (80.22 mg, 0.564 mmol, 0.5 equiv) in a 5mL vacuum tube filled with Ar at room temperature. The final reaction mixture was irradiated with microwave radiation for 1h at 140°C.39% desired product could be detected by LCMS. The reaction was quenched by the addition of Water (10mL) at room temperature. The resulting mixture was extracted with EA (3 x 15mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA 100%) to afford 3-{5-[4-(6- methoxynaphthalen-2-yl) imidazol-1-yl]-1-oxo-3H-isoindol-2-yl}-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (90 mg, 13.60%) as a brown solid. [000240] LC-MS: (ES,m / z): [M+1]+=587.30 [000241] Synthesis of 3-(5-[4-(6-methoxynaphthalen-2-yl) imidazol-1-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione[000242] Into a 25mL round-bottom flask were added 3-(5-[4-(6-methoxynaphthalen-2-yl) imidazol-1-yl]-1-oxo-3H-isoindol-2-yl-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (45 mg, 0.077 mmol, 1.0 equiv), TFA (2 mL) and TfOH (2 mL) at room temperature. The resulting mixture was stirred for 2h at 70oC under nitrogen atmosphere.75% desired product could be detected by LCMS. The reaction was quenched by the addition of ice water (10mL). The resulting mixture was extracted with ethyl acetate (3 x 15mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS30*150 mm, 5m; Mobile Phase A: Water (10mmol / L ammonium bicarbonate+0.05% aqueous ammonia), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 60% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 6.52) to afford 3-(5-[4-(6-methoxynaphthalen-2-yl) imidazol-1-yl]-1- oxo-3H-isoindol-2-ylpiperidine-2,6-dione (4.2 mg, 11.20%) as a white solid. [000243] LC-MS: (ES,m / z): [M+1]+=467.10 [000244]1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.56 – 8.44 (m, 2H), 8.33 (d, J = 1.7 Hz, 1H), 8.05 (s, 1H), 8.03 – 7.81 (m, 5H), 7.32 (d, J = 2.5 Hz, 1H), 7.17 (dd, J = 8.9, 2.5 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.57 (d, J = 17.6 Hz, 1H), 4.44 (d, J = 17.5 Hz, 1H), 3.89 (s, 3H), 3.03 – 2.85 (m, 1H), 2.64-2.59 (m, 1H), 2.54-2.50(m, 1H), 1.23 (s, 1H). [000245] Example 1.5. Synthesis of 3-(5-(4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-9)[000246] The synthesis of Compound I-9 was completed following the procedure in Example 1.1 using 3-(5-azido-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione and 1-ethynyl-2- methoxybenzene. [000247] LC-MS: (ES,m / z): [M+H]+: 418.14 [000248]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.09 (s, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.21 (q, J = 8.1, 1.9 Hz, 2H), 7.96 (d, J = 8.3 Hz, 1H), 7.41 (t, J = 8.5, 7.4, 1.8 Hz, 1H), 7.20 (d, J = 8.5, 1.1 Hz, 1H), 7.11 (t, J = 7.5, 1.1 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 3.99 (s, 3H), 2.94-2.91 (m, 1H), 2.66-2.57 (m, 1H), 2.49-2.41 (m, 1H), 2.10-1.99 (m, 1H). [000249] Example 1.6. Synthesis of 3-(5-(4-(6-methoxynaphthalen-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-18)[000250] The synthesis of Compound I-18 was completed following the procedure in Example 1.1 using 3-(5-azido-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione and 2-ethynyl-6- methoxynaphthalene. [000251] LC-MS: (ES, m / z): [M+H] + = 468.15 [000252]1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.51 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.10 – 7.87 (m, 4H), 7.38 (s, 1H), 7.23 (d, J = 9.3 Hz, 1H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.66 – 4.45 (m, 2H), 3.90 (s, 3H), 2.99-2.90 (m, 1H), 2.66-2.60 (m, 1H), 2.44-2.40 (m, 1H), 2.07-1.99 (m, 1H). [000253] Example 1.7. Synthesis of 3-(5-(3-(6-methoxynaphthalen-2-yl)-1H-1,2,4- triazol-5-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-44)[000254] Synthesis of 6-methoxynaphthalene-2-carbonitrile[000255] Into a 30 mL sealed tube were added Pd2(dba)3(194.02 mg, 0.337 mmol, 0.04 equiv) and 2-(2-Methoxyphenyl)-1-methyl-3-diphenylphosphino)-1H-indole (142.21 mg, 0.337 mmol, 0.04 equiv) in CH3CN (10 mL) and H2O (10 mL) at 25°C. Then was added 2-bromo-6- methoxynaphthalene (2.0 g, 8.435 mmol, 1 equiv) and potassium tert-butoxide (236.64 mg, 2.109 mmol, 0.25 equiv), tetrapotassium hexacyanoferrate trihydrate (2.05 g, 1.940 mmol, 0.23 equiv). The resulting mixture was stirred for overnight at 50°C under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL) and the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel columnchromatography, eluted with PE / EA (10 / 1) to afford 6-methoxynaphthalene-2-carbonitrile (1.38 g, 84.38%) as a light yellow solid. [000256] LC-MS: (ES, m / z): [M+H]+: no mass [000257]1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.57 (dd, J = 8.5, 1.7 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.17 (s, 1H), 3.95 (s, 3H). [000258] Synthesis of 6-methoxynaphthalene-2-carboximidamide[000259] To a stirred solution of 6-methoxynaphthalene-2-carbonitrile (830 mg, 4.530 mmol, 1 equiv) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (22.6 mL, 22.650 mmol, 5 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred for overnight at 25°C under argon atmosphere. The reaction was monitored by LCMS. To the above mixture was added HCl (gas)in 1,4-dioxane (1651.75 mg, 45.300 mmol, 10 equiv) dropwise at 0°C under argon atmosphere. Then resulting mixture was stirred for overnight at 25°C under argon atmosphere. The precipitated solids were collected by filtration and washed with ethyl acetate (3x30 mL). This resulted in 6-methoxynaphthalene-2-carboximidamide hydrochloride (2.4 g, crude) as an off-white solid. The crude product was used in the next step directly without further purification. [000260] LC-MS: (ES, m / z): [M+H]+: 201.00 [000261] Synthesis of 2-(2,6-dioxopiperidin-3-yl)-N-(6-methoxynaphthalene-2- carboximidoyl)-1-oxo-3H-isoindole-5-carboxamide[000262] Into a 100 mL 2-necked round-bottom flask were added 6-methoxynaphthalene-2- carboximidamide hydrochloride (450 mg, 1.901 mmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)- 1-oxo-3H-isoindole-5-carboxylic acid (438.42 mg, 1.521 mmol, 0.8 equiv) in DMF (10 mL) at 25°C. Then was added HBTU (1586.20 mg, 4.182 mmol, 2.2 equiv) and DIPEA (982.87 mg,7.604 mmol, 4 equiv) at 0°C under argon atmosphere. The resulting mixture was stirred for 4 hours at 25°C under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL) and the combined organic layers were dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (10 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 70% gradient in 20 min; detector, UV 254 nm to afford 2-(2,6-dioxopiperidin-3-yl)-N-(6-methoxynaphthalene-2-carboximidoyl)-1-oxo-3H-isoindole-5- carboxamide (400 mg, 44.72%) as an off-white solid. [000263] LC-MS: (ES, m / z): [M +H]+: 471.00 [000264]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.59 (s, 1H), 9.57 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.28 (dd, J = 8.6, 1.9 Hz, 1H), 8.00 (dd, J = 20.3, 8.8 Hz, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 9.1, 2.5 Hz, 2H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.59 (d, J = 17.4 Hz, 1H), 4.51 – 4.41 (m, 2H), 3.93 (s, 3H), 3.01 – 2.87 (m, 1H), 2.63 (d, J = 17.7 Hz, 1H), 2.42 (dt, J = 14.1, 7.0 Hz, 1H), 2.06 (d, J = 14.1 Hz, 1H). [000265] Synthesis of 3-{5-[5-(6-methoxynaphthalen-2-yl)-2H-1,2,4-triazol-3-yl]-1-oxo- 3H-isoindol-2-yl}piperidine-2,6-dione[000266] Into a 20 mL sealed tube was added 2-(2,6-dioxopiperidin-3-yl)-N-(6- methoxynaphthalene-2-carboximidoyl)-1-oxo-3H-isoindole-5-carboxamide (200 mg, 0.425 mmol, 1 equiv) in AcOH (5 mL) and hydrazine hydrate (42.56 mg, 0.850 mmol, 2 equiv) under argon atmosphere. The resulting mixture was stirred for 5 hours at 80°C under argon atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The residue was dissolved in DMSO (15 mL). The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 70% gradient in 25 min; detector, UV 254 nm to afford 3-{5-[5-(6-methoxynaphthalen-2-yl)-2H-1,2,4-triazol-3-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (33.4 mg, 16.25%) as an off-white solid. [000267] LC-MS: (ES, m / z): [M+H]+: 468.00 [000268]1H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 11.03 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.99 – 7.90 (m, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.41(d, J = 2.0 Hz, 1H), 7.27 – 7.24 (m, 1H), 5.19 (dd, J = 13.2, 5.2 Hz, 1H), 4.60 (d, J = 17.8 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 3.82 (s, 3H), 3.01 – 2.87 (m, 1H), 2.67 – 2.61 (m, 1H), 2.49 – 2.43 (m, 1H), 2.07– 2.00 (m, 1H). [000269] Example 1.8. Synthesis of 3-(5-(3-(6-methoxynaphthalen-2-yl)-1H-pyrazol-5- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-48)[000270] Synthesis of 3-(5-ethenyl-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione[000271] To a stirred mixture of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (3.0 g, 9.284 mmol, 1 equiv) and Pd(dppf)Cl2(1.3 g, 1.857 mmol, 0.2 equiv) in 1,4-dioxane(30 mL) was added tributyl(ethenyl)stannane (3.5 g, 11.141 mmol, 1.2 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 110oC under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature and extracted with CH2Cl2 / MeOH (6 / 1) (3 x 200 mL). The combined organic layers were washed with brine (1x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1) to afford 3-(5-ethenyl-1- oxo-3H-isoindol-2-yl)piperidine-2,6-dione (2.8 g, 82.57%) as a yellow solid. [000272] LC-MS: (ES, m / z): [M+H]+ : 271[000273]1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.76 – 7.61 (m, 3H), 6.87 (dd, J = 17.6, 10.8 Hz, 1H), 6.01 (d, J = 17.7 Hz, 1H), 5.42 (d, J = 10.8 Hz, 1H), 5.12 (dd, J = 13.4, 5.0 Hz, 1H), 4.52 – 4.27 (m, 2H), 2.92 (ddd, J = 18.3, 13.6, 5.3 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.41 (qd, J = 13.4, 12.8, 4.2 Hz, 1H), 2.10 – 1.92 (m, 1H). [000274] Synthesis of 2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindole-5-carbaldehyde[000275] To a stirred solution of 3-(5-ethenyl-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (2.8 g, 10.359 mmol, 1 equiv) and NaIO4(8.86 g, 41.436 mmol, 4 equiv) in dioxane (85mL) and H2O (85mL) were added K2OsO4.2H2O (13.63 mg, 0.037 mmol, 0.2 equiv) and 2,6-lutidine (2.22 g, 20.718 mmol, 2 equiv) in portions at 0 °C under argon atmosphere. The resulting mixture was stirred for 2 h at 0 °C under argon atmosphere. The reaction was monitored by TLC. The reaction was quenched with Water / Ice at 0oC and extracted with CH2Cl2 / MeOH (6 / 1) (3 x 200 mL). The combined organic layers were washed with brine (1x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindole-5-carbaldehyde (760 mg, 26.95%) as a white solid. [000276] LC-MS: (ES, m / z): [M+H]+ : 273 [000277]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.15 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 17.7 Hz, 1H), 4.46 (d, J = 17.7 Hz, 1H), 3.01 – 2.87 (m, 1H), 2.67 – 2.61 (m, 1H), 2.49 – 2.43 (m, 1H), 2.07– 2.00 (m, 1H). [000278] Synthesis of 3-(5-[(1E)-3-(6-methoxynaphthalen-2-yl)-3-oxoprop-1-en-1-yl]-1- oxo-3H-isoindol-2-ylpiperidine-2,6-dione[000279] To a stirred solution 2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindole-5- carbaldehyde (300 mg, 1.102 mmol, 1 equiv) and PTSA (37.95 mg, 0.220 mmol, 0.2 equiv) in toluene(15mL) was added 1-(6-methoxynaphthalen-2-yl)ethanone (220.64 mg, 1.102 mmol, 1.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 days at 100 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) and CH2Cl2 / MeOH (10 / 1) to afford 3-(5-[(1E)-3-(6- methoxynaphthalen-2-yl)-3-oxoprop-1-en-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (300 mg) as a yellow solid. The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 3-(5-[(1E)-3-(6- methoxynaphthalen-2-yl)-3-oxoprop-1-en-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (150 mg, 29.95%) as an off-white solid. [000280] LC-MS: (ES, m / z): [M+H]+: 455 [000281]1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 15.6 Hz, 1H), 8.18 (s, 1H), 8.14 (dd, J = 8.6, 1.8 Hz, 1H), 8.09 (dd, J = 8.7, 6.2 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 15.6 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.31 (dd, J = 9.0, 2.5 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 – 4.37 (m, 2H), 3.94 (s, 3H), 3.01 – 2.87 (m, 1H), 2.67 – 2.61 (m, 1H), 2.49 – 2.43 (m, 1H), 2.07– 2.00 (m, 1H). [000282] Synthesis of 3-(5-(3-(6-methoxynaphthalen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione[000283] To a stirred solution of 3-(5-[(1E)-3-(6-methoxynaphthalen-2-yl)-3-oxoprop-1-en- 1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (60 mg, 0.132 mmol, 1 equiv) in EtOH (2 mL)was added hydrazine hydrate (23.79 mg, 0.475 mmol, 3.6 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 60°C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. [000284] LC-MS: (ES, m / z): [M+H]+: 469 [000285] Synthesis of 3-(5-[5-(6-methoxynaphthalen-2-yl)-2H-pyrazol-3-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione[000286] To a stirred solution of 3-(5-[5-(6-methoxynaphthalen-2-yl)-3,4-dihydro-2H- pyrazol-3-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (60 mg, 0.128 mmol, 1 equiv) in DMSO (2 mL) was added I2(3.25 mg, 0.013 mmol, 0.1 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h at 110°C under argon atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 27% B to 47% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 10) to afford 3-(5-[5-(6- methoxynaphthalen-2-yl)-2H-pyrazol-3-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (17.3 mg, 28.12%) as a white solid. [000287] LC-MS: (ES, m / z): [M+H]+: 467 [000288]1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 11.01 (s, 1H), 8.31 (s, 1H), 8.22 – 7.66 (m, 6H), 7.39 (d, J = 17.2 Hz, 2H), 7.23 (d, J = 9.5 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 17.2 Hz, 1H), 4.42 (d, J = 17.2 Hz, 1H), 3.90 (s, 3H), 3.01 – 2.87 (m, 1H), 2.62 (ddd, J = 17.2, 4.5, 2.3 Hz, 1H), 2.49 – 2.43 (m, 1H), 2.10 – 1.99 (m, 1H). [000289] Example 1.9. Synthesis of 3-(6-(4-(6-ethoxypyridin-2-yl)-1H-1,2,3-triazol-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-156)[000290] Synthesis of 2-ethoxy-6-((trimethylsilyl)ethynyl)pyridine[000291] To a stirred mixture of 2-bromo-6-ethoxypyridine (900 mg, 4.454 mmol, 1 equiv) and CuI (42.42 mg, 0.223 mmol, 0.05 equiv) in TEA (10 mL) were added Pd(PPh3)2Cl2(312.65 mg, 0.445 mmol, 0.1 equiv) and trimethylsilylacetylene (1.31 g, 13.362 mmol, 3 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 3 h at 80°C. Desired product could be detected by LCMS. The reaction was quenched with Water (50 ml) at room temperature and extracted with EtOAc (2 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-ethoxy-6-[2- (trimethylsilyl)ethynyl]pyridine (1 g, 71.64%) as a yellow oil. [000292] LC-MS (ES, m / z) [M+H]+: 220.11 [000293] NMR: (400 MHz, Acetonitrile-d3) δ 7.60 (ddd, J = 8.3, 7.3, 0.8 Hz, 1H), 7.06 (dt, J = 7.3, 0.9 Hz, 1H), 6.73 (dt, J = 8.4, 0.9 Hz, 1H), 4.29 (qd, J = 7.1, 0.8 Hz, 2H), 1.34 (td, J = 7.1, 0.9 Hz, 3H), 0.25 (d, J = 0.9 Hz, 9H). [000294] Synthesis of 2-ethoxy-6-ethynylpyridine[000295] A solution of 2-ethoxy-6-[2-(trimethylsilyl)ethynyl]pyridine (200 mg, 0.912 mmol, 1 equiv) and K2CO3(126.01 mg, 0.912 mmol, 1 equiv) in MeOH (3 mL) was stirred for 1h at room temperature under argon atmosphere. Desired product could be detected by LCMS. The reaction was quenched with Water (20 ml) at room temperature. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 2-ethoxy-6-ethynylpyridine (100 mg, 74.52%) as a yellow oil. [000296] LC-MS (ES, m / z) [M+H]+: 148.07 [000297]1H NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J = 8.4, 7.3 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.31 – 4.24 (m, 3H), 1.30 (t, J = 7.0 Hz, 3H). [000298] Synthesis of 3-(6-(4-(6-ethoxypyridin-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000299] To a stirred mixture of 2-ethoxy-6-ethynylpyridine (80 mg, 0.544 mmol, 1 equiv) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine-2,6-dione (77.53 mg, 0.272 mmol, 0.5 equiv) in DMSO (4 mL) were added CuSO4.5H2O (40.72 mg, 0.163 mmol, 0.3 equiv) in Water (1 ml) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (97.41 mg, 0.490 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 30% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(6-(4-(6-ethoxypyridin-2-yl)-1H- 1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(86.5 mg, 36.62%) as a white solid. [000300] LC-MS (ES, m / z):433.15 [000301]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.46 (s, 1H), 8.42 – 8.32 (m, 2H), 7.90 – 7.80 (m, 2H), 7.68 (dd, J = 7.3, 0.8 Hz, 1H), 6.79 (dd, J = 8.3, 0.8 Hz, 1H), 5.20 (dd,J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 17.7 Hz, 1H), 4.51 – 4.43 (m, 3H), 2.94 (ddd, J = 18.0, 13.6, 5.4 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.43 (td, J = 13.3, 4.5 Hz, 2H), 2.11 – 2.02 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H). [000302] Example 1.10. Synthesis of 3-(6-(4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-153)[000303] Synthesis of 2-methoxy-3-((trimethylsilyl)ethynyl)pyridine[000304] To a stirred solution of 3-iodo-2-methoxypyridine (1 g, 4.255 mmol, 1 equiv) and CuI (81.03 mg, 0.425 mmol, 0.1 equiv) and Bis(triphenylphosphine)palladium(II) chloride (14.93 mg, 0.021 mmol, 0.05 equiv) in N,N-Dimethylformamide (10 mL) were added Triethylamine (1291.69 mg, 12.765 mmol, 3 equiv) and trimethylsilylacetylene (1253.74 mg, 12.765 mmol, 3 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water (20mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-methoxy-3-[2- (trimethylsilyl)ethynyl]pyridine (850 mg, 97.29%) as a yellow oil. [000305] LC-MS (ES, m / z) [M+H]+: 206[000306]1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 5.0, 1.9 Hz, 1H), 7.58 (dd, J = 7.4, 1.9 Hz, 1H), 6.76 (dd, J = 7.4, 5.0 Hz, 1H), 3.67 (s, 3H), 0.00 (s, 9H). [000307] Synthesis of 3-ethynyl-2-methoxypyridine[000308] To a stirred solution of 2-methoxy-3-[2-(trimethylsilyl)ethynyl]pyridine (300 mg, 1.461 mmol, 1 equiv) in Methanol (3 mL) was added Potassium carbonate (201.92 mg, 1.461 mmol, 1 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with Methanol (3 mL) (3x5 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 3-ethynyl-2-methoxypyridine (160 mg, 82.25%) as a yellow oil. [000309] Synthesis of 3-(6-(4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000310] To a stirred mixture of 3-ethynyl-2-methoxypyridine (74.68 mg, 0.560 mmol, 2 equiv) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.280 mmol, 1.00 equiv) in Dimethyl sulfoxide (6 mL) were added CuSO4.5H2O (42.01 mg, 0.168 mmol, 0.6 equiv) in water (1.5 mL) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5- dihydrofuran-2-one (12.56 mg, 0.063 mmol, 0.9 equiv) in water (1.5 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 days at room temperature under argon atmosphere. The reaction was monitored by LCMS. The residue was dissolved in Dimethyl sulfoxide (6 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17%B to 37%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.78; Number Of Runs: 3) to afford 3-(6-(4-(2-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (44.5 mg, 37.58%) as a white solid. [000311] LC-MS (ES, m / z) [M+H]+: 419 [000312]1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.23 (s, 1H), 8.59 – 8.20 (m, 4H), 7.88 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 7.5, 4.9 Hz, 1H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 – 4.41 (m, 2H), 4.08 (s, 3H), 3.02 – 2.88 (m, 1H), 2.63 (ddd, J = 17.2, 4.5, 2.3 Hz, 1H), 2.43 (td, J = 13.1, 4.4 Hz, 1H), 2.12 – 2.02 (m, 1H). [000313] Example 1.11. Synthesis of 3-(6-(4-(6-cyclopropoxypyridin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(I-152)[000314] Synthesis of 2-bromo-6-cyclopropoxypyridine[000315] A mixture of 2-bromo-6-fluoropyridine (1 g, 5.682 mmol, 1 equiv) and cyclopropanol (1.98 g, 34.092 mmol, 6.00 equiv) in NMP (10 mL) was stirred for 5 min at 0°C under argon atmosphere. Then were added Potassium tert-butoxide in THF (1 M) (0.38 g, 3.409 mmol, 0.6 equiv) dropwise at 0°C. The resulting mixture was stirred for overnight at 25°C under argon atmosphere. The reaction was monitored by LCMS. To the above mixture was added PE / EA / H2O (20mL:20mL:40mL) at 0°C. The organic layer was washed with 5% LiCl aqueous solution (20 mL), the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The resulting mixture was dissolved in DCM (3 mL). The residuewas purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2- bromo-6-cyclopropoxypyridine (380 mg, 31.24%) as a light yellow liquid. [000316] LC-MS (ES, m / z) [M +H]+:214.00 [000317]1H NMR (400 MHz, Chloroform-d) δ 7.43 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.21 (tt, J = 6.4, 3.2 Hz, 1H), 0.84 – 0.71 (m, 4H). [000318] Synthesis of 2-cyclopropoxy-6-((trimethylsilyl)ethynyl)pyridine[000319] Into a 20 mL sealed tube were added 2-bromo-6-cyclopropoxypyridine (280 mg, 1.308 mmol, 1 equiv) and CuI (14.68 mg, 0.077 mmol, 0.05 equiv), Pd(PPh3)2Cl2 (91.81 mg, 0.131 mmol, 0.10 equiv), trimethylsilylacetylene (642.37 mg, 6.540 mmol, 5 equiv) in Et3N (5 mL) under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 85°C under argon atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. To the above mixture was added H2O, the aqueous layer was extracted with EtOAc (3x20mL). the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum and dissolved in DCM (2 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-cyclopropoxy-6-[2- (trimethylsilyl)ethynyl]pyridine (300 mg, 99.13%) as a colorless liquid. [000320] LC-MS (ES, m / z) [M +H]+: 232.00 [000321]1H NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J = 8.4, 7.4 Hz, 1H), 7.10 (dd, J = 7.4, 0.8 Hz, 1H), 6.74 (dd, J = 8.4, 0.8 Hz, 1H), 4.27 (tt, J = 6.3, 3.3 Hz, 1H), 0.80 – 0.74 (m, 4H), 0.26 (s, 9H). [000322] Synthesis of 2-cyclopropoxy-6-ethynylpyridine[000323] Into a 20 mL 2-necked round-bottom flask were added 2-cyclopropoxy-6-[2- (trimethylsilyl)ethynyl]pyridine (100 mg, 0.432 mmol, 1 equiv) and K2CO3(119.47 mg, 0.864 mmol, 2 equiv) in MeOH (2 mL) under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 25°C under argon atmosphere. The reaction was monitored by LCMS. The mixture was collected by filtration and washed with EtOAc (3x20mL). The combined organic layerswere dried with Na2SO4, filtered, and concentrated under vacuum and dissolved in DCM (2 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-cyclopropoxy-6-ethynylpyridine (65 mg, 94.47%) as a colorless liquid. [000324] LC-MS (ES, m / z) [M +H]+: 160.00 [000325]1H NMR (400 MHz, Chloroform-d) δ 7.55 (dd, J = 8.4, 7.3 Hz, 1H), 7.13 (dd, J = 7.4, 0.8 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.29 (tt, J = 6.2, 3.1 Hz, 1H), 3.13 (s, 1H), 0.84 – 0.72 (m, 4H). [000326] Synthesis of 3-(6-(4-(6-cyclopropoxypyridin-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000327] Into a 20 mL sealed tube were added 2-cyclopropoxy-6-ethynylpyridine (40 mg, 0.251 mmol, 1 equiv) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine-2,6-dione (57.34 mg, 0.201 mmol, 0.8 equiv) in DMSO(4 mL) at 25°C. Then CuSO4.5H2O (12.55 mg, 0.050 mmol, 0.2 equiv) in H2O (1 mL) and Sodium ascorbate (30.02 mg, 0.151 mmol, 0.60 equiv) in H2O (1 mL) was added under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was dissolved in DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 20% to 95% gradient in 25 min to afford 3-(6-(4-(6-cyclopropoxypyridin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(78.0 mg, 69.49%) as a white solid. [000328] LC-MS (ES, m / z) [M +H]+:445.00 [000329]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.43 (s, 1H), 8.39 – 8.30 (m, 2H), 7.92 – 7.84 (m, 2H), 7.75 (dd, J = 7.4, 0.8 Hz, 1H), 6.90 (dd, J = 8.3, 0.8 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 17.8 Hz, 1H), 4.50 – 4.41 (m, 2H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.06 (dq, J = 10.5, 3.3 Hz, 1H), 0.89 – 0.80 (m, 2H), 0.80 – 0.69 (m, 2H).[000330] Example 1.12. Synthesis of 3-(6-(4-(2-ethoxyphenyl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (I-155) [[000332] Into a 50 mL 2-necked round-bottom flask were added benzaldehyde, 2-ethoxy- (400 mg, 2.664 mmol, 1 equiv), MeOH (12 mL) and Seyferth-Gilbert reagent (614.03 mg, 3.197 mmol, 1.2 equiv) at room temperature. To the above mixture was added K2CO3 (441.73 mg, 3.197 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. The reaction was quenched with the Water / Ice (10 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (12:1) to afford 1-ethoxy-2-ethynylbenzene (320 mg, 77.25%) as a white oil. [000333] LC-MS (ES, m / z) [M+H]+:147 [000334]1H NMR (400 MHz, DMSO-d6) δ 7.45 – 7.27 (m, 2H), 7.03 (dd, J = 8.4, 1.0 Hz, 1H), 6.91 (td, J = 7.5, 1.0 Hz, 1H), 4.19 (s, 1H), 4.08 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). [000335] Synthesis of 3-(6-(4-(2-ethoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione[000336] Into a 50 mL round-bottom flask were added 1-ethoxy-2-ethynylbenzene (100 mg, 0.684 mmol, 1 equiv), DMSO (5 mL) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine-2,6- dione (97.57 mg, 0.342 mmol, 0.5 equiv) at room temperature. To the above mixture was added CuSO4.5H2O (51.24 mg, 0.205 mmol, 0.3 equiv) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]- 3,4-dihydroxy-2,5-dihydrofuran-2-one (122.58 mg, 0.616 mmol, 0.9 equiv) in water (2.5 mL) at room temperature. The resulting mixture was stirred for 2 days at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with DMSO (25 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 70% gradient in 25 min; detector, UV 254 nm to afford 3-(6-(4-(2-ethoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (101.5 mg, 33.57%) as an off-white solid. [000337] LC-MS (ES, m / z) [M+H]+:432 [000338]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.98 (s, 1H), 8.31 – 8.23 (m, 2H), 8.19 (dd, J = 7.7, 1.8 Hz, 1H), 7.93 – 7.84 (m, 1H), 7.38 (ddd, J = 8.9, 7.3, 1.8 Hz, 1H), 7.17 (dd, J = 8.5, 1.1 Hz, 1H), 7.09 (td, J = 7.5, 1.1 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.69 – 4.38 (m, 2H), 4.25 (q, J = 6.9 Hz, 2H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.63 (ddd, J = 17.3, 4.5, 2.3 Hz, 1H), 2.41 (dd, J = 13.2, 4.4 Hz, 1H), 2.22 – 1.96 (m, 1H), 1.48 (t, J = 6.9 Hz, 3H). [000339] Example 1.13. Synthesis of 3-(1-oxo-6-(4-(6-(trifluoromethoxy)pyridin-2-yl)- 1H-1,2,3-triazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione(I-151)[000340] Synthesis of 2-(trifluoromethoxy)-6-((trimethylsilyl)ethynyl)pyridine[000341] To a stirred mixture of 2-chloro-6-(trifluoromethoxy)pyridine (800 mg, 4.050 mmol, 1 equiv) in TEA (20 mL) were added CuI (38.56 mg, 0.203 mmol, 0.05 equiv) and Pd(PPh3)4(467.99 mg, 0.405 mmol, 0.1 equiv) in portions at room temperature under argon atmosphere. To the above mixture was added trimethylsilylacetylene (3.98 g, 40.500 mmol, 10 equiv) dropwise at room temperature. The resulting mixture wasstirred for overnight at 90 C. Desired product could be detected by LCMS. The reaction wasquenched with Water (100 ml) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-(trifluoromethoxy)-6-[2-(trimethylsilyl)ethynyl]pyridine (600 mg, 57.14%) as a yellow oil. [000342] LC-MS (ES, m / z):[M+H]+:260.06 [000343]1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J = 8.3, 7.5 Hz, 1H), 7.60 (dd, J = 7.6, 0.8 Hz, 1H), 7.33 (dd, J = 8.4, 0.8 Hz, 1H), 0.27 (s, 9H). [000344] Synthesis of 2-ethynyl-6-(trifluoromethoxy)pyridine[000345] A mixture of 2-(trifluoromethoxy)-6-[2-(trimethylsilyl)ethynyl]pyridine (500 mg, 1.928 mmol, 1 equiv) and K2CO3 (266.49 mg, 1.928 mmol, 1 equiv) in MeOH (5 mL) was stirred for 1 h at room temperature under argon atmosphere. Desired product could be detected by LCMS. The reaction was quenched with Water (50 ml) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 2-ethynyl-6-(trifluoromethoxy)pyridine (130 mg, 36.03%) as a yellow oil. [000346] LC-MS (ES, m / z) [M+H]+:188.02 [000347]1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 8.3, 7.5 Hz, 1H), 7.62 (dd, J = 7.5, 0.7 Hz, 1H), 7.35 (dd, J = 8.3, 0.7 Hz, 1H), 4.53 (s, 1H). [000348] Synthesis of 3-(1-oxo-6-(4-(6-(trifluoromethoxy)pyridin-2-yl)-1H-1,2,3-triazol-1- yl)isoindolin-2-yl)piperidine-2,6-dione[000349] To a stirred mixture of 2-ethynyl-6-(trifluoromethoxy)pyridine (100 mg, 0.534 mmol, 1 equiv) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine-2,6-dione (76.22 mg, 0.267 mmol, 0.5 equiv) in DMSO (6 mL) were added CuSO4.5H2O (40.03 mg, 0.160 mmol, 0.3 equiv) in Water (1 ml) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5- dihydrofuran-2-one (95.77 mg, 0.481 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 48 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (4 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 30% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(1-oxo-6-(4-(6- (trifluoromethoxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione(70.2 mg, 27.67%) as a white solid.[000350] LC-MS (ES, m / z) [M+H]+:473.11 [000351]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.46 (s, 1H), 8.41 – 8.32 (m, 2H), 8.22 – 8.12 (m, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 7.9, 1.0 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 17.8 Hz, 1H), 4.46 (d, J = 17.9 Hz, 1H), 2.94 (ddd, J = 17.9, 13.6, 5.4 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.11 – 2.02 (m, 1H). [000352] Example 1.14. Synthesis of 3-(6-(4-(2-cyclopropoxyphenyl)-1H-1,2,3-triazol- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(I-150)[000353] Synthesis of ((2-cyclopropoxyphenyl)ethynyl)trimethylsilane[000354] Into a 50 mL round-bottom flask were added 1-bromo-2-cyclopropoxybenzene (500 mg, 2.347 mmol, 1 equiv), TEA (5 mL) and trimethylsilylacetylene (691.45 mg, 7.041 mmol, 3 equiv) at room temperature under argon atmosphere. To the above mixture was added CuI (89.38 mg, 0.469 mmol, 0.2 equiv) and Pd(PPh3)2Cl2(164.71 mg, 0.235 mmol, 0.1 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at 60 °C. The reaction was monitored by LCMS and TLC. The reaction was quenched with Water / Ice at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 70 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (10:1) to afford [2-(2-cyclopropoxyphenyl)ethynyl]trimethylsilane (380 mg, 67.48%) as an off-white oil.[000355] LC-MS (ES, m / z) [M+H]+:231 [000356]1H NMR (400 MHz, DMSO-d6) δ 7.22 – 7.06 (m, 3H), 6.73 (td, J = 7.4, 1.2 Hz, 1H), 3.69 (tt, J = 6.0, 2.9 Hz, 1H), 0.67 – 0.56 (m, 2H), 0.45 (tq, J = 3.2, 2.3, 1.6 Hz, 2H), 0.00 (s, 9H). [000357] Synthesis of 1-cyclopropoxy-2-ethynylbenzene[000358] Into a 25 mL round-bottom flask were added [2-(2- cyclopropoxyphenyl)ethynyl]trimethylsilane (300 mg, 1.302 mmol, 1 equiv) and MeOH (3 mL) at room temperature under argon atmosphere. To the above mixture was added K2CO3(359.94 mg, 2.604 mmol, 2 equiv) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 1-cyclopropoxy-2-ethynylbenzene (160 mg, 73.78%) as an off-white oil. [000359] LC-MS (ES, m / z) [M+H]+:159 [000360]1H NMR (400 MHz, DMSO-d6) δ 7.44 – 7.37 (m, 2H), 7.33 (dd, J = 8.8, 1.3 Hz, 1H), 6.96 (td, J = 7.4, 1.3 Hz, 1H), 4.18 (s, 1H), 3.88 (tt, J = 6.0, 3.0 Hz, 1H), 0.89 – 0.77 (m, 2H), 0.77 – 0.63 (m, 2H). [000361] Synthesis of 3-(6-(4-(2-cyclopropoxyphenyl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000362] Into a 50 mL round-bottom flask were added 1-cyclopropoxy-2-ethynylbenzene (160 mg, 1.011 mmol, 1 equiv), DMSO (5 mL) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (144.25 mg, 0.505 mmol, 0.5 equiv) at room temperature. To the above mixture wasadded CuSO4.5H2O (75.76 mg, 0.303 mmol, 0.3 equiv, H2O (2.5 mL) and sodium (5R)-5-[(1S)- 1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (181.24 mg, 0.910 mmol, 0.9 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (30 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 40% to 60% gradient in 15 min; detector, UV 254 nm. This resulted in 3-(6-(4-(2-cyclopropoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione(73.3 mg, 15.90%) as a white solid. [000363] LC-MS (ES, m / z) [M+H]+:444 [000364]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.87 (s, 1H), 8.32 – 8.24 (m, 2H), 8.16 (dd, J = 7.7, 1.7 Hz, 1H), 7.87 (dd, J = 8.1, 0.8 Hz, 1H), 7.52 – 7.36 (m, 2H), 7.13 (td, J = 7.5, 1.2 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 – 4.40 (m, 2H), 4.01 (tt, J = 5.9, 3.1 Hz, 1H), 2.95 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.69 – 2.58 (m, 1H), 2.46 – 2.33 (m, 1H), 2.14 – 1.99 (m, 1H), 0.98 – 0.79 (m, 4H). [000365] Example 1.15. Synthesis of 3-(1-oxo-6-(4-(o-tolyl)-1H-1,2,3-triazol-1- yl)isoindolin-2-yl)piperidine-2,6-dione (I-154)[000366] Into a 20 mL sealed tube were added 1-ethynyl-2-methylbenzene (30 mg, 0.258 mmol, 1 equiv) and 3-(6-azido-1-oxoisoindolin-2-yl)piperidine-2,6-dione (73.67 mg, 0.258 mmol, 1 equiv) in DMSO(6 mL) at 25°C. Then CuSO4.5H2O (12.90 mg, 0.052 mmol, 0.2 equiv) in H2O (1.5 mL) and Sodium ascorbate (30.85 mg, 0.155 mmol, 0.6 equiv) in H2O (1.5 mL) was added under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was dissolved in DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 70% gradient in 25 min; detector, UV 254 nm to afford 3-(1-oxo-6-(4-(o-tolyl)-1H- 1,2,3-triazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione(70.2 mg, 64.46%) as an off-white solid.[000367] LC-MS (ES, m / z): [M +H]+:402.00 [000368]1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.25 (s, 1H), 8.40 – 8.30 (m, 2H), 7.92 – 7.79 (m, 2H), 7.40 – 7.28 (m, 3H), 5.24 – 5.12 (m, 1H), 4.59 (d, J = 17.8 Hz, 1H), 4.46 (d, J = 17.7 Hz, 1H), 2.94 (ddd, J = 17.7, 13.5, 5.3 Hz, 1H), 2.55 (s, 4H), 2.43 (td, J = 13.0, 4.2 Hz, 1H), 2.10 – 2.02 (m, 1H). [000369] Example 1.16. Synthesis of 3-(5-(4-(5-fluoro-6-methoxypyridin-2-yl)-1H- 1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-123)[000370] Synthesis of 3-fluoro-2-methoxy-6-((trimethylsilyl)ethynyl)pyridine[000371] To a stirred mixture of 6-chloro-3-fluoro-2-methoxypyridine (500 mg, 3.095 mmol, 1 equiv) and trimethylsilylacetylene (3.04 g, 30.950 mmol, 10 equiv) in TEA (5 mL) were added CuI (29.47 mg, 0.155 mmol, 0.05 equiv) and Pd(PPh3)2Cl2 (357.63 mg, 0.310 mmol, 0.1 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 90 °C under argon atmosphere. The reaction was quenched with Water / Ice at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 30% to 95% gradient in 25 min; detector, UV 254 nm. This resulted in 3-fluoro-2-methoxy-6-[2-(trimethylsilyl)ethynyl]pyridine (300 mg, 34.73%) as a brown oil. [000372] Synthesis of 6-ethynyl-3-fluoro-2-methoxypyridine[000373] To a stirred mixture of 3-fluoro-2-methoxy-6-[2-(trimethylsilyl)ethynyl]pyridine (200 mg, 0.896 mmol, 1 equiv) in MeOH (8.00 mL, 197.684 mmol, 220.63 equiv) was added K2CO3(123.77 mg, 0.896 mmol, 1 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (8.00 mL) (2x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford 6-ethynyl-3-fluoro-2-methoxypyridine (100 mg, 73.88%) as a brown oil. [000374] Synthesis of 3-(5-(4-(5-fluoro-6-methoxypyridin-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000375] To a stirred mixture of 6-ethynyl-3-fluoro-2-methoxypyridine (40 mg, 0.265 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (60.40 mg, 0.212 mmol, 0.8 equiv) in DMSO (2 mL) were added CuSO4.5H2O (19.82 mg, 0.080 mmol, 0.3 equiv) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (47.19 mg, 0.239 mmol, 0.9 equiv) in H2O (1 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at room temperature under argon atmosphere. Desired product could be detected by LCMS. The residue was dissolved in DMSO (5 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in 3-(5-[4-(5-fluoro-6-methoxypyridin-2-yl)-1,2,3-triazol-1- yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (20.9 mg, 17.75%) as a white solid. [000376] LC-MS (ES, m / z) [M+H]+: 437 [000377]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.38 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.21 (dd, J = 8.2, 1.9 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.82 (dd, J = 10.5, 8.1 Hz, 1H), 7.71 (dd, J = 8.1, 3.0 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.48 (d, J =17.7 Hz, 1H), 4.10 (s, 3H), 2.94 (ddd, J = 18.0, 13.5, 5.4 Hz, 1H), 2.62 (d, J = 17.4 Hz, 1H), 2.49 – 2.39 (m, 1H), 2.09 – 2.02 (m, 1H). [000378] Example 1.17. Synthesis of 3-(5-(4-(6-methoxy-5-methylpyridin-2-yl)-1H- 1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-122)[000379] Synthesis of 2-methoxy-3-methyl-6-((trimethylsilyl)ethynyl)pyridine[000380] Into a 25 mL sealed tube were added 6-bromo-2-methoxy-3-methylpyridine (500 mg, 2.475 mmol, 1 equiv), trimethylsilylacetylene (729.17 mg, 7.425 mmol, 3 equiv) and CuI (94.26 mg, 0.495 mmol, 0.2 equiv), Pd(PPh3)2Cl2 (347.39 mg, 0.495 mmol, 0.2 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 60 °C. The reaction was monitored by LCMS and TLC. Desired product could be detected by LCMS and TLC. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (12:1) to afford 2-methoxy-3-methyl-6-[2-(trimethylsilyl)ethynyl]pyridine (590 mg, 108.69%) as an off-white oil. [000381] LC-MS (ES, m / z) [M +H]+:220.00 [000382]1H NMR (400 MHz, Chloroform-d) δ 7.30 (dt, J = 7.3, 1.0 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 3.98 (d, J = 1.2 Hz, 3H), 2.18 (s, 3H), 0.27 (d, J = 1.4 Hz, 9H). [000383] Synthesis of 6-ethynyl-2-methoxy-3-methylpyridine[000384] Into a 25 mL round-bottom flask were added 2-methoxy-3-methyl-6-[2- (trimethylsilyl)ethynyl]pyridine (200 mg, 0.912 mmol, 1 equiv) in MeOH(4 mL) and K2CO3 (252.02 mg, 1.824 mmol, 2 equiv) at 25°C. The resulting mixture was stirred for 30 min at room temperature under argon atmosphere. The reaction was monitored by LCMS. The aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (3 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 6-ethynyl-2-methoxy-3- methylpyridine (130 mg, 96.88%) as a white solid. [000385] LC-MS (ES, m / z) [M +H]+:148.00 [000386] Synthesis of 3-(5-(4-(6-methoxy-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000387] To a stirred mixture of 6-ethynyl-2-methoxy-3-methylpyridine (60 mg, 0.408 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (93.04 mg, 0.326 mmol, 0.8 equiv) in DMSO (6 ml) were added CuSO4.5H2O (20.36 mg, 0.082 mmol, 0.2 equiv) in Water (1.5 ml) and Sodium ascorbate (48.70 mg, 0.245 mmol, 0.6 equiv) in Water (1.5 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24 h at room temperature. Desired product could be detected by LCMS. The residue was dissolved in DMSO (15mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 3-{5-[4-(6-methoxy-5-methylpyridin- 2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione as an off-white solid. [000388] LC-MS: (ES, m / z): [M +H]+:433.00[000389]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.33 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.22 (dd, J = 8.2, 2.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.71 – 7.58 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.6 Hz, 1H), 4.03 (s, 3H), 2.94 (ddd, J = 17.9, 13.5, 5.4 Hz, 1H), 2.62 (dd, J = 16.0, 3.1 Hz, 1H), 2.44 (td, J = 13.2, 4.5 Hz, 1H), 2.24 – 2.15 (s, 3H), 2.09 – 2.01 (m, 1H). [000390] Example 1.18. Synthesis of 3-(5-(4-(2-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-138)[000391] To a stirred solution of 3-(5-[4-(2-methoxyphenyl)-1,2,3-triazol-1-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione (90 mg, 0.216 mmol, 1 equiv) in CH2Cl2 was added BBr3 (4 mL, 0.480 mmol, 20 equiv) dropwise at -10 °C under argon atmosphere. The resulting mixture was stirred for 6 h at room temperature under argon atmosphere. The reaction was quenched with sat. NaHCO3 (aq.) at 0℃. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to40% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.27) to afford 3-(5-[4-(2-hydroxyphenyl)-1,2,3-triazol-1-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione (13.9 mg, 15.82%) as an off-white solid. [000392] LC-MS (ES, m / z) M+1=404 [000393]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.33 (s, 1H), 9.05 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.14 (ddd, J = 23.4, 8.0, 1.8 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.24 (ddd, J = 8.7, 7.3, 1.8 Hz, 1H), 7.11 – 6.87 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 – 4.42 (m, 2H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.62 (ddd, J = 17.2, 4.5, 2.3 Hz, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.11 – 2.00 (m, 1H).[000394] Example 1.19. Synthesis of 3-(5-(4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (I-137)[000395] To a stirred mixture of 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (55.87 mg, 0.196 mmol, 0.5 equiv) and 2-ethynylquinoline (60 mg, 0.392 mmol, 1.00 equiv) in DMSO (4 mL) were added CuSO4.5H2O (29.34 mg, 0.118 mmol, 0.3 equiv) in Water (1 ml) and Sodium ascorbate (70.19 mg, 0.353 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in 3-(5-[4-(1H-indol-5-yl)-1,2,3-triazol- 1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (12.8 mg, 7.49%) as a brown solid. [000396] LC-MS (ES, m / z) [M+H]+:427.1 [000397]1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 11.03 (s, 1H), 9.34 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 2.7 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.62 (d, J = 17.7 Hz, 1H), 4.49 (d, J = 17.7 Hz, 1H), 2.94 (ddd, J = 18.1, 13.5, 5.4 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.48 – 2.38 (m, 1H), 2.09 – 2.03 (m, 1H). [000398] Example 1.20. Synthesis of 3-(5-(4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (I-118)[000399] To a stirred mixture of 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (50 mg, 0.175 mmol, 1 equiv) and 5-ethynyl-1H-indazole (49.84 mg, 0.350 mmol, 2 equiv) inDMSO (6 mL) were added CuSO4.5H2O (8.75 mg, 0.035 mmol, 0.2 equiv) and Sodium ascorbate (20.94 mg, 0.105 mmol, 0.6 equiv) in H2O (3 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 days at room temperature under argon atmosphere. Desired product could be detected by LCMS. The residue was dissolved in DMSO (6 mL). The product was precipitated by the addition of DMSO (6 mL). The resulting mixture was washed with 2x20 mL of H2O (3 mL). This resulted in 3-(5-[4-(1H-indazol-5-yl)-1,2,3- triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (22.0 mg, 28.63%) as an off-white solid. [000400] LC-MS (ES, m / z) [M+H]+: 428 [000401]1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 11.03 (s, 1H), 9.44 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.21 – 8.11 (m, 2H), 8.03 – 7.93 (m, 2H), 7.68 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 17.7 Hz, 1H), 4.49 (d, J = 17.7 Hz, 1H), 3.01 – 2.87 (m, 1H), 2.63 (d, J = 17.6 Hz, 1H), 2.49 – 2.39 (m, 0H), 2.06 (d, J = 12.6 Hz, 1H). [000402] Example 1.21. Synthesis of 3-(5-(4-(1H-benzo[d]imidazol-5-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-136)[000403] Synthesis of 6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole[000404] To a stirred solution of 5-iodo-3H-1,3-benzodiazole (500 mg, 2.049 mmol, 1 equiv) and CuI (39.02 mg, 0.205 mmol, 0.1 equiv) and Bis(triphenylphosphine)palladium(II) chloride, Dichlorobis(triphenylphosphine) palladium(II) (71.91 mg, 0.102 mmol, 0.05equiv) and TEA (0.85 mL, 6.147 mmol, 3 equiv) in THF were added trimethylsilylacetylene (603.72 mg, 6.147 mmol, 3 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at room temperature under argon atmosphere. The reaction was quenched with water and extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 5-[2-(trimethylsilyl)ethynyl]-3H-1,3- benzodiazole (400 mg, 91.08%) as a yellow solid. [000405] LC-MS (ES, m / z) [M+1]= 215.09 [000406] Synthesis of 6-ethynyl-1H-benzo[d]imidazole[000407] A solution of 5-[2-(trimethylsilyl)ethynyl]-3H-1,3-benzodiazole (300 mg, 1.400 mmol, 1 equiv) and K2CO3 (193.44 mg, 1.400 mmol, 1 equiv) in MeOH was stirred for 1 h at room temperature under argon atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / EA (1:1) to afford 5- ethynyl-3H-1,3-benzodiazole (150 mg, 75.39%) as a light yellow oil. [000408] LC-MS (ES, m / z) [M+1]=143.05 [000409] Synthesis of 3-(5-(4-(1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000410] To a stirred solution of 5-ethynyl-3H-1,3-benzodiazole (99.67 mg, 0.702 mmol, 2 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (100 mg, 0.351 mmol, 1.00 equiv) in DMSO were added CuSO4.5H2O (35.01 mg, 0.140 mmol, 0.40 equiv) in H2O and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (16.75 mg, 0.084 mmol, 0.60 equiv) in H2O at room temperature under argon atmosphere. The resultingmixture was stirred for 2 days at room temperature under argon atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30*150 mm, 5m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 2% B to 17% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.65) to afford 3-(5-[4-(1H-1,3-benzodiazol-5-yl)-1,2,3-triazol-1-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione (42.2 mg, 27.94%) as a white solid. [000411] LC-MS (ES, m / z) [M+1]=428 [000412]1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 11.03 (s, 1H), 9.45 (s, 1H), 8.40 – 8.08 (m, 4H), 7.99 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 43.3 Hz, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 – 4.39 (m, 2H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.63 (ddd, J = 17.3, 4.7, 2.4 Hz, 1H), 2.58 – 2.38 (m, 1H), 2.06 (dtd, J = 12.4, 5.3, 2.1 Hz, 1H). [000413] Example 1.22. Synthesis of 3-(5-(4-(isoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (I-149)[000414] To a stirred mixture of 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (55.87 mg, 0.196 mmol, 0.5 equiv) and 6-ethynylisoquinoline (60 mg, 0.392 mmol, 1.00 equiv) in DMSO (4 mL) were added CuSO4.5H2O (29.34 mg, 0.118 mmol, 0.3 equiv) in Water (1 ml) and Sodium ascorbate (70.19 mg, 0.353 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24h at room temperature. Desired product could be detected by LCMS. The residue was dissolved in DMSO (20 mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(5-[4-(isoquinolin-6-yl)-1,2,3- triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (23.9 mg, 13.49%) as a white solid. [000415] LC-MS (ES, m / z) [M+H]+:439.1 [000416]1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.69 (s, 1H), 9.35 (s, 1H), 8.60 – 8.53 (m, 2H), 8.33 – 8.22 (m, 3H), 8.16 (dd, J = 8.2, 1.9 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 17.7 Hz, 1H), 4.50 (d, J = 17.7Hz, 1H), 2.95 (ddd, J = 17.9, 13.6, 5.3 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.50 – 2.39 (m, 2H), 2.07 (q, J = 5.4 Hz, 1H). [000417] Example 1.23. Synthesis of 3-(5-(4-(3-methoxynaphthalen-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-126)[000418] To a stirred mixture of 2-ethynyl-3-methoxynaphthalene (102.21 mg, 0.560 mmol, 2 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (80 mg, 0.280 mmol, 1.00 equiv) in DMSO (4 mL) were added CuSO4.5H2O (21.01 mg, 0.084 mmol, 0.3 equiv) in H2O(1 mL) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5- dihydrofuran-2-one (50.00 mg, 0.252 mmol, 0.9 equiv) in H2O(1 mL) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature under argon atmosphere. Desired product could be detected by LCMS. The residue was dissolved in DMSO (4 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 3-(5-[4-(3-methoxynaphthalen-2-yl)- 1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (35.0 mg, 25.84%) as an off- white solid. [000419] LC-MS (ES, m / z) [M+H]+: 468 [000420]1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.21 (s, 1H), 8.77 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.23 (dd, J = 8.2, 1.9 Hz, 1H), 7.99 (dd, J = 13.6, 8.2 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H), 7.59 – 7.47 (m, 2H), 7.41 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.6 Hz, 1H), 4.49 (d, J = 17.6 Hz, 1H), 4.10 (s, 3H), 2.94 (ddd, J = 18.4, 13.6, 5.3 Hz, 1H), 2.63 (d, J = 17.8 Hz, 1H), 2.45 (td, J = 13.0, 4.3 Hz, 1H), 2.11 – 2.02 (m, 1H). [000421] Example 1.24. Synthesis of 3-(5-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-135)[000422] To a stirred mixture of 1-ethynyl-4-methoxybenzene (100 mg, 0.757 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (215.84 mg, 0.757 mmol, 1 equiv) in DMSO (4 mL) were added CuSO4.5H2O (5668 mg, 0.227 mmol, 0.3 equiv) and Sodium ascorbate (135.59 mg, 0.681 mmol, 0.9 equiv) in H2O (2 mL) at room temperature. The resulting mixture was stirred for 2 days at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was dissolved in DMSO (15 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 20% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(5-[4-(4-methoxyphenyl)-1,2,3- triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (14.5 mg, 4.46%) as a yellow solid. [000423] LC-MS (ES, m / z) [M+H]+: 418 [000424]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.34 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.12 (dd, J = 8.2, 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.93 – 7.85 (m, 2H), 7.13 – 7.05 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 3.82 (s, 3H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.63 (ddd, J = 17.2, 4.4, 2.2 Hz, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.10 – 2.00 (m, 1H). [000425] Example 1.25. Synthesis of 3-(5-(4-(5-methoxypyridin-2-yl)-1H-1,2,3-triazol- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-134)[000426] To a stirred mixture of 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (50 mg, 0.175 mmol, 1 equiv) and 2-ethynyl-5-methoxypyridine (23.34 mg, 0.175 mmol, 1 equiv) in DMSO(5 ml) were added CuSO4.5H2O (28.13 mg, 0.113 mmol, 0.3 equiv) in Water (1ml) and Sodium ascorbate (67.29 mg, 0.338 mmol, 0.9 equiv) in Water (1.5 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24 h at room temperature. Desired product could be detected by LCMS. The residue was dissolved in DMSO (5mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 60% gradient in 20 min; detector, UV 254 nm. The crude product (20 mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14%B to 34%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.98; Number Of Runs: 2) to afford 3-(5-[4-(5-methoxypyridin-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2- ylpiperidine-2,6-dione (8.6 mg, 11.63%) as a yellow solid. [000427] LC-MS (ES, m / z) [M+H]+ 419 [000428]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.34 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 5.17 (dt, J = 13.3, 3.7 Hz, 1H), 4.60 (d, J = 17.6 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 3.90 (d, J = 2.6 Hz, 3H), 3.39 (s, 0H), 3.01 – 2.87 (m, 1H), 2.62 (d, J = 17.3 Hz, 1H), 2.45 (d, J = 12.3 Hz, 1H), 2.06 (d, J = 12.9 Hz, 1H). [000429] Example 1.26. Synthesis of 3-(5-(4-(3,5-dimethoxypyridin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-133)[000430] Into a 20 mL round-bottom flask were added 3-(5-azido-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (60 mg, 0.210 mmol, 1 equiv) in DMSO:H2O(3:1.5mL), then was treated with 2-ethynyl-3,5-dimethoxypyridine (68.64 mg, 0.420 mmol, 2 equiv), CuSO4.5H2O (10.50 mg, 0.042 mmol, 0.2 equiv), Sodium ascorbate (25.13 mg, 0.126 mmol, 0.6 equiv) under nitrogen atmosphere. The resulting mixture was stirred for 3 days at room temperature under argon atmosphere. The reaction was monitored by LCMS. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase,MeCN in Water, 10% to 70% gradient in 25 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MEOH; Flow rate: 60 mL / min mL / min; Gradient: 31% B to 46% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 13.62) to afford 3-{5-[4-(3,5-dimethoxypyridin-2-yl)-1,2,3-triazol-1-yl]-1-oxo- 3H-isoindol-2-yl}piperidine-2,6-dione (13.2 mg, 7.60%) as an off white solid. [000431] LC-MS (ES, m / z) [M +H]+:449.00 [000432]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.33 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.06 (t, J = 2.1 Hz, 1H), 8.00 – 7.93 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 5.22 – 5.13 (m, 1H), 4.61 (d, J = 17.6 Hz, 1H), 4.49 (d, J = 17.5 Hz, 1H), 4.01 (d, J = 1.8 Hz, 3H), 3.94 (d, J = 1.7 Hz, 3H), 2.94 (d, J = 17.1 Hz, 1H), 2.63 (d, J = 17.1 Hz, 1H), 2.42 (s, 1H), 2.07 (dd, J = 10.3, 4.7 Hz, 1H). [000433] Example 1.27. Synthesis of 3-(5-(4-(2,4-dimethoxyphenyl)-1H-1,2,3-triazol-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-132)[000434] To a stirred mixture of 1-ethynyl-2,4-dimethoxybenzene (113.71 mg, 0.701 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (100.00 mg, 0.350 mmol, 0.5 equiv) in DMSO (6 ml) were added CuSO4.5H2O (52.52 mg, 0.210 mmol, 0.3 equiv) in Water (1.5 ml) and Sodium ascorbate (125.64 mg, 0.631 mmol, 0.9 equiv) in Water (1.5 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for additional 24 h at room temperature. Desired product could be detected by LCMS. The residue was dissolved in DMSO (15mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in 3-{5-[4-(2,4- dimethoxyphenyl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (76.3 mg, 23.45%) as an off-white solid. [000435] LC-MS (ES, m / z) [M +H]+: 448.00[000436]1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.96 (s, 1H), 8.30 (d, J = 1.8 Hz, 1H), 8.18 (dd, J = 8.2, 1.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 6.76 – 6.67 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.6 Hz, 1H), 4.47 (d, J = 17.6 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 2.94 (ddd, J = 18.0, 13.5, 5.3 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.48 – 2.39 (m, 1H), 2.09 – 2.01 (m, 1H). [000437] Example 1.28. Synthesis of 3-(5-(4-(5-methoxybenzofuran-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-131)[000438] Into a 20 mL round-bottom flask were added 2-ethynyl-5-methoxy-1-benzofuran (30 mg, 0.174 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (99.40 mg, 0.348 mmol, 2 equiv) in DMSO (4 mL) at 25°C. Then CuSO4.5H2O (8.700 mg, 0.023 mmol, 0.2 equiv) in H2O (1 mL), Sodium ascorbate (20.82 mg, 0.70 mmol, 0.6 equiv) in H2O (1 mL) was added under argon atmosphere. The resulting mixture was stirred for overnight at room temperature under argon atmosphere. The reaction was monitored by LCMS. The residue was dissolved in DMSO (20 mL), and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 70% gradient in 25 min; detector, UV 254 nm to afford 3-{5-[4-(5-methoxy-1-benzofuran-2-yl)-1,2,3- triazol-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (5.0 mg, 6.14%) as a light yellow solid. [000439] LC-MS (ES, m / z) [M +H]+:458.00 [000440]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.48 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.18 (dd, J = 8.2, 1.9 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 0.9 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 9.0, 2.6 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 3.82 (s, 3H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.63 (ddd, J = 17.3, 4.6, 2.5 Hz, 1H), 2.44 (td, J = 13.1, 4.4 Hz, 1H), 2.05 (ddd, J = 10.3, 5.2, 2.7 Hz, 1H). [000441] Example 1.29. Synthesis of 3-(5-(4-(6-methoxybenzofuran-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-121)[000442] Synthesis of 2-ethynyl-6-methoxybenzofuran[000443] Into a 25 mL round-bottom flask were added 6-methoxy-1-benzofuran-2- carbaldehyde (100 mg, 0.568 mmol, 1 equiv), Seyferth-Gilbert reagent (130.86 mg, 0.682 mmol, 1.2 equiv) and MeOH (3 mL) at room temperature. To the above mixture was added K2CO3(94.14 mg, 0.682 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of Water / Ice at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-ethynyl-6-methoxy-1-benzofuran (95 mg, 97.20%) as an off-white solid. [000444] LC-MS (ES, m / z) [M+H]+:198 [000445]1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J = 8.6 Hz, 1H), 7.28 – 7.17 (m, 2H), 6.93 (dd, J = 8.6, 2.3 Hz, 1H), 4.90 (s, 1H), 3.81 (s, 3H). [000446] Synthesis of 3-(5-(4-(6-methoxybenzofuran-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000447] To a stirred mixture of 2-ethynyl-6-methoxy-1-benzofuran (120.72 mg, 0.702 mmol, 2 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (100 mg, 0.351 mmol, 1.00 equiv) in DMSO (8 mL) were added CuSO4.5H2O (26.26 mg, 0.105 mmol, 0.3 equiv) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (62.50 mg, 0.316 mmol, 0.9 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 days at room temperature under argon atmosphere. The reaction was monitored by LCMS. The residue was dissolved in DMSO (8 mL) (10 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-(5-[4-(6-methoxy-1-benzofuran-2-yl)-1,2,3-triazol-1-yl]-1-oxo- 3H-isoindol-2-ylpiperidine-2,6-dione (13.2 mg, 7.93%) as a yellow solid. [000448] LC-MS (ES, m / z) [M+1]=458 [000449]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.41 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.18 (dd, J = 8.2, 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.35 – 7.25 (m, 2H), 6.96 (dd, J = 8.5, 2.2 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 3.85 (s, 3H), 2.94 (ddd, J = 17.6, 13.5, 5.3 Hz, 1H), 2.63 (d, J = 17.2 Hz, 1H), 2.49 – 2.38 (m, 1H), 2.10 – 2.01 (m, 1H). [000450] Example 1.30. Synthesis of 3-(1-oxo-5-(4-(thiazol-2-yl)-1H-1,2,3-triazol-1- yl)isoindolin-2-yl)piperidine-2,6-dione (I-130)[000451] Synthesis of 2-((trimethylsilyl)ethynyl)thiazole[000452] Into a 25 mL round-bottom flask were added 2-Bromothiazole (500 mg, 3.048 mmol, 1 equiv), trimethylsilylacetylene (598.83 mg,6.906 mmol, 2 equiv), Pd(PPh3)4 (176.14 mg, 0.152 mmol, 0.05 equiv), CuI (58.06 mg, 0.305 mmol, 0.1 equiv) and TEA (2 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 3 hours at 60 °C. Desired product could be detected by LCMS. To the mixture was added H2O (20 mL), the mixture was collected by filtration and extracted with EtOAc (3x20mL). The mixture was dried over anhydrous Na2SO4. After filtration. The resulting mixture was concentrated under vacuum and dissolved in DCM (2 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-[2-(trimethylsilyl)ethynyl]-1,3-thiazole (280 mg, 50.65%) as a colorless liquid. [000453] LC-MS (ES, m / z) [M +H]+:182.00 [000454]1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 3.3 Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 0.28 (d, J = 2.1 Hz, 9H). [000455] Synthesis of 2-ethynylthiazole[000456] Into a 25 mL round-bottom flask were added 2-[2-(trimethylsilyl)ethynyl]-1,3- thiazole (200 mg, 1.103 mmol, 1 equiv), THF (4 mL) and TBAF (288.38 mg, 1.103 mmol, 1equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. To the mixture was added H2O (20 mL), The resulting mixture was extracted with CH2Cl2, the mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. [000457] Synthesis of 3-(1-oxo-5-(4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)isoindolin-2- yl)piperidine-2,6-dione[000458] Into a 25 mL round-bottom flask were added 2-ethynyl-1,3-thiazole (110 mg, 1.008 mmol, 1 equiv), DMSO (6 mL) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (143.74 mg, 0.504 mmol, 0.5 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added CuSO4.5H2O (75.49 mg, 0.302 mmol, 0.3 equiv) in H2O (1.50 mL), Sodium ascorbate (180.60 mg, 0.907 mmol, 0.9 equiv) in H2O (1.50 mL) was added in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (25 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 80% gradient in 30 min; detector, UV 254 nm. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 10% B to 28% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.43) to afford 3-{1-oxo-5-[4-(1,3-thiazol-2-yl)-1,2,3- triazol-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (11.4 mg, 2.80%) as a white solid. [000459] LC-MS (ES, m / z): [M +H]+:395.00 [000460]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.55 (s, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 8.2, 1.9 Hz, 1H), 8.01 (d, J = 3.2 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 3.2 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H),3.01 – 2.87 (m, 1H), 2.63 (ddd, J = 17.3, 4.5, 2.2 Hz, 1H), 2.44 (td, J = 13.1, 4.5 Hz, 1H), 2.06 (dtd, J = 10.7, 5.6, 5.2, 2.7 Hz, 1H). [000461] Example 1.31. Synthesis of 3-(5-(4-(6-methoxybenzo[d]thiazol-2-yl)-1H- 1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-125)[000462] To a stirred mixture of 2-ethynyl-6-methoxy-1,3-benzothiazole (90 mg, 0.476 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (67.84 mg, 0.238 mmol, 0.5 equiv) in DMSO (4 mL) were added CuSO4.5H2O (35.63 mg, 0.143 mmol, 0.3 equiv) in Water (1 ml) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5- dihydrofuran-2-one (85.23 mg, 0.428 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 40% to 80% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 3-(5-[4-(6-methoxy-1,3-benzothiazol-2-yl)-1,2,3-triazol-1-yl]-1-oxo- 3H-isoindol-2-ylpiperidine-2,6-dione (49.3 mg, 20.84%) as a yellow solid. [000463] LC-MS (ES, m / z) [M+H]+: 475.1 [000464]1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.74 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.22 (dd, J = 8.2, 2.0 Hz, 1H), 7.97 (dd, J = 8.6, 6.6 Hz, 2H), 7.79 (d, J = 2.6 Hz, 1H), 7.18 (dd, J = 8.9, 2.6 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.8 Hz, 1H), 4.48 (d, J = 17.8 Hz, 1H), 3.88 (s, 3H), 2.94 (ddd, J = 17.8, 13.4, 5.3 Hz, 1H), 2.63 (d, J = 17.2 Hz, 1H), 2.44 (td, J = 13.0, 4.3 Hz, 1H), 2.06 (dd, J = 11.0, 4.9 Hz, 1H). [000465] Example 1.32 Synthesis of 3-(5-(4-(3,5-dimethoxypyridin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-124)[000466] A solution of methyl 5-ethynyl-1-methyl-2-oxopyridine-3-carboxylate (40 mg, 0.209 mmol, 1 equiv) in DMSO:H2O(6:3mL) was treated with 3-(5-azido-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (119.37 mg, 0.418 mmol, 2 equiv), CuSO4.5H2O (15.67 mg, 0.063 mmol, 0.3 equiv), Sodium ascorbate (25.00 mg, 0.125 mmol, 0.6 equiv) under nitrogen atmosphere, The resulting mixture was stirred for 1 day at room temperature under argon atmosphere. The reaction was monitored by LCMS. The residue was dissolved in DMSO(10 mL) and purified by reversed-phase flash chromatography MeCN in Water, 10% to 70% gradient in 25 min; The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MEOH; Flow rate: 60 mL / min mL / min; Gradient: 31% B to 46% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 13.62) to afford methyl 5-{1-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1,2,3-triazol-4-yl}-1-methyl-2-oxopyridine-3- carboxylate as an off-white solid. [000467] LC-MS (ES, m / z) [M +H]+:477.00 [000468]1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.37 (s, 1H), 8.72 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.3, 1.9 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 5.17 (dd, J = 13.4, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.8 Hz, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 2.98 – 2.89 (m, 1H), 2.66 – 2.60 (m, 1H), 2.47 – 2.39 (m, 1H), 2.07 – 2.00 (m, 1H). [000469] Example 1.33. Synthesis of tert-butyl 3-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (I-148)[000470] To a stirred mixture of tert-butyl 3-[(4-ethynylpyrazol-1-yl)methyl]azetidine-1- carboxylate (100 mg, 0.383 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine- 2,6-dione (54.58 mg, 0.192 mmol, 0.5 equiv) in DMSO (6 mL) were added CuSO4.5H2O (28.66 mg, 0.115 mmol, 0.3 equiv) in Water (1.5 ml) and Sodium ascorbate (68.57 mg, 0.345 mmol, 0.9 equiv) in Water (1.5 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for additional 72 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (40 mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl 3-[(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1,2,3- triazol-4-yl}pyrazol-1-yl)methyl]azetidine-1-carboxylate (30.9 mg, 14.77%) as an off-white solid. [000471] LC-MS (ES, m / z) [M +H]+:547.00 [000472]1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.10 (s, 1H), 8.27 – 8.19 (m, 2H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.41 (d, J = 7.3 Hz, 2H), 3.90 (d, J = 8.3 Hz, 2H), 3.71 (s, 2H), 3.02 (tt, J = 9.3, 6.2 Hz, 1H), 2.98 – 2.87 (m, 1H), 2.67 – 2.57 (m, 1H), 2.43 (td, J = 13.1, 4.5 Hz, 1H), 2.10 – 2.00 (m, 1H), 1.37 (s, 9H). [000473] Example 1.34. Synthesis of 3-(5-(4-(6-ethoxypyridin-2-yl)-1H-1,2,3-triazol-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-147)[000474] To a stirred mixture of 2-ethoxy-6-ethynylpyridine (80 mg, 0.544 mmol, 1 equiv), 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (77.53 mg, 0.272 mmol, 0.5 equiv) in DMSO (4 mL) were added CuSO4.5H2O (40.72 mg, 0.163 mmol, 0.3 equiv) in Water (1 ml) and Sodium ascorbate (97.41 mg, 0.490 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at room temperature. Desired product could be detected by LCMS. The resultingmixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 30% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(5-[4-(6- ethoxypyridin-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (51.7 mg, 21.86%) as a white solid. [000475] LC-MS (ES, m / z) [M+H]+433 [000476]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.36 (s, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.22 (dd, J = 8.2, 1.9 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.84 (dd, J = 8.2, 7.4 Hz, 1H), 7.73 – 7.66 (m, 1H), 6.84 – 6.77 (m, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.53 – 4.42 (m, 3H), 2.94 (ddd, J = 17.9, 13.5, 5.4 Hz, 1H), 2.67 – 2.58 (m, 1H), 2.46 (dd, J = 13.0, 4.4 Hz, 1H), 2.10 – 2.01 (m, 1H), 1.38 (t, J = 7.0 Hz, 3H). [000477] Example 1.35. Synthesis of 3-(5-(4-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-146)[000478] To a stirred mixture of 3-ethynyl-2-methoxypyridine (74.68 mg, 0.560 mmol, 2 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (80 mg, 0.280 mmol, 1.00 equiv) in DMSO (6 mL) were added CuSO4.5H2O (42.01 mg, 0.168 mmol, 0.6 equiv) and Sodium ascorbate (12.56 mg, 0.063 mmol, 0.9 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 days at room temperature under argon atmosphere. The reaction was monitored by LCMS. The residue was dissolved in DMSO (6 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-(5-[4-(2-methoxypyridin-3-yl)-1,2,3-triazol-1-yl]- 1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (85.1 mg, 71.58%) as an off-white solid. [000479] LC-MS (ES, m / z) [M+H]+=419 [000480]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.16 (s, 1H), 8.55 (dd, J = 7.5, 1.9 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.28 – 8.17 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 7.19 (dd, J =7.5, 4.9 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 – 4.42 (m, 2H), 4.08 (s, 3H), 2.94 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.44 (td, J = 13.1, 4.5 Hz, 1H), 2.11 – 2.01 (m, 1H). [000481] Example 1.36. Synthesis of 3-(5-(4-(6-cyclopropoxypyridin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-145)[000482] Into a 20 mL sealed tube were added 2-cyclopropoxy-6-ethynylpyridine (66.96 mg, 0.420 mmol, 2 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (60 mg, 0.210 mmol, 1.00 equiv) in DMSO (6 mL) at 25°C. Then CuSO4.5H2O (12.55 mg, 0.050 mmol, 0.2 equiv) in H2O (1 mL) and Sodium ascorbate (30.02 mg, 0.151 mmol, 0.60 equiv) in H2O (3 mL) was added under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was dissolved in DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 95% gradient in 25 min; detector, UV 254 nm to afford 3-(5-[4-(6-cyclopropoxypyridin-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2- ylpiperidine-2,6-dione (70.0 mg, 74.88%) as a yellow solid. [000483] LC-MS (ES, m / z) M+1=445 [000484]1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.36 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.21 (dd, J = 8.2, 1.9 Hz, 1H), 8.01 – 7.86 (m, 2H), 7.76 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.52 – 4.33 (m, 2H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.67 – 2.57 (m, 1H), 2.44 (td, J = 13.1, 4.4 Hz, 1H), 2.10 – 2.01 (m, 1H), 0.90 – 0.67 (m, 4H). [000485] Example 1.37. Synthesis of 3-(5-(4-(2-ethoxyphenyl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (I-144)[000486] Into a 50 mL round-bottom flask were added 1-ethoxy-2-ethynylbenzene (100 mg, 0.684 mmol, 1 equiv), DMSO (5 mL) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (97.57 mg, 0.342 mmol, 0.5 equiv) at room temperature. To the above mixture was added CuSO4.5H2O (51.24 mg, 0.205 mmol, 0.3 equiv) and (+)-Sodium L-ascorbate (122.58 mg, 0.616 mmol, 0.9 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 days at room temperature. The reaction was monitored by LCMS. The resulting mixture was dissolved in DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 25% to 60% gradient in 25 min; detector, UV 254nm. This resulted in 3- (5-[4-(2-ethoxyphenyl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (77.8 mg, 25.65%) as an off-white solid. [000487] LC-MS (ES, m / z) M+1=432 [000488]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.93 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 7.7, 1.8 Hz, 1H), 8.13 (dd, J = 8.2, 1.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.39 (ddd, J = 8.8, 7.3, 1.8 Hz, 1H), 7.21 – 7.02 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.6 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 4.25 (q, J = 6.9 Hz, 2H), 2.94 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.43 (td, J = 13.1, 4.5 Hz, 1H), 2.06 (ddd, J = 9.5, 5.4, 2.6 Hz, 1H), 1.49 (t, J = 6.9 Hz, 3H). [000489] Example 1.38. Synthesis of 3-(5-(4-(2-cyclopropoxyphenyl)-1H-1,2,3-triazol- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-143)[000490] To a stirred mixture of 1-cyclopropoxy-2-ethynylbenzene (100 mg, 0.632 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (90.16 mg, 0.316 mmol,0.5 equiv) in DMSO (6 mL) were added CuSO4.5H2O (47.35 mg, 0.190 mmol, 0.3 equiv) in Water (1.5 ml) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2- one (113.27 mg, 0.569 mmol, 0.9 equiv) in Water (1.5 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 72 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (40 mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 60% gradient in 30 min; detector, UV 254 nm. This resulted in 3-{5-[4-(2-cyclopropoxyphenyl)-1,2,3-triazol-1-yl]- 1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (56.6 mg, 19.73%) as an off-white solid. [000491] LC-MS (ES, m / z) [M +H]+:444.00 [000492]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.81 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.16 (ddd, J = 18.1, 8.0, 1.8 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 8.4, 1.2 Hz, 1H), 7.43 (ddd, J = 8.4, 7.2, 1.7 Hz, 1H), 7.14 (td, J = 7.4, 1.2 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.6 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 4.02 (tt, J = 6.0, 3.2 Hz, 1H), 2.94 (ddd, J = 17.1, 13.6, 5.4 Hz, 1H), 2.63 (ddd, J = 17.3, 4.5, 2.3 Hz, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.11 – 2.01 (m, 1H), 0.95 – 0.81 (m, 4H). [000493] Example 1.39. Synthesis of 3-(1-oxo-5-(4-(o-tolyl)-1H-1,2,3-triazol-1- yl)isoindolin-2-yl)piperidine-2,6-dione (I-129)[000494] To a stirred mixture of 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (61.39 mg, 0.215 mmol, 0.5 equiv) and 1-ethynyl-2-methylbenzene (50 mg, 0.430 mmol, 1 equiv) in DMSO (4 mL)were added CuSO4.5H2O (32.24 mg, 0.129 mmol, 0.3 equiv) in Water (1 ml) and Sodium ascorbate (77.13 mg, 0.387 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at room temperature. Desired product could be detected by LCMS. The residue was dissolved in DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 20 min; detector, UV 254 nm. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30*150 mm, 5m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 29% B to 49% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.28) to afford 3-(5-[4-(2-methylphenyl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (30.6 mg, 17.41%) as a white solid. [000495] LC-MS (ES, m / z) [M+H]+:402.15 [000496]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.18 (s, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.18 (dd, J = 8.2, 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.87 – 7.79 (m, 1H), 7.40 – 7.29 (m, 3H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.6 Hz, 1H), 4.49 (d, J = 17.7 Hz, 1H), 2.94 (ddd, J = 17.8, 13.7, 5.4 Hz, 1H), 2.67 – 2.58 (m, 1H), 2.54 (s, 3H), 2.44 (td, J = 13.1, 4.3 Hz, 1H), 2.10 – 2.02 (m, 1H). [000497] Example 1.40. Synthesis of 3-(5-(4-(3,6-dimethoxynaphthalen-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-128)[000498] Synthesis of 2-bromo-3,6-dimethoxynaphthalene[000499] Into a 40 mL vial were added 3-bromonaphthalene-2,7-diol (500 mg, 2.091 mmol, 1 equiv), K2CO3 (578.10 mg, 4.182 mmol, 2 equiv) and DMF (6 mL) at room temperature. The resulting mixture was stirred for 15 min at room temperature under nitrogen atmosphere. To the above mixture was added CH3I (1187.44 mg, 8.364 mmol, 4 equiv) dropwise at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resultingmixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 2-bromo-3,6-dimethoxynaphthalene (430 mg, 76.97%) as a yellow solid. [000500]1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.04 (dd, J = 8.9, 2.5 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H). [000501] Synthesis of ((3,6-dimethoxynaphthalen-2-yl)ethynyl)trimethylsilane[000502] Into a 40 mL vial were added 2-bromo-3,6-dimethoxynaphthalene (380 mg, 1.423 mmol, 1 equiv), trimethylsilylacetylene (419.17 mg, 4.269 mmol, 3 equiv), CuI (27.09 mg, 0.142 mmol, 0.1 equiv), Pd(PPh3)2Cl2 (49.93 mg, 0.071 mmol, 0.05 equiv), TEA (431.86 mg, 4.269 mmol, 3 equiv) and THF (4 mL) at room temperature. The resulting mixture was stirred for additional overnight at 80 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford [2-(3,6- dimethoxynaphthalen-2-yl)ethynyl]trimethylsilane (120 mg, 19.87%) as a brown oil. [000503] Synthesis of 2-ethynyl-3,6-dimethoxynaphthalene[000504] Into a 10 mL vial were added [2-(3,6-dimethoxynaphthalen-2- yl)ethynyl]trimethylsilane (110 mg, 0.387 mmol, 1 equiv), K2CO3 (53.45 mg, 0.387 mmol, 1 equiv) and MeOH (2 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 15% gradient in 10 min; detector, UV 254 nm. This resulted in 2-ethynyl-3,6-dimethoxynaphthalene (25 mg, 30.46%) as a yellow solid. [000505] LC-MS (ES, m / z) [M+H]+: 213.00[000506]1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 8.9, 2.5 Hz, 1H), 4.22 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H). [000507] Synthesis of 3-(5-(4-(3,6-dimethoxynaphthalen-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000508] In a 50 mL round-bottom flask, a stirred mixture of 2-ethynyl-3,6- dimethoxynaphthalene (20 mg, 0.094 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (26.88 mg, 0.094 mmol, 1 equiv) in DMSO (2 mL) were added CuSO4.5H2O (7.06 mg, 0.028 mmol, 0.3 equiv) and Sodium ascorbate (16.89 mg, 0.085 mmol, 0.9 equiv) in Water (1 mL) dropwise at room temperature under argon atmosphere. To The resulting mixture was stirred for additional 24 h at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 70% gradient in 15min; detector, UV 254 nm. This resulted in 3-(5-[4-(3,6-dimethoxynaphthalen-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione (25.3 mg, 52.78%) as a yellow solid. [000509] LC-MS (ES, m / z) [M+H]+: 498.15 [000510]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.13 (s, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.05 (dd, J = 8.7, 2.4 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.49 (d, J = 17.6 Hz, 1H), 4.08 (s, 3H), 3.89 (s, 3H), 3.01 – 2.85 (m, 1H), 2.68 – 2.59 (m, 1H), 2.49 – 2.39 (m, 1H), 2.11 – 2.03 (m, 1H). [000511] Example 1.41. Synthesis of 3-(1-oxo-5-(4-(4-(tetrahydrofuran-3-yl)phenyl)- 1H-1,2,3-triazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione (I-120)[000512] Synthesis of 4-(4-bromophenyl)tetrahydrofuran-2-ol[000513] To a stirred solution of 4-bromoiodobenzene (3 g, 10.6 mmol, 1 equiv) and 2- butene-1,4-diol (cis) (1214.59 mg, 13.79 mmol, 1.3 equiv) in ACN (10 mL, 190.24 mmol, 17.94 equiv) were added tetrabutylazanium chloride (2947.1 mg, 10.6 mmol, 1 equiv), NaHCO3(1781.64 mg, 21.21 mmol, 2 equiv) and Pd(OAc)2 (476.15 mg, 2.121 mmol, 0.2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for additional overnight at 60°C. Desired product could be detected by LCMS. The reaction was quenched with Water / Ice at 0°C. The resulting mixture was extracted with EtOAc (2 x500 mL). The combined organic layers were washed with brine (3x400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 100% gradient in 30 min; detector, UV 254 nm to afford 4-(4-bromophenyl)oxolan-2-ol (1.6 g, 62.07%) as a white solid. [000514] LC-MS (ES, m / z) no mass signal[000515]1H NMR (400 MHz, DMSO-d6) δ 7.54 – 7.44 (m, 2H), 7.33 – 7.17 (m, 2H), 6.18 (dd, J = 4.8, 1.0 Hz, 1H), 5.49 (m, J = 4.7, 2.3 Hz, 1H), 4.28 – 4.15 (m, 1H), 3.69 – 3.50 (m, 2H), 2.09 (m, J = 12.6, 7.1, 1.3 Hz, 1H), 1.98 (m, J = 13.0, 9.0, 5.0 Hz, 1H). [000516] Synthesis of 3-(4-bromophenyl)tetrahydrofuran[000517] Into a 100mL round-bottom flask, a stirred solution of 4-(4-bromophenyl)oxolan- 2-ol (1.6 g, 6.582 mmol, 1 equiv) in DCM (50 mL, 786.53 mmol, 119.5 equiv) were added Et3SiH (0.84 g, 7.24 mmol, 1.1 equiv) and BF3.Et2O (1.03 g, 7.24 mmol, 1.1 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred for additional 2h at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 100% gradient in 30 min; detector, UV 254 nm to afford 3-(4-bromophenyl)oxolane (1.2 g, 80.28%) as a white solid. [000518] LC-MS (ES, m / z): no mass signal [000519]1H NMR (400 MHz, DMSO-d6) δ 7.53 – 7.45 (m, 2H), 7.28 – 7.21 (m, 2H), 4.00 (t, J = 7.8 Hz, 1H), 3.93 (d, J = 8.3, 4.6 Hz, 1H), 3.78 (q, J = 7.8 Hz, 1H), 3.52 (t, J = 7.8 Hz, 1H), 3.37 (d, J = 7.8 Hz, 1H), 2.30 (dd, J = 12.3, 7.7, 4.5 Hz, 1H), 1.87 (dq, J = 12.3, 8.0 Hz, 1H). [000520] Synthesis of trimethyl((4-(tetrahydrofuran-3-yl)phenyl)ethynyl)silane[000521] Into a 8mL vial ; To a stirred solution of 3-(4-bromophenyl)oxolane (500 mg, 2.202 mmol, 1 equiv) and trimethylsilylacetylene (648.74 mg, 6.606 mmol, 3 equiv) in DMF (15.00 mL, 193.842 mmol, 88.03 equiv) were added CuI (41.93 mg, 0.220 mmol, 0.1 equiv); TEA (668.38 mg, 6.606 mmol, 3 equiv) and Dichlorobis(triphenylphosphine)palladium(II) (154.53 mg, 0.220 mmol, 0.1 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for additional overnight at 90°C. Trace desired product was detected by LCMS, The residue was purified by reversed-phase flash chromatography with thefollowing conditions: column, C18 silica gel; mobile phase, MeCN in Water ; 5% to 100% gradient in 30 min; detector, UV 254 nm to afford trimethyl({2-[4-(oxolan-3- yl)phenyl]ethynyl})silane (130 mg, 24.16%) as a white solid. [000522] LC-MS (ES, m / z): no mass signal [000523] Synthesis of 3-(4-ethynylphenyl)tetrahydrofuran[000524] Into a 25 mL round-bottom flask were added trimethyl({2-[4-(oxolan-3- yl)phenyl]ethynyl})silane (80 mg, 0.327 mmol, 1 equiv), THF (2 mL) was added TBAF (0.49 mL, 0.491 mmol, 1.5 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for additional 1h at room temperature. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 100% gradient in 30 min; detector, UV 254 nm to afford 3-(4-ethynylphenyl)oxolane as a solid. [000525] LC-MS (ES, m / z): no mass signal [000526] Synthesis of 3-(1-oxo-5-(4-(4-(tetrahydrofuran-3-yl)phenyl)-1H-1,2,3-triazol-1- yl)isoindolin-2-yl)piperidine-2,6-dione[000527] Into a 20mL vial ,To a stirred mixture of 3-(4-ethynylphenyl)oxolane (100 mg, 0.581 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (165.63 mg, 0.581 mmol, 1 equiv) in DMSO (20.00 mL, 281.762 mmol, 484.96 equiv) were added CuSO4.5H2O (43.49 mg, 0.174 mmol, 0.3 equiv) in H2O and sodium (5R)-5-[(1S)-1,2- dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (104.05 mg, 0.523 mmol, 0.9 equiv) in H2O dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for additional overnight at room temperature. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 100% gradient in 30 min; detector, UV 254 nm to afford 3-(1-oxo-5-{4-[4-(oxolan-3-yl)phenyl]-1,2,3-triazol-1-yl}-3H-isoindol-2-yl)piperidine-2,6-dione (145.3 mg, 50.93%) as a yellow solid. [000528] LC-MS (ES, m / z):[M+H]+: 458.1 [000529]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.42 (s, 1H), 8.26 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 – 4.43 (m, 2H), 4.12 – 3.93 (m, 2H), 3.82 (d, J = 7.8 Hz, 1H), 3.60 (d, J = 7.9 Hz, 1H), 3.44 (d, J = 7.7 Hz, 1H), 2.94 (s, 1H), 2.62 (d, J = 17.6 Hz, 1H), 2.48 – 2.25 (m, 2H), 2.11 – 1.89 (m, 2H). [000530] Example 1.42. Synthesis of 3-(5-(4-(5-methoxypyrimidin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-142)[000531] Synthesis of 5-methoxy-2-((trimethylsilyl)ethynyl)pyrimidine[000532] Into a 20 mL vial were added 2-bromo-5-methoxypyrimidine (500 mg, 2.645 mmol, 1 equiv), trimethylsilylacetylene (779.47 mg, 7.935 mmol, 3 equiv), Pd(PPh3)2Cl2(92.84 mg, 0.132 mmol, 0.05 equiv), TEA (803.07 mg, 7.935 mmol, 3 equiv), CuI (50.38 mg, 0.265 mmol, 0.1 equiv) and THF (10.00 mL, 123.428 mmol, 46.66 equiv) at room temperature. The resulting mixture was stirred for additional overnight at 60 C. Desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with ethyl acetate (3x10 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford 5-methoxy-2-[2-(trimethylsilyl)ethynyl]pyrimidine (550 mg, 96.74%) as an orange solid.[000533] LC-MS (ES, m / z) [M+ ACN]+:207.15[000534] 1H NMR (400 MHz, DMSO-d6) 8.53 (s, 2H), 3.94 (s, 3H), 0.26 (s, 9H).[000535] Synthesis of 2-ethynyl-5-methoxypyrimidine[000536] Into a 10 mL vial were added 5-methoxy-2-[2-(trimethylsilyl)ethynyl]pyrimidine (300 mg, 1.454 mmol, 1 equiv) and MeOH (3 mL, 74.096 mmol, 50.96 equiv) at room temperature. To the above mixture was added K2CO3 (200.96 mg, 1.454 mmol, 1 equiv) in portions over 1 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x1 mL). The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-ethynyl-5-methoxypyrimidine (180 mg, 90.44%) as a white solid. [000537] LC-MS (ES, m / z) [M+H]+:135.05[000538] 1H NMR (400 MHz, DMSO-d6) 8.55 (s, 2H), 4.21 (s, 1H), 3.95 (s, 3H).[000539] Synthesis of 3-(5-(4-(5-methoxypyrimidin-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000540] Into a 10 mL vial were added 2-ethynyl-5-methoxypyrimidine (100 mg, 0.746 mmol, 1 equiv), 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (212.66 mg, 0.746 mmol, 1 equiv) and THF (5.00 mL, 61.714 mmol, 82.78 equiv) at room temperature. To the above mixture was added CuSO4.5H2O (55.84 mg, 0.224 mmol, 0.3 equiv) and 3-{5-[4-(5- methoxypyrimidin-2-yl)-1,2,3-triazol-1-yl]-1- oxo-3H-isoindol-2-yl}piperidine-2,6-dione (61.0 mg, 18.61%) in H2O (1.00 mL, 55.509 mmol, 74.46 equiv) dropwise over 1 min at room temperature. The resulting mixture was stirred for additional 2 days at room temperature. Desired product could be detected by LCMS. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobilephase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min, 40%; detector, UV 254 nm. This resulted in 3-{5-[4-(5-methoxypyrimidin-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2- yl}piperidine-2,6-dione (61.0 mg, 18.61%) as a yellow solid. [000541] LC-MS (ES, m / z) [M+H]+:288.10[000542] 1H NMR (400 MHz, DMSO-d6) 11.02 (s, 1H), 9.48 (s, 1H), 8.69 (s, 2H), 8.388.31 (m, 1H), 8.22(dd, J = 8.3, 1.9 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 3.99 (s, 2H), 2.94 (ddd, J = 18.1, 13.5, 5.3 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.42 (dd, J = 13.6, 4.5 Hz, 1H), 2.10-2.00 (m, 1H). [000543] Example 1.43. Synthesis of 3-(5-(4-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-141)[000544] To a stirred mixture of 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (58.56 mg, 0.205 mmol, 0.5 equiv) and 5-ethynyl-2H-1,3-benzodioxole (60 mg, 0.411 mmol, 1.00 equiv) in DMSO (4 mL)were added CuSO4.5H2O (30.75 mg, 0.123 mmol, 0.3 equiv) in Water (1 ml) and sodium Sodium ascorbate (73.57 mg, 0.370 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 20% to 55% gradient in 20 min; detector, UV 254 nm. The product was purified by Prep- HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: MeOH--HPLC; Flow rate: 60 mL / min mL / min; Gradient: 40% B to60% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.12) to afford 3-(5-[4-(2H-1,3-benzodioxol-5-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2- ylpiperidine-2,6-dione (8.3 mg, 4.63%) as an off-white solid. [000545] LC-MS (ES, m / z) [M+H]+:432.1[000546]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.34 (s, 1H), 8.23 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.3, 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.10 – 7.03 (m, 1H), 6.09 (s, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 2.94 (ddd, J = 18.1, 13.5, 5.4 Hz, 1H), 2.67 – 2.58 (m, 1H), 2.43 (td, J = 13.1, 4.5 Hz, 1H), 2.10 – 2.00 (m, 1H). [000547] Example 1.44. Synthesis of 3-(5-(4-(1,5-naphthyridin-2-yl)-1H-1,2,3-triazol- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-127)[000548] Into a 50 mL round-bottom flask were added 2-ethynyl-1,5-naphthyridine (60 mg, 0.389 mmol, 1 equiv), DMSO (4 mL) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (55.51 mg, 0.195 mmol, 0.5 equiv) at room temperature under argon atmosphere. To the above mixture was added CuSO4.5H2O (29.15 mg, 0.117 mmol, 0.3 equiv), H2O (2 mL) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (69.74 mg, 0.350 mmol, 0.9 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 55% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(5-[4-(1,5- naphthyridin-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (53.8 mg, 30.92%) as a brown solid. [000549] LC-MS (ES,m / z) [M+H]+:440.14 [000550]1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.68 (s, 1H), 9.06 – 9.00 (m, 1H), 8.58 (q, J = 8.8 Hz, 2H), 8.49 – 8.43 (m, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.27 (dd, J = 8.2, 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.91 – 7.81 (m, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 17.6 Hz, 1H), 4.49 (d, J = 17.6 Hz, 1H), 2.95 (ddd, J = 18.0, 13.6, 5.4 Hz, 1H), 2.63 (dt, J = 15.1, 2.9 Hz, 1H), 2.49 – 2.39 (m, 1H), 2.11 – 1.95 (m, 1H).[000551] Example 1.45. Synthesis of 3-(5-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (I-117) [[000553] Into a 25 mL sealed tube were added 2-bromofuran (500 mg, 3.402 mmol, 1 equiv), Pd(PPh3)2Cl2 (477.58 mg, 0.680 mmol, 0.2 equiv), CuI (129.58 mg, 0.680 mmol, 0.2 equiv) and TEA (7.5 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 60 °C. The reaction was monitored by LCMS and TLC. Desired product could be detected by LCMS and TLC. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and purified by silica gel column chromatography, eluted with PE / EA (12:1) to afford [2-(furan-2-yl)ethynyl]trimethylsilane (180 mg, 32.21%) as an colorless oil. [000554]1H NMR (400 MHz, Chloroform-d) δ 7.35 (dd, J = 1.9, 0.7 Hz, 1H), 6.60 (dd, J = 3.4, 0.8 Hz, 1H), 6.36 (dd, J = 3.4, 1.9 Hz, 1H), 0.25 (s, 9H). [000555] Synthesis of 2-ethynylfuran[000556] Into a 25 mL round-bottom flask were added [2-(furan-2- yl)ethynyl]trimethylsilane (180 mg, 1.096 mmol, 1 equiv) in MeOH (4 mL) and K2CO3 (302.86 mg, 2.191 mmol, 2.00 equiv) at 25°C. The resulting mixture was stirred for 30 min at room temperature under argon atmosphere. The reaction was monitored by LCMS. The mixture was washed with THF (3x10 mL). The combined organic layers was concentrated under reduced pressure directly used in nest step. [000557] Synthesis of 3-(5-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione[000558] To a stirred mixture of 2-ethynylfuran (45 mg, 0.489 mmol, 1 equiv) and 3-(5- azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (69.69 mg, 0.244 mmol, 0.50 equiv) in DMSO (6 ml) were added CuSO4.5H2O (24.40 mg, 0.098 mmol, 0.2 equiv) in Water (1.5 ml) and Sodium ascorbate (58.37 mg, 0.293 mmol, 0.60 equiv) in Water (1.5 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24 hours at room temperature. Desired product could be detected by LCMS. The residue was dissolved in DMSO (15mL). The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in 3-{5-[4-(furan-2-yl)-1,2,3-triazol-1- yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (56.7 mg, 30.54%) as a white solid. [000559] LC-MS (ES, m / z) [M +H]+: 378.00 [000560]1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.26 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 3.3 Hz, 1H), 6.67 (dd, J = 3.4, 1.9 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 2.93 (ddd, J = 18.0, 13.6, 5.4 Hz, 1H), 2.62 (d, J = 17.4 Hz, 1H), 2.43 (td, J = 13.3, 4.7 Hz, 1H), 2.05 (d, J = 4.4 Hz, 1H). [000561] Example 1.46. Synthesis of 3-(5-(4-(4-methoxypyrimidin-2-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-140)[000562] Into a 50 mL round-bottom flask were added 2-ethynyl-4-methoxypyrimidine (100 mg, 0.746 mmol, 1 equiv),3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (127.60 mg, 0.448 mmol, 0.6 equiv) and DMSO (5 mL) at room temperature under nitrogen atmosphere. To the above mixture was added CuSO4.5H2O (55.84 mg, 0.224 mmol, 0.3 equiv), Sodium ascorbate (133.60 mg, 0.671 mmol, 0.9 equiv) and H2O (2.5 mL) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with DMSO (25 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 25% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10%B to 30%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.55; Number Of Runs: 1) to afford 3-(5-[4-(4- methoxypyrimidin-2-yl)-1,2,3-triazol-1-yl]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (24.4 mg, 7.60%) as an off-white solid. [000563] LC-MS (ES, m / z) [M+H]+420 [000564]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.58 (s, 1H), 8.64 (d, J = 5.8 Hz, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.23 (dd, J = 8.2, 2.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 5.8 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 4.07 (s, 3H), 2.94 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.63 (d, J = 17.3 Hz, 1H), 2.48 – 2.42 (m, 1H), 2.06 (d, J = 8.2 Hz, 1H).119 [000565] Example 1.47. Synthesis of 3-(1-oxo-5-(4-(6-(trifluoromethoxy)pyridin-2-yl)- 1H-1,2,3-triazol-1-yl)isoindolin-2-yl)piperidine-2,6-dione (I-119)[000566] To a stirred mixture of 2-ethynyl-6-(trifluoromethoxy)pyridine (80 mg, 0.428 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (60.98 mg, 0.214 mmol, 0.5 equiv) in DMSO (4 mL) were added CuSO4.5H2O (32.02 mg, 0.128 mmol, 0.3 equiv) in Water (1 ml) and sodium (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5- dihydrofuran-2-one (76.23 mg, 0.385 mmol, 0.9 equiv) in Water (1 ml) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 24 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was diluted with DMSO (20 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 40% to 80% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 30% B in 2 min, 30% to 46% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.78) to afford 3-(1-oxo-5-(4-[6-(trifluoromethoxy)pyridin-2-yl]- 1,2,3-triazol-1-yl-3H-isoindol-2-yl)piperidine-2,6-dione (22.4 mg, 10.90%) as a white solid. [000567] LC-MS (ES, m / z) [M+H]+: 473.11 [000568]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.37 (s, 1H), 8.39 – 8.34 (m, 1H), 8.27 – 8.12 (m, 3H), 7.96 (d, J = 8.3 Hz, 1H), 7.33 (dd, J = 7.8, 1.1 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 2.94 (ddd, J = 17.7, 13.6, 5.4 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.48 – 2.40 (m, 1H), 2.06 (dd, J = 9.1, 3.7 Hz, 1H). [000569] Example 1.48. Synthesis of 3-(5-(4-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1H- 1,2,3-triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-112)[000570] Synthesis of tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azetidine-1-carboxylate[000571] To a stirred mixture of tert-butyl 3-iodoazetidine-1-carboxylate (1000 mg, 3.532 mmol, 1 equiv) and 4-iodopyrazole (822.19 mg, 4.238 mmol, 1.2 equiv) in DMF (10.00 mL) was added K2CO3(976.34 mg, 7.064 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 80 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with acetonitrile (3 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. To afford tert-butyl 3-(4-iodopyrazol-1- yl)azetidine-1-carboxylate (1 g, yield 90%) as a yellow solid. [000572] LC-MS (ES, m / z) [M+H-100+44]+: 293.85 [000573]1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.65 (s, 1H), 5.20 (m, 1H), 4.26 (t, J = 8.5 Hz, 2H), 4.10 (s, 2H), 1.40 (s, 9H).[000574] Synthesis of tert-butyl 3-(4-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)azetidine-1- carboxylate[000575] To a stirred solution of tert-butyl 3-(4-iodopyrazol-1-yl)azetidine-1-carboxylate (1000 mg, 2.864 mmol, 1 equiv) and Pd(PPh3)2Cl2(100.51 mg, 0.143 mmol, 0.05 equiv) and CuI (5.45 mg, 0.029 mmol, 0.1 equiv) and TEA (86.94 mg, 0.858 mmol, 3 equiv) in DMF (10 mL) were added trimethylsilylacetylene (843.88 mg, 8.592 mmol, 3 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with the following conditions: column, silica gel; mobile phase, EA in PE, 0% to 50% gradient in 40 min; detector, UV 254 nm. To afford tert- butyl 3-(4-[2-(trimethylsilyl)ethynyl]pyrazol-1-ylazetidine-1-carboxylate (800 mg, yield 80%) as a brown solid. [000576] LC-MS (ES, m / z) [M+H-100+44]+: 264.10 [000577]1H NMR (300 MHz, Chloroform-d) δ 7.69 (d, J = 2.2 Hz, 2H), 5.04 (m, 1H), 4.43 – 4.33 (m, 2H), 4.27 (m, 2H), 0.24 (s, 9H). [000578] Synthesis of tert-butyl 3-(4-ethynyl-1H-pyrazol-1-yl)azetidine-1-carboxylate[000579] Into a 50 mL vial were added tert-butyl 3-(4-[2-(trimethylsilyl)ethynyl]pyrazol-1- ylazetidine-1-carboxylate (600 mg, 1.878 mmol, 1 equiv) and K2CO3 (519.11 mg, 3.756 mmol, 2 equiv) and MeOH (12 mL) at room temperature. The resulting mixture was stirred for 30 min at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was dissolved in EtOAc (50 mL). The resulting mixture was washed with water (2 x 20 mL). The organic layer was dried overanhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with the following conditions: column, silica gel; mobile phase, EA in PE, 30% to 50% gradient in 20 min; detector, UV 254 nm. To afford tert- butyl 3-(4-ethynylpyrazol-1-yl)azetidine-1-carboxylate (320 mg, yield 65%) as a white solid. [000580] LC-MS (ES, m / z) [M+H-100+44]+: 192.00 [000581]1H NMR (300 MHz, Chloroform-d) δ 7.70 (s, 2H), 5.03 (m, 1H), 4.44 – 4.27 (m, 4H), 3.04 (s, 1H), 1.48 (s, 9H). [000582] Synthesis of tert-butyl 3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate[000583] Into a 50 mL round-bottom flask were added tert-butyl 3-(4-ethynylpyrazol-1- yl)azetidine-1-carboxylate (120 mg, 0.485 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (276.84 mg, 0.970 mmol, 2 equiv) and DMSO (9 mL) and H2O (4.5 mL) and CuSO4 (23.23 mg, 0.145 mmol, 0.3 equiv) and sodium (5R)-5-[(1S)-1,2- dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (86.52 mg, 0.436 mmol, 0.9 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with DMSO / H2O=1:2 (2 x 2 mL) and H2O (2 x 2 mL). The filter cake was dried over. To afford tert-butyl 3-(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- isoindol-5-yl]-1,2,3-triazol-4-yl}pyrazol-1-yl)azetidine-1-carboxylate (215 mg, yield 79%) as a white solid. [000584] LC-MS (ES, m / z) [M+H]+: 533.25 [000585]1H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.14 (s, 1H), 8.36 (s, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 8.03 – 7.95 (m, 2H), 5.33 (q, J = 5.5 Hz, 1H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.65 – 4.43 (m, 2H), 4.33 (t, J = 8.3 Hz, 2H), 4.18 (s, 2H), 3.03 – 2.85 (m, 1H), 2.62 (d, J = 16.9 Hz, 1H), 2.48 – 2.36 (m, 1H), 2.09 – 1.96 (m, 1H), 1.43 (s, 9H).[000586] Synthesis of 3-(5-(4-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000587] Into a 25 mL round-bottom flask were added tert-butyl 3-(4-(1-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1,2,3-triazol-4-ylpyrazol-1-yl)azetidine-1- carboxylate (100 mg, 0.188 mmol, 1 equiv) and DCM (1 mL) and TFA (1 mL, 13.463 mmol) at 0 °C. The resulting mixture was stirred for h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 20 min; detector, UV 254 nm to afford 3-(5-(4-[1-(azetidin-3-yl)pyrazol-4-yl]-1,2,3-triazol-1-yl-1-oxo- 3H-isoindol-2-yl)piperidine-2,6-dione;trifluoroacetic acid (76.6 mg, yield 93%) as a white solid. [000588] LC-MS (ES, m / z) [M+H]+: 433.00 [000589]1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.17 (s, 1H), 9.10 (br, 2H), 8.36 (s, 1H), 8.22 (d, J = 1.9 Hz, 1H), 8.14 – 8.05 (m, 2H), 7.97 (d, J = 8.3 Hz, 1H), 5.52 (p, J = 7.4 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 17.8 Hz, 1H), 4.53 – 4.32 (m, 5H), 3.02 – 2.86 (m, 1H), 2.62 (d, J = 17.5 Hz, 1H), 2.43 (m, 1H), 2.04 (m, 1H). [000590] Example 1.49. Synthesis of 3-(5-(4-(4-(furan-3-yl)phenyl)-1H-1,2,3-triazol-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-139)[000591] Synthesis of ((4-(furan-3-yl)phenyl)ethynyl)trimethylsilane[000592] Into a 40 mL vial , To a stirred mixture of [2-(4- iodophenyl)ethynyl]trimethylsilane (500 mg, 1.67 mmol, 1 equiv) and furan-3-ylboronic acid (186.35 mg, 1.67 mmol, 1 equiv) in Dioxane (10 mL, 118.04 mmol, 70 equiv) were added k2CO3(575.44 mg, 4.16 mmol, 2.5 equiv), H2O (1 mL, 55.51 mmol, 33.33 equiv) and Pd(dppf)Cl2 (121.86 mg, 0.17 mmol, 0.1 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for additional overnight at 100°C. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x300 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford {2-[4-(furan-3- yl)phenyl]ethynyl}trimethylsilane (190 mg, 47.46%) as a white solid. [000593] LC-MS (ES, m / z): [M+H]+: (no mass signal) [000594]1H NMR (400 MHz, DMSO-d6) δ 8.03 (t, J = 1.2 Hz, 1H), 7.52 (t, J = 1.7 Hz, 1H), 7.49 – 7.35 (m, 2H), 7.29 – 7.13 (m, 2H), 6.76 (dd, J = 1.9, 0.9 Hz, 1H), -0.05 (s, 9H). [000595] Synthesis of 3-(4-ethynylphenyl)furan[000596] Into a 20 mL vial , To a stirred mixture of {2-[4-(furan-3- yl)phenyl]ethynyl}trimethylsilane (190 mg, 0.79 mmol, 1 equiv) in MeOH (5 mL, 246.98 mmol, 312.42 equiv) was added K2CO3 (109.24 mg, 0.79 mmol, 1 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for additional 2h at room temperature. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 100% gradient in 30 min; detector, UV 254 nm to afford 3-(4-ethynylphenyl)furan (110 mg, 82.74%) as an off- white oil.[000597] LC-MS (ES, m / z) [M+H]+: (no mass signal) [000598]1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 1.8 Hz, 1H), 4.21 (s, 1H). [000599] Synthesis of 3-(5-(4-(4-(furan-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione[000600] Into a 20 mL vial ; To a stirred mixture of 3-(4-ethynylphenyl)furan (50 mg, 0.29 mmol, 1 equiv) and 3-(5-azido-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (84.80 mg, 0.29 mmol, 1 equiv) in DMSO (5 mL, 70.395 mmol, 118.40 equiv) were added CuSO4.5H2O (22.27 mg, 0.09 mmol, 0.3 equiv) in H2O (1 mL, 55.51 mmol, 93.36 equiv) and sodium (5R)-5-[(1S)- 1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (106.54 mg, 0.54 mmol, 0.9 equiv) in H2O (1 mL, 55.509 mmol, 93.36 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for additional overnight at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 10% gradient in 30 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 27% B to 42% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.78) to afford 3-(5-{4-[4-(furan-3-yl)phenyl]-1,2,3-triazol-1-yl}-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (3.3 mg, 2.45%) as a yellow solid. [000601] LC-MS (ES, m / z) [M+H]+: 454.10 [000602]1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.47 (s, 1H), 8.27 (d, J = 2.7 Hz, 2H), 8.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.99 (dd, J = 8.2, 4.1 Hz, 3H), 7.81 – 7.74 (m, 3H), 7.04 (d, J = 1.9 Hz, 1H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.62 (d, J = 17.7 Hz, 1H), 4.49 (d, J = 17.6 Hz, 1H), 2.93 – 2.83 (m, 1H), 2.68 – 2.58 (m, 1H), 2.50 – 2.39 (m, 1H), 2.10 – 2.01 (m, 1H).[000603] Example 1.50. Synthesis of 3-(5-(4-(8-methoxy-2H-chromen-3-yl)-1H-1,2,3- triazol-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-157)[000604] Synthesis of 3-(2,2-dibromovinyl)-8-methoxy-2H-chromene[000605] Into a 50 mL 3-necked round-bottom flask were added 8-methoxy-2H-chromene- 3-carbaldehyde (1 g, 5.258 mmol, 1 equiv) and PPh3(2.76 g, 10.516 mmol, 2 equiv) in DCM (20 mL) at 25°C. CBr4 (3.49 g, 10.516 mmol, 2 equiv) and Zn (0.69 g, 10.516 mmol, 2 equiv) were added at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water at 0°C. After addition of water (20 mL). The aqueous layer was extracted with EtOAc (3x20 mL) and the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in DCM (10 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 3-(2,2- dibromoethenyl)-8-methoxy-2H-chromene (700 mg, 34.24%) as a white solid. [000606]1H NMR (400 MHz, Chloroform-d) δ 7.00 (s, 1H), 6.83 – 6.71 (m, 2H), 6.65 – 6.57 (m, 2H), 5.10 (d, J = 1.3 Hz, 2H), 3.80 (s, 3H). [000607] Synthesis of 3-ethynyl-8-methoxy-2H-chromene[000608] Into a 250 mL sealed t...

Claims

We claim:

1. A compound having the structure of formula I:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring A is substituted with m instances of Rx; each Rxis independently selected from oxo, halogen, -NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CX2)zY; or: two instances of Rx, together with the atoms to which they are attached, form a 5- to 6- membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each X is independently selected from hydrogen, C1-4alkyl, and halogen; Y is selected from -N(R)2, -OR, -O(CH2)2OR, -C(O)R, -CO2R, -OC(O)R, -C(O)N(R)2, - N(R)C(O)R, -N(R)C(O)OR, -SO2R, -SO2N(R)2, and -N(R)SO2R; L is selected from a covalent bond or a C1-2aliphatic chain wherein one methylene unit is optionally substituted with –N(R)-, -S-, –O- or –C(=O)-; Ring B is selected from a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is substituted with n instances of Ry; each Ryis selected from halogen, C1-3alkyl, and lower haloalkyl;Ring C is a bivalent group comprisingor; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0-3; n is 0-2; y is 0-2; and z is 0-1.

2. The compound according to claim 1, wherein the compound is of formula II:or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, wherein Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. The compound according to claim 3, wherein Ring B is a triazolylene ring.

5. The compound according to claim 4, wherein Ring B is .

6. The compound according to claim 5, wherein Ring B is , wherein * indicates the point of attachment to Ring A.

7. The compound according to claim 5, wherein Ring B is, wherein * indicates the point of attachment to Ring A.

8. The compound according to claim 4, wherein Ring B is.

9. The compound according to claim 8, wherein Ring B iswherein * indicates the point of attachment to Ring A.

10. The compound according to claim 8, wherein Ring B is, wherein * indicates the point of attachment to Ring A.

11. The compound according to claim 3, wherein Ring B is a pyrazolylene ring.

12. The compound according to claim 11, wherein Ring B is.

13. The compound according to claim 12, wherein Ring B is, wherein * indicates the point of attachment to Ring A.

14. The compound according to claim 12, wherein Ring B is , wherein * indicates the point of attachment to Ring A.

15. The compound according to claim 11, wherein Ring B is. 1 The compound according to claim 11, wherein Ring B is.

17. The compound according to claim 16, wherein Ring B is , wherein * indicates the point of attachment to Ring A.

18. The compound according to claim 16, wherein Ring B is, wherein * indicates the point of attachment to Ring A.

19. The compound according to claim 11, wherein Ring B is.

20. The compound according to claim 19, wherein Ring B is , wherein * indicates the point of attachment to Ring A.

21. The compound according to claim 19, wherein Ring B iswherein * indicates the point of attachment to Ring A.

22. The compound according to any one of claims 1-21, wherein Ring A is selected from:

23. The compound according to claim 22, wherein Ring A is selected from24. The compound according to any one of claims 1-23, wherein the compound is not a compound set forth in Table 2.

25. The compound according to claim 1, wherein the compound is selected from those in Table 1, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1- 25, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

27. A method of treating a cancer, the method comprising administering a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

28. The method according to claim 27, wherein the cancer is a CK1α-mediated cancer.

29. The method according to claim 27, wherein the cancer is a WNT-mediated cancer.

30. The method according to claim 27, wherein the cancer is a p53-mediated cancer.

31. A method of modulating an oncogenic pathway, the method comprising contacting a biological sample or administering to a subject in need thereof a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

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