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 C, L, Rx, and m 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 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 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 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, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 -OR, -N(R)2, -O(CH2)2OR, -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 a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, - S(O)2-, and -CF2-; each Ryis selected from hydrogen, C1-3alkyl and lower haloalkyl; Ring C is a bivalent group comprisingwherein 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; 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. and March, 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 offive 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 unit dosage 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, 5,6,7,8-tetrahydroquinolinyl, 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 unsaturatedring 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, 1,2,3,4-tetrahydroisoquinolinyl, or 1,2,3,4- 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 substituent selected 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 thatresult 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; –(C1–4straight 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, C1–6 aliphatic, –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 independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NRl2, –NO2, –SiRl3, – OSiR●3, -C(O)SR●, –( C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –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, C1–6aliphatic 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, C1–6aliphatic 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, – R●, -(haloR●), -OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –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, C1–6aliphatic 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 interveningatom(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, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –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 and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonicsaline; 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)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceuticallyacceptable 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 therapeuticregimen. 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 aswell 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: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, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, - S(O)2-, and -CF2-; each Ryis selected from hydrogen, C1-3alkyl or lower haloalkyl; Ring C is a bivalent group comprisingeach 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; y is 0-2; and z is 0-1.

[0046] In some embodiments, the present disclosure provides a compound of formula I’: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, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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, a 9- to 10-memberedbicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, - S(O)2-, and -CF2-; each Ryis selected from hydrogen, C1-3alkyl or lower haloalkyl; Ring C is a bivalent group comprising, wherein 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; 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, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 -OR, -N(R)2, -O(CH2)2OR, -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 a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, - S(O)2-, and -CF2-; each Ryis selected from hydrogen, C1-3alkyl and lower haloalkyl; Ring C is a bivalent group comprising, wherein 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; y is 0-2; and z is 0-1.

[0048] As defined generally above, Ring C is a bivalent group comprisingor. In some embodiments, Ring C is a bivalent group comprising. In some embodiments, Ring C is a bivalent group comprising. In some embodiments, Ring C has the structure. In some embodiments, Ring C has the structure. In some embodiments, Ring C has the structure. In some such embodiments, Ring C has the structure. In some embodiments, Ring C has the structure. In some embodiments, Ring C has the structure. In some embodiments, Ring C has the structure. In some such embodiments, Ring C has the structure. In 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: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, Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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, 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 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 ofFormula 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 1-2 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 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, Ring A is a piperidinyl 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 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 is a 1,2,3,4-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.

[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 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[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. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a pyrimidinyl ring. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a pyridazinyl ring. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a pyrazinyl ring. 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 ofFormula I, I’, I”, II, II-a, III, or III-a, Ring A is a benzo[d]isoxazolyl, benzo[c][1,2,5]thiadiazolyl ring, a thiazolo[5,4-b]pyridinyl ring, or a benzo[d]thiazolyl ring.

[0061] 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 a 9- membered bicyclic heteroaryl ring having 2-4 nitrogen atoms. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is selected from a 1H-pyrazolo[3,4-b]pyridinyl ring, a 1H- pyrazolo[4,3-b]pyridinyl ring, 2H-pyrazolo[4,3-b]pyridinyl ring, a 3H-imidazo[4,5-b]pyridinyl ring, a 3H-imidazo[4,5-c]pyridinyl ring, a [1,2,3]triazolo[1,5-a]pyridinyl ring, a 7H-pyrrolo[2,3- d]pyrimidinyl ring, a 1H-indazolyl ring, a 2H-indazolyl ring, a 1H-benzo[d]imidazolyl ring, a 1H-pyrazolo[3,4-d]pyrimidinyl ring, 1H-pyrazolo[3,4-d]pyrimidinyl ring, a [1,2,4]triazolo[4,3- b]pyridazinyl ring, 1H-pyrazolo[3,4-b]pyrazinyl ring, a 5H-pyrrolo[2,3-b]pyrazinyl ring, a 1H- pyrrolo[2,3-b]pyridinyl ring, or a [1,2,4]triazolo[1,5-a]pyrimidinyl ring. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is selected from a 1H-pyrazolo[3,4-b]pyridinyl ring, a 1H-pyrazolo[4,3-b]pyridinyl ring, 2H-pyrazolo[4,3-b]pyridinyl ring, a 3H-imidazo[4,5- b]pyridinyl ring, a 3H-imidazo[4,5-c]pyridinyl ring, a [1,2,3]triazolo[1,5-a]pyridinyl ring, a 7H- pyrrolo[2,3-d]pyrimidinyl ring, a 1H-indazolyl ring, a 2H-indazolyl ring, a 1H- benzo[d]imidazolyl ring, a 1H-pyrazolo[3,4-d]pyrimidinyl ring, 1H-pyrazolo[3,4-d]pyrimidinyl ring, a [1,2,4]triazolo[4,3-b]pyridazinyl ring, 1H-pyrazolo[3,4-b]pyrazinyl ring, a 5H- pyrrolo[2,3-b]pyrazinyl ring, a 1H-pyrrolo[2,3-b]pyridinyl ring, or a [1,2,4]triazolo[1,5- a]pyrimidinyl ring, or a [1,2,4]triazolo[4,3-a]pyridinyl ring.

[0062] 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, Ring A is a cinnolinyl ring, 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 nitrogenatom. 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. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a 5,6,7,8-tetrahydroquinolinyl ring.

[0063] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is selected from:

[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 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. In 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.

[0067] 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 is In 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 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. 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. 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.

[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 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. 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.

[0070] As defined generally above, each Rxis independently selected from oxo, halogen, - NO2, -(CH2)yR, –CN, –OR, -N(R)2, -SR, and -(CH2)zY. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Rxis oxo. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Rxis halogen. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Rxis –OR. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Rxis -N(R)2. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Rxis -(CH2)yR. In some embodiments of Formula I, 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, each Y is selected from –OR, -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; 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’, I”, II, II-a, III, or III-a, Y is –CO2R. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Y is –OR.

[0072] As defined generally above for formula I”, Y is selected from -OR, -N(R)2, - O(CH2)2OR, -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”, Y is -OR. In some embodiments of formula I”, Y is -N(R)2. In some embodiments of formula I”, Y is -OCH2CH2OR.

[0073] As defined generally above, L is a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from – N(Ry)-, -C(=O)-, -O-, -S(O)2-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-3aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, -S(O)2-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-2aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, -S(O)2-, and -CF2-.

[0074] In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally andindependently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-3aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-2aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, and -CF2-.

[0075] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-4aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, -S(O)2-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-3aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, -S(O)2-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-2aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, - C(=O)-, -O-, -S(O)2-, and -CF2-.

[0076] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-4aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-3aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from – N(Ry)-, -C(=O)-, -O-, and -CF2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-2aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, and - CF2-.

[0077] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-4aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, and -O-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-3aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, - C(=O)-, and -O-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is a C1-2aliphatic chain wherein one or two methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, and -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 –N(Ry)-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is –CH2N(Ry)- or –N(Ry)CH2-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is –N(Ry)-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is -OCH2- or -CH2O-.

[0080] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is.In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A.

[0081] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is.In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A.

[0082] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is, wherein *denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III- a, L is, wherein * denotes the attachment to Ring A.

[0083] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is, wherein * denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III- a, L is, wherein * denotes the attachment to Ring A.

[0084] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is . In some embodiments of Formula, wherein * denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A.

[0085] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is, wherein * denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is, wherein * denotes the attachment to Ring A.

[0086] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is, wherein * denotes the attachment to Ring A.

[0087] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A.

[0088] As defined generally above, each Ryis selected from hydrogen, C1-3alkyl or lower haloalkyl. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ryis hydrogen. Accordingly, in some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is selected from – C(=O)-, –NH-, –CH2NH-, –NHCH2-,wherein * denotes the attachment to Ring A.

[0089] in some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is selected from – C(=O)-, –NH-, -CH2O-, -OCH2-, –CH2NH-, –NHCH2-,wherein * denotes the attachment to Ring A.

[0090] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is. In some embodiments of Formula I, I’, I’’, II, II-a, III, or III-a, L is.

[0091] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ryis C1-3alkyl or lower haloalkyl. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ryis C1-3alkyl. In some such embodiments, 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 -CF2H.

[0092] As defined generally above, 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 partiallyunsaturated 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 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.

[0093] 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 C1-4aliphatic. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is optionally substituted C1-2aliphatic. 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. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is –CH3, -CH2CH3, -CH(CH3)2, -CD(CH3)2, -CH(CH3)CH2CH3, or – CF3.

[0094] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is C1-2aliphatic 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.

[0095] 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.

[0096] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is an optionally substituted phenyl.

[0097] 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 oxetanyl or azetidinyl ring optionally substituted with –(CH2)0-4Rº, –(CH2)0-4ORº, or –(CH2)0-4CO2Rº, wherein Rº is C1-6aliphatic. In some such embodiments, Rº is substituted with –(CH2)0- 2OR●or –(CH2)0-2OH, wherein R●is C1-4aliphatic. 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 piperidinyl ring or a tetrahydropyranyl ring. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is a piperidinyl ring optionally substituted with –(CH2)0-4Rº, –(CH2)0-4ORº, or –(CH2)0-4CO2Rº, wherein Rº is C1-6aliphatic. In some such embodiments, Rº is substituted with –(CH2)0-2OR●or –(CH2)0-2OH, wherein R●is C1-4aliphatic.

[0098] 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 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.

[0099] As defined generally above, m is 0-3. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-am is 0. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 1. Insome 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. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 1-2. [000100] As defined generally above, 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. [000101] As defined generally above, 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. [000102] In some embodiments, the compound is selected from a compound in Table 1. Table 1.or a pharmaceutically acceptable salt thereof. [000103] In some embodiments, the compound is not a compound in Table 2. Table 2.4. Pharmaceutical Compositions [000104] 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. [000105] 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.[000106] 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 solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [000107] 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. [000108] 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.[000109] 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. [000110] 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. [000111] 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. [000112] 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. [000113] 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. [000114] 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, absorptionpromoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. [000115] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. [000116] 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. [000117] 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. [000118] 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. [000119] 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. [000120] 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 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. 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. [000121] 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. [000122] 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, benzylalcohol, 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. [000123] 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, for example, 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. [000124] 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. [000125] 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. [000126] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritatingexcipients 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. [000127] 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 dissolving or 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. [000128] 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. [000129] 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 maintenance doses are about the same amount. In some embodiments, a maintenance dose is of a higher amount than another maintenance dose. [000130] 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. [000131] 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 [000132] 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. [000133] 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. [000134] 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. [000135] 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 promoterand 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 some embodiments, 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. [000136] 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. [000137] 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. [000138] 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 [000139] 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. [000140] 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). [000141] 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, thedestruction 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. [000142] 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 modulates expression 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. [000143] 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 saltthereof. 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. [000144] 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). [000145] 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 ordecrease 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 may modulate 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. [000146] 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. [000147] 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 CK1αhas 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 cellular functioning 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). [000148] 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. [000149] 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. [000150] 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). [000151] 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 ubiquitinligase 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. [000152] 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. [000153] 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 insightthat 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. [000154] Insights contained herein recognize that hyperactivation of cellular pathways provides additional routes for cancer therapeutics to target various cancers. For example, such hyperactivation 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. [000155] 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. [000156] 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 interactwith 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 Rxgroup) comprises at least one atom that interacts with CK1α Arg21. In some embodiments, L comprises at least one atom that interacts with CK1α Lys18, CRBN Glu377, and / or CRBN His353. [000157] 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. [000158] 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. [000159] 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 someembodiments, 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 or composition 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. [000160] 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 increasingexpression 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. [000161] 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 causing death 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. [000162] 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. [000163] 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. [000164] 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.[000165] 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. [000166] 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. [000167] 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 comprisesadministering 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 cancer comprises 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. [000168] 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. [000169] 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. [000170] 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, Burkittlymphoma, 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.[000171] 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. [000172] 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. [000173] 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). [000174] 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. [000175] 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 someembodiments, a subject is susceptible to or suffering from a cancer, e.g., a cancer described herein. [000176] 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 described herein 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. [000177] 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. [000178] 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 [000179] 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). [000180] In some embodiments, an additional treatment comprises or is surgery. In some embodiments, an additional treatment comprises or is radiation. [000181] 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. [000182] 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 aprovided 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. [000183] 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 some embodiments, 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. [000184] 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. [000185] 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.[000186] 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.[000187] 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. [000188] 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. [000189] 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, achemotherapeutic 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. In some 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. [000190] 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. [000191] 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. [000192] 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. [000193] 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. [000194] 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. [000195] 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. [000196] 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.[000197] 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 [000198] Example 1. Synthesis of Exemplary Compounds [000199] General synthetic schemes for Compounds of Formula I:[000200] Example 1.1. Synthesis of N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]-6-methoxynaphthalene-2-carboxamide (I-15)[000201] Into a 25 mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (30 mg, 0.116 mmol, 1 equiv), DMF (3.00 mL), 6-methoxynaphthalene-2- carboxylic acid (25.74 mg, 0.128 mmol, 1.1 equiv), DIEA (29.91 mg, 0.232 mmol, 2 equiv) and HATU (131.99 mg, 0.348 mmol, 3 equiv) at room temperature. The resulting mixture was stirredfor overnight at 65°C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (2x10 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 (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]-6-methoxynaphthalene-2-carboxamide (35 mg, 68.00%) as a white solid. [000202] LC-MS: (ES, m / z): [M+H]+: 444.10. [000203]1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.66 (s, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 1.7 Hz, 1H), 8.07 – 7.84 (m, 4H), 7.73 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 9.0, 2.5 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.57 – 4.24 (m, 2H), 3.93 (s, 3H), 2.93 (ddd, J = 17.8, 13.4, 5.3 Hz, 1H), 2.77 – 2.57 (m, 1H), 2.38 (td, J = 13.2, 4.5 Hz, 1H), 2.08 – 1.95 (m, 1H). [000204] Example 1.2. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- hydroxy-1H-indazole-5-carboxamide (I-24)[000205] Synthesis of 1-(tert-butoxycarbonyl)-3-hydroxyindazole-5-carboxylic acid[000206] To a solution of 3-hydroxy-1H-indazole-5-carboxylic acid (200 mg, 1.123 mmol, 1 equiv) in DMF (10 mL) In a 25mL round-bottom flask was added sodium hydride (53.88 mg, 1.348 mmol, 1.2 equiv, 60% in oil) at 0°C. The mixture was stirred for 15 min. Boc2O (367.53 mg, 1.684 mmol, 1.5 equiv) was added and the mixture was allowed to warm to room temperature and stirred for 1 overnight. The reaction was quenched with ice water(50 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The water phase wasneutralized after pH 7 with 1 mol / L hydrochloric acid aqueous solution. The water phase was lyophilized. This resulted in 1-(tert-butoxycarbonyl)-3-hydroxyindazole-5-carboxylic acid (524 mg, crude) as a solid. [000207] LC-MS: (ES, m / z): [M-H]-: 277.0 [000208] The synthesis of Compound I-24 was completed following the procedure in Example 1.1 using 1-(tert-butoxycarbonyl)-3-hydroxyindazole-5-carboxylic acid and Boc removal. [000209] LC-MS: (ES, m / z): [M+H]+: 418.10 [000210]1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.45 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.99 – 7.93 (m, 2H), 7.58 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 3.00 – 2.83 (m, 1H), 2.61 (d, J = 16.8 Hz, 1H), 2.47 – 2.37 (m, 1H) 2.08 – 1.95 (m, 1H). [000211] Example 1.3. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7- methoxy-1,5-naphthyridine-3-carboxamide (I-7)[000212] Synthesis of diethyl 2-(((5-methoxypyridin-3-yl)amino)methylene)malonate[000213] Into a 100 mL round-bottom flask were added 5-methoxypyridin-3-amine (2.0 g, 16.110 mmol, 1 equiv), 1,3-diethyl 2-(ethoxymethylidene) propanedioate (3.5 g, 16.110 mmol, 1.0 equiv) and EtOH (60 mL) at room temperature. The resulting mixture was stirred for overnight at 85°C under air atmosphere. The resulting mixture was concentrated under vacuum. This resulted in 4.5 g crude product as a brown oil. The crude product was used in the next step directly without further purification. [000214] LC-MS: (ES,m / z):[M+H]+: 295.10 [000215] Synthesis of ethyl 4-chloro-7-methoxy-1,5-naphthyridine-3-carboxylate)[000216] Into a 20 mL pressure tank reactor were added 1,3-diethyl 2-{[(5-methoxypyridin-3- yl) amino] methylidene}propanedioate (1.5 g, 5.097 mmol, 1 equiv) and POCl3(15.68 g, 101.940 mmol, 20 equiv) at room temperature. The final reaction mixture was irradiated with microwave radiation for 1.5 h at 160°C. The resulting mixture was concentrated under vacuum. The reaction was quenched with water at 0°C. The mixture was basified to pH 8 with saturated Na2CO3(aq.). The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were 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 ethyl 4-chloro-7-methoxy-1,5-naphthyridine-3-carboxylate) (350 mg, 30.5%) as a light yellow solid. [000217] LC-MS: (ES,m / z): [M+H]+:267.05 [000218] Synthesis of ethyl 7-methoxy-1,5-naphthyridine-3-carboxylate[000219] Into a 25 mL round-bottom flask were added ethyl 4-chloro-7-methoxy-1,5- naphthyridine-3-carboxylate (140 mg, 0.525 mmol, 1.0 equiv), ACN (5.0 mL), triethylsilane (122.09 mg, 1.050 mmol, 2.0 equiv) and bis(triphenylphosphine)palladium(II) chloride (73.70 mg, 0.105 mmol, 0.2 equiv) at rt. The resulting mixture was stirred for 3h at 70°C. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with chloromethane (3 x 10mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford ethyl 7-methoxy-1,5-naphthyridine-3- carboxylate (50 mg, 41.01%) as a white solid. [000220] LC-MS: (ES,m / z):[M+H]+:233.10[000221]1H NMR (400 MHz, Chloroform-d) δ 9.45 (d, J = 2.1 Hz, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.8 Hz, 1H), 7.68 (d, J = 2.9 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). [000222] Synthesis of 7-methoxy-1,5-naphthyridine-3-carboxylic acid[000223] Into a 25 mL round-bottom flask were added ethyl 7-methoxy-1,5-naphthyridine-3- carboxylate (50 mg, 0.215 mmol, 1.0 equiv), THF (3 mL) and H2O (1 mL) at room temperature. Then LiOH (10.31 mg, 0.430 mmol, 2.0 equiv) was added to the above mixture. The resulting mixture was stirred for 2h at room temperature. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 4M. HCl aqueous. The resulting mixture was concentrated under reduced pressure. This resulted in 7-methoxy-1,5-naphthyridine-3-carboxylic acid (75 mg, crude) as a white solid. The crude product was used directly in the next step. [000224] LC-MS: (ES,m / z):[M+H]+:205.10 [000225] The synthesis of Compound I-7 was completed following the procedure in Example 1.1 using 7-methoxy-1,5-naphthyridine-3-carboxylic acid. [000226] LC-MS: (ES,m / z):[M+H]+: 446.10 [000227]1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.93 (s, 1H), 9.41 (d, J = 2.2 Hz, 1H), 9.00 (d, J = 2.2 Hz, 1H), 8.89 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.90 (q, J = 3.2 Hz, 2H), 7.76 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.51 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 4.04 (s, 3H), 2.96 – 2.84 (m, 1H), 2.61 (d, J = 16.6 Hz, 1H), 2.47 – 2.32 (m, 1H), 2.08 – 1.97 (m, 1H). [000228] Example 1.4. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7- methoxy-2,6-naphthyridine-3-carboxamide (I-8)[000229] Synthesis of 5-bromo-4-(dimethoxymethyl)-2-methoxypyridine[000230] Into a 50 mL round-bottom flask was charged with 5-bromo-2-methoxypyridine-4- carbaldehyde (1 g, 4.629 mmol, 1 equiv) dissolved in MeOH (20 mL) under air. H2SO4(0.57 mL, 10.694 mmol, 2.31 equiv) was added dropwise to the reaction. The reaction was stirred at room temperature for 4 h. Then, the reaction was detected by LCMS and m / z: 261 was detected. The mixture was basified to pH 7 with saturated Na2CO3aqueous. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 5- Bromo-4-(dimethoxymethyl)-2-methoxypyridine (930 mg, 76.65%) was not purified and used for the next step. [000231] LC-MS: (ES, m / z): [M+H]+262.05 [000232] Synthesis of 4-(dimethoxymethyl)-6-methoxynicotinaldehyde[000233] Into a 100 mL three necked round-bottom flask was charged with 5-bromo-4- (dimethoxymethyl)-2-methoxypyridine (3.1 g, 11.827 mmol, 1 equiv) dissolved in THF (50 mL) under Ar. The reaction was cooled to -60°C. n-BuLi (2.5 M in hexane, 5.6 mL, 14.192 mmol, 1.2 equiv) was added dropwise to the reaction. The reaction was stirred at -60°C for 0.5 h. Then, dimethylformamide (2.59 g, 35.481 mmol, 3 equiv) was added dropwise to the reaction. The reaction was stirred at -60 °C for 15 min. Then, the reaction was stirred at -30 °C for 15 min. The reaction was detected by LCMS and desired product was obtained. The reaction was quenched by the addition of saturated ammonium chloride aqueous (50 mL) at -30 °C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated NaCl aqueous (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue (2.0 g, 60.85%) was used for the next step without further purification. [000234] LC-MS: (ES, m / z): [M+H]+212.15[000235] Synthesis of methyl (2E)-3-[4-(dimethoxymethyl)-6-methoxypyridin-3-yl]-2- acetamidoprop-2-enoate[000236] Into a 50 mL round bottom flask was charged with methyl 2-(dimethoxyphosphoryl)- 2-acetamidoacetate (1.36 g, 5.681 mmol, 1.2 equiv) dissolved in DCM (20 mL). DBU (1.06 mL, 7.095 mmol, 1.50 equiv) was added dropwise to the reaction. Then, 4-(dimethoxymethyl)-6- methoxypyridine-3-carbaldehyde (1 g, 4.734 mmol, 1 equiv) dissolved in DCM was added dropwise to the reaction. The reaction was stirred at room temperature for 3 h. The reaction was detected by LCMS and desired product was detected. The reaction was quenched by the addition of aqueous Na2CO3(20 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 20mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to afford methyl (2E)-3-[4-(dimethoxymethyl)-6-methoxypyridin-3-yl]-2-acetamidoprop-2-enoate (1.4 g, 91.17%) as a white solid. [000237] LC-MS: (ES, m / z): [M+H]+325.15 [000238] Synthesis of methyl 7-methoxy-2,6-naphthyridine-3-carboxylate[000239] Into a 50 mL round-bottom flask was charged with methyl (2E)-3-[4- (dimethoxymethyl)-6-methoxypyridin-3-yl]-2-acetamidoprop-2-enoate (700 mg, 2.158 mmol, 1 equiv) dissolved in toluene (20 mL) under air. TsOH (297.32 mg, 1.726 mmol, 0.8 equiv) was added to the reaction. The reaction was stirred at 110°C for 12 h. The reaction was detected by LCMS and desired product was obtained. The solvent was removed under reduced pressure. Theresidue was quenched by the addition of aqueous NaHCO3(20 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3x20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Methyl 7-methoxy-2,6-naphthyridine-3-carboxylate (350 mg, 74.32%) was not purified and used for the next step. [000240] LC-MS: (ES, m / z): [M+H]+219.10 [000241] Synthesis of 7-Methoxy-2,6-naphthyridine-3-carboxylic acid[000242] Into a 50 mL round-bottom flask was charged with methyl 7-methoxy-2,6- naphthyridine-3-carboxylate (300 mg, 1.604 mmol, 1 equiv) dissolved in THF (30 mL) under air. NaOH (320.76 mg, 8.020 mmol, 5 equiv) dissolved in H2O (8 mL) was added dropwise to the reaction. The reaction was stirred at room temperature for 2 h. The reaction was detected by LCMS and major product was detected. The solvent was removed under reduced pressure and was added water (10mL) and was extracted with EA (2 x 20 mL). The aqueous layer was acidified by the addition of aqueous HCl (5 mL, 1M). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.7- Methoxy-2,6-naphthyridine-3-carboxylic acid (150 mg, 45.8%) was not purified and used for the next step. [000243] LC-MS: (ES, m / z): [M+H]+205.10 [000244] The synthesis of Compound I-8 was completed following the procedure in Example 1.1 using 7-methoxy-2,6-naphthyridine-3-carboxylic acid. [000245] LC-MS: (ES, m / z): [M+H]+446.15 [000246]1H NMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 12.4 Hz, 1H), 9.49 (s, 2H), 8.82 (s, 1H), 8.32 (s, 2H), 8.07-8.05 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 5.12 (d, J = 9.2 Hz, 1H), 4.52-4.33 (m, 2H), 4.05 (s, 3H), 2.67-2.63 (m, 1H), 2.50-2.33 (m, 2H), 2.03-1.89 (m, 1H). [000247] Example 1.5. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- [1,2,3]triazolo[1,5-a]pyridine-4-carboxamide (I-12)[000248] The synthesis of Compound I-12 was completed following the procedure in Example 1.1 using [1,2,3]triazolo[1,5-a]pyridine-4-carboxylic acid. [000249] LC-MS: (ES, m / z): [M+1]+: 405.05 [000250]1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.91 (s, 1H), 9.32 (dt, J = 7.0, 0.9 Hz, 1H), 8.46 (d, J = 1.0 Hz, 1H), 8.20 – 8.11 (m, 2H), 7.85 (dd, J = 8.3, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 7.0 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000251] Example 1.6. Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)carbamoyl)-2-naphthoic acid (I-28)[000252] The synthesis of Compound I-28 was completed following the procedure in Example 1.1 using naphthalene-2,6-dicarboxylic acid. [000253] LC-MS: (ES, m / z): [M+H]+: 458.00 [000254]1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 10.99 (s, 1H), 10.83 (s, 1H), 8.68 (d, J = 11.2 Hz, 2H), 8.33 – 8.05 (m, 5H), 7.89 (dd, J = 8.3, 1.9 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000255] Example 1.7. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-6- fluoroquinoline-2-carboxamide (I-3)[000256] The synthesis of Compound I-3was completed following the procedure in Example 1.1 using 6-fluoroquinoline-2-carboxylic acid. [000257] LC-MS: (ES, m / z): [M+H]+: 433.15 [000258]1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 2H), 8.64 (d, J = 8.6 Hz, 1H), 8.39 – 8.25 (m, 3H), 8.05 (dd, J = 8.3, 1.9 Hz, 1H), 7.97 (dd, J = 9.4, 2.9 Hz, 1H), 7.87 (d, J = 8.9, 3.0 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.2 Hz, 1H), 4.37 (d, J = 17.2 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000259] Example 1.8. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-6- hydroxyquinoline-2-carboxamide (I-10)[000260] The synthesis of Compound I-10 was completed following the procedure in Example 1.1 using 6-hydroxyquinoline-2-carboxylic acid. [000261] LC-MS: (ES, m / z): [M+H]+431.05 [000262]1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.94 (s, 1H), 10.49 (s, 1H), 8.60 - 8.40 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.14 - 8.13 (m, 2H), 8.11- 8.03(m, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.50 - 7.48 (m, 1H), 7.27 (d, J = 2.7 Hz, 1H), 5.20 - 5.10 (m, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 2.94 - 2.92 (m, 1H), 2.62 - 2.59 (m, 1H), 2.42 - 2.39 (m, 1H), 2.04 - 2.02 (m, 1H). [000263] Example 1.9. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4- hydroxy-7-methoxyquinoline-3-carboxamide (I-13)[000264] The synthesis of Compound I-13 was completed following the procedure in Example 1.1 using 4-hydroxy-7-methoxyquinoline-3-carboxylic acid. [000265] LC-MS: (ES, m / z): [M+H]+: 461.10[000266]1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 12.95 - 12.60 (m, 1H), 10.98 (s, 1H), 8.84 (d, J = 3.2 Hz, 1H), 8.23 (d, J = 8.9 Hz, 1H), 8.08 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 5.10 (d, J = 13.0 Hz, 1H), 4.47 (d, J = 16.8 Hz, 1H), 4.33 (d, J = 17.1 Hz, 1H), 3.91 (d, J = 3.1 Hz, 3H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000267] Example 1.10. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-4)[000268] The synthesis of Compound I-4 was completed following the procedure in Example 1.1 using 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. [000269] LC-MS: (ES, m / z): [M+H]+: 418.00 [000270]1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.62 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 5.11 (dd, J = 13.4, 5.0 Hz, 1H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 3.88 (d, J = 2.5 Hz, 3H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000271] Example 1.11. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)thiazolo[5,4-b]pyridine-5-carboxamide (I-11)[000272] The synthesis of Compound I-11 was completed following the procedure in Example 1.1 using thiazolo[5,4-b]pyridine-5-carboxylic acid. [000273] LC-MS: (ES, m / z): [M+H]+:421.95 [000274]1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 11.01 (s, 1H), 9.78 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 8.04 (dd, J = 8.4, 1.8 Hz, 1H), 7.75 (d, J =8.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000275] Example 1.12. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (I-21)[000276] The synthesis of Compound I-21 was completed following the procedure in Example 1.1 using 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid. [000277] LC-MS: (ES, m / z): [M+H]+: 405.05 [000278]1H NMR (400 MHz, DMSO-d6) δ 13.98 (s, 1H), 11.00 (s, 1H), 10.75 (s, 1H), 9.10 (d, J = 2.1 Hz, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 8.17 (d, J = 1.9 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 5.17 – 5.08 (m, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.35= 17.3 Hz, 1H), 2.99 – 2.86 (m, 1H), 2.66 – 2.57 (m, 1H), 2.48 – 2.33 (m, 1H), 2.06 – 1.98 (m, 1H). [000279] Example 1.13. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6-carboxamide (I-30)[000280] The synthesis of Compound I-30 was completed following the procedure in Example 1.1 using [1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid. [000281] LC-MS: (ES, m / z): [M+H]+: 406.0 [000282]1H NMR (400 MHz, DMSO-d6) δ 11.11 (d, J = 88.5 Hz, 2H), 9.82 (s, 1H), 8.57 (d, J = 9.7 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.5, 1.9 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.99 - 2.80 (m, 1H), 2.66 – 2.57 (m, 1H), 2.50 – 2.30 (m, 1H), 2.10 – 1.98 (m, 1H). [000283] Example 1.14. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1,6-naphthyridine-2-carboxamide (I-14)[000284] The synthesis of Compound I-14 was completed following the procedure in Example 1.1 using 1,6-naphthyridine-2-carboxylic acid. [000285] LC-MS: (ES, m / z): [M+H]+: 416.00 [000286]1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 11.02 (s, 1H), 9.57 (s, 1H), 8.87 (dd, J = 14.8, 7.2 Hz, 2H), 8.46 – 8.36 (m, 2H), 8.18 – 8.09 (m, 2H), 7.64 (d, J = 8.2 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 3.00 – 2.96 (m, 1H), 2.66 – 2.57 (m, 1H), 2.48 – 2.35 (m, 1H), 2.09 – 1.99 (m, 1H). [000287] Example 1.15. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (I-5)[000288] The synthesis of Compound I-5 was completed following the procedure in Example 1.1 using 2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid. [000289] LC-MS: (ES, m / z): [M+H]+: 419.15 [000290]1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.99 (s, 1H), 10.65 (s, 1H), 8.86 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 11.2 Hz, 1H), 5.14-5.08 (m, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000291] Example 1.16. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-benzo[d]imidazole-5-carboxamide (I-29)[000292] The synthesis of Compound I-29 was completed following the procedure in Example 1.1 using 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid. [000293] LC-MS: (ES,m / z): [M+H]+: 418.00 [000294]1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.54 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.4, 4.5 Hz, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.48 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 3.90 (s, 3H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000295] Example 1.17. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 3H-imidazo[4,5-c]pyridine-6-carboxamide (I-9)[000296] The synthesis of Compound I-9 was completed following the procedure in Example 1.1 using 3H-imidazo[4,5-c]pyridine-6-carboxylic acid. [000297] LC-MS: (ES, m / z): [M+H]+: 405.05 [000298]1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 2H), 9.08 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.68 – 2.50 (m, 1H), 2.43 – 2.37 (m, 1H), 2.09 – 1.98 (m, 1H). [000299] Example 1.18. Synthesis of 1-cyclopropyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-20)[000300] The synthesis of Compound I-20 was completed following the procedure in Example 1.1 using 1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid. [000301] LC-MS: (ES, m / z):[M+H]+446.05 [000302]1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 11.00 (s, 1H), 9.52 (s, 1H), 8.49 (s, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.4, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.12 (dd, J= 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.20 - 4.10 (m, 1H), 3.00 - 2.80 (m, 1H), 2.66 – 2.57 (m, 1H), 2.50 - 2.30 (m, 1H), 2.07 – 1.98 (m, 1H), 1.34 – 1.23 (m, 2H), 1.26 – 1.16 (m, 2H). [000303] Example 1.19. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazole-5-carboxamide (I-32)[000304] The synthesis of Compound I-32 was completed following the procedure in Example 1.1 using 1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazole-5-carboxylic acid. [000305] LC-MS: (ES, m / z): [M+H]+497.25 [000306]1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.23 (d, J = 21.0 Hz, 2H), 7.91 – 7.85 (m, 2H), 7.72 – 7.62 (m, nH), 5.11 (dd, J = 13.7, 5.2 Hz, 1H), 4.56 – 4.16 (m, 4H), 3.75 –3.68 (m, 3H), 2.96 – 2.87 (m, 2H), 2.67 – 2.54 (m, 4H), 2.44 - 2.38 (m, 1H), 2.05 – 1.97 (m, 1H). [000307] Example 1.20. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 7-hydroxy-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide (I-19)[000308] The synthesis of Compound I-19 was completed following the procedure in Example 1.1 using 7-hydroxy-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid. [000309] LC-MS: (ES, m / z):[M+H]+: 422.00 [000310]1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.98 (s, 1H), 8.81 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.76 – 7.63 (m, 2H), 7.21 -6.95 (m, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 2.96 – 2.87 (m, 1H), 2.67 – 2.54 (m, 1H), 2.44 - 2.38 (m, 1H), 2.05 – 1.97 (m, 1H). [000311] Example 1.21. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1H-pyrazolo[4,3-b]pyridine-5-carboxamide (I-6)[000312] The synthesis of Compound I-6 was completed following the procedure in Example 1.1 using 1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid. [000313] LC-MS: (ES, m / z): [M-H]+: 403.00 [000314]1H NMR (400 MHz, DMSO-d6) δ 13.73 (s, 1H), 11.01 (s, 2H), 8.53 (s, 1H), 8.29 – 8.20 (m, 3H), 8.04 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 5.14 – 5.10 (m, 1H), 4.45 – 4.32 (m, 2H), 2.96 – 2.90 (m, 1H), 2.63 – 2.50 (m, 1H), 2.43 – 2.35 (m, 1H), 2.07– 2.00 (m, 1H). [000315] Example 1.22. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)benzo[c][1,2,5]thiadiazole-5-carboxamide (I-31)[000316] The synthesis of Compound I-31 was completed following the procedure in Example 1.1 using benzo[c][1,2,5]thiadiazole-5-carboxylic acid. [000317] LC-MS: (ES, m / z): [M+H]+: 421.95 [000318]1H NMR (400 MHz, DMSO-d6) δ 10.95 (d, J = 31.6 Hz, 2H), 8.80 (s, 1H), 8.23 (dd, J = 18.8, 9.2 Hz, 3H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 – 4.10 (m, 2H), 2.95 – 2.83 (m, 1H), 2.70 – 2.55 (m, 1H), 2.50 – 2.40 (m, 1H), 2.10- 1.99 (m, 1H). [000319] Example 1.23. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 3-methylbenzamide (I-17)[000320] The synthesis of Compound I-17 was completed following the procedure in Example 1.1 using 3-methylbenzoic acid.[000321] LC-MS: (ES, m / z): [M+H]+= 378.1 [000322]1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.91 – 7.66 (m, 4H), 7.44 (dd, J = 4.1, 1.7 Hz, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.57 – 4.23 (m, 2H), 2.99 – 2.87 (m, 1H), 2.61 (ddd, J = 17.1, 4.4, 2.3 Hz, 1H), 2.41 (s, 3H), 2.38 – 2.32 (m, 1H), 2.04 – 1.98 (m, 1H). [000323] Example 1.24. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 8-methoxy-2H-chromene-3-carboxamide (I-16)[000324] The synthesis of Compound 16 was completed following the procedure in Example 1.1 using 8-methoxy-2H-chromene-3-carboxylic acid. [000325] LC-MS: (ES, m / z): [M+H]+448.15 [000326]1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.38 (s, 1H), 8.06 (d, J = 1.7 Hz, 1H), 7.85 – 7.65 (m, 2H), 7.53 (d, J = 1.4 Hz, 1H), 7.11 – 6.80 (m, 3H), 5.11(dd, J = 5.1 Hz, 17.6 Hz, 1H), 4.97 (d, 0.9 Hz, 1H), 4.55 – 4.23 (m, 2H), 3.79 (s, 3H), 3.02 – 2.83 (m, 1H), 2.62 – 2.50 (m, 1H), 2.45 – 2.37 (m, 1H), 2.08 – 1.90 (m, 1H). [000327] Example 1.25. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 6-methoxy-2-naphthamide (I-15)[000328] The synthesis of Compound I-15 was completed following the procedure in Example 1.1 using 6-methoxy-2-naphthoic acid. [000329] LC-MS: (ES, m / z): [M+H]+: 444.10. [000330]1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.66 (s, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 1.7 Hz, 1H), 8.07 – 7.84 (m, 4H), 7.73 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 2.5 Hz,1H), 7.28 (dd, J = 9.0, 2.5 Hz, 1H), 5.12 (dd, J = 13.2, 5.0 Hz, 1H), 4.57 – 4.24 (m, 2H), 3.93 (s, 3H), 2.93 (ddd, J = 17.8, 13.4, 5.3 Hz, 1H), 2.77 – 2.57 (m, 1H), 2.38 (td, J = 13.2, 4.5 Hz, 1H), 2.08 – 1.95 (m, 1H). [000331] Example 1.26. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 6-hydroxy-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-2)[000332] Synthesis of N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-6-methoxy-1H- pyrrolo[2,3-b] pyridine-5-carboxamide[000333] Into a 50 mL round-bottom flask were added 6-methoxy-1H-pyrrolo[2,3-b] pyridine- 5-carboxylic acid (250 mg, 1.301 mmol, 1.0 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (337.28 mg, 1.301 mmol, 1.0 equiv), DMF (5 mL), DIEA (672.55 mg, 5.204 mmol, 4 equiv) and HATU (989.30 mg, 2.602 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for overnight at 60°C. The mixture was directly purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-6-methoxy-1H-pyrrolo[2,3-b] pyridine-5-carboxamide (150 mg, 26.60%) as a brown solid. [000334] LC-MS: (ES, m / z): [M+H]+: 434.05 [000335]1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 11.01 (s, 1H), 10.33 (s, 1H), 8.42 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 13.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.36 – 7.30 (m, 1H), 6.50 (dd, J = 3.6, 1.7 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.2 Hz, 1H),4.32 (d, J = 17.1 Hz, 1H), 4.07 (s, 3H), 2.95 (dd, J = 13.3, 5.1 Hz, 1H), 2.61 (d, J = 17.3 Hz, 1H), 2.41 (tt, J = 13.3, 6.7 Hz, 1H), 2.05-1.99 (m, 1H). [000336] Synthesis of N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-6-hydroxy-1H- pyrrolo[2,3-b] pyridine-5-carboxamide[000337] Into a 25 mL round-bottom flask were added N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 3H-isoindol-5-yl]-6-methoxy-1H-pyrrolo[2,3-b] pyridine-5-carboxamide (45 mg, 0.104 mmol, 1 equiv) and BBr3 (1mmol / ml in DCM, 2 mL) at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The reaction was quenched with Water / Ice at room temperature. The resulting mixture was extracted with DCM / MeOH 5:1 (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. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to 39% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.43) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-6-hydroxy- 1H-pyrrolo[2,3-b] pyridine-5-carboxamide (9.3 mg, 20.33%) as a white solid. [000338] LC-MS: (ES, m / z): [M+H]+: 420.0 [000339]1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 11.45 (s, 1H), 11.00 (s, 1H), 8.72 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.46 (d, J = 3.4 Hz, 1H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.30 (d, J = 17.1 Hz, 1H), 2.99 – 2.85 (m, 1H), 2.61 (d, J = 16.7 Hz, 1H), 2.02 (s, 1H), 1.23 (s, 1H). [000340] Example 1.27. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 7-methoxycinnoline-3-carboxamide (I-25)[000341] Synthesis of ethyl (2E)-3-(piperidin-1-yl) prop-2-enoate[000342] Into a 25 mL round-bottom flask was charged with ethyl propiolate (1.0 g, 10.194 mmol, 1.0 equiv) dissolved in ACN (10 mL). piperidine (0.87 g, 10.194 mmol, 1.0 equiv) was added dropwise to the reaction. The reaction was stirred at room temperature for 15 min. Then, the reaction was detected by TLC and one new spot was detected. The solvent was removed under reduced pressure. The product ethyl (2E)-3-(piperidin-1-yl) prop-2-enoate (1.5 g, crude) was obtained as a yellow oil. The crude product was not purified and directly used for the next step. [000343] LC-MS: (ES, m / z): [M+H]+184.15 [000344] Synthesis of 3-methoxybenzenediazonium tetrafluoroborate[000345] Into a 25 mL round-bottom flask were added M-anisidine (2.0 g, 16.240 mmol, 1.0 equiv) at room temperature. Then, HCl aqueous (8 mL, 6M) was added to the reaction. The reaction was cooled to 0 °C and Sodium nitrite (1.34 g, 19.420 mmol, 1.2 equiv) dissolved in H2O (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred for additional 30 min at 0 °C. To the above mixture was added saturated sodium fluoroborate. The precipitation solid was washed by Et2O for several times. The product (1.2 g, crude) was obtained as a brown solid. The crude product was not purified and directly used for the next step. [000346] LC-MS: (ES, m / z): [M+H]+no exact MS signal [000347] Synthesis of ethyl 7-methoxycinnoline-3-carboxylate[000348] Into a 25 mL round-bottom flask was charged with ethyl (2E)-3-(piperidin-1-yl) prop- 2-enoate (500 mg, 2.728 mmol, 1.0 equiv) dissolved in ACN (10 mL).3-methoxybenzenediazonium (604 mg, 4.469 mmol, 1.64 equiv) was added in portions to the reaction. The reaction was stirred at 80 °C for 1 h. The reaction was deteceted by LCMS and desired product was detected. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford ethyl 7- methoxycinnoline-3-carboxylate (200 mg, 31.56%) as a red solid. [000349] LC-MS: (ES, m / z): [M+H]+233.10 [000350] Synthesis of 7-methoxycinnoline-3-carboxylic acid[000351] Into a 25 mL round-bottom flask was charged with ethyl 7-methoxycinnoline-3- carboxylate (200 mg, 0.861 mmol, 1.0 equiv), THF (3 mL) and H2O (3 mL). The mixture was stirred for 2h. Then the mixture was adjusted to PH =2 with 1M HCl aqueous. Then the mixture was extracted by EA (3X15 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 7-methoxycinnoline-3-carboxylic acid (170 mg, crude) was obtained and used for the next step without further purification. [000352] LC-MS: (ES, m / z): [M+H]+205.10 [000353] Synthesis of N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-7- methoxycinnoline-3-carboxamide[000354] Into a 10 mL microwave vial was charged with 7-methoxycinnoline-3-carboxylic acid (150 mg, 0.735 mmol, 1 equiv) dissolved in ACN (2 mL). POCl3(337.90 mg, 2.205 mmol, 3 equiv) was added dropwise to the reaction. The reaction was stirred at 80 °C for 3 h. The reaction was detected by LCMS and desired product was detected. The reaction was quenched by the addition of H2O (10 mL) at 0 °C. Then, the resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with NaCl (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue waspurified by Pre-HPLC (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 22% B to 27% B in 12 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.07). The desired product N- [2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-7-methoxycinnoline-3-carboxamide (9.1 mg, 2.67%) was obtained as an off-white solid. [000355] LC-MS: (ES, m / z): [M+H]+: 446.05 [000356]1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.92 (s, 1H), 8.48-8.43 (m, 2H), 8.36-8.30 (m, 1H), 8.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.68 – 7.63 (m, 2H), 5.14 (dd, J = 13.1, 5.1 Hz, 1H), 4.62 – 4.24 (m, 2H), 4.08 (s, 3H), 3.00 – 2.79 (m, 1H), 2.73 – 2.58 (m, 1H), 2.55-2.50(m, 1H), 2.21 – 1.74 (m, 1H). [000357] Example 1.28. Synthesis of 3-(5-[(7-methoxyisoquinolin-3-yl) amino]-1-oxo-3H- isoindol-2-ylpiperidine-2,6-dione (I-59)[000358] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (100 mg, 0.386 mmol, 1.0 equiv), (1,3-bis[2,6-bis(heptan-4-yl) phenyl]-4,5- dichloro-2,3-dihydro-1H-imidazol-2-yldichloro(3-chloro-1lambda4-pyridin-1-yl) palladium (37.56 mg, 0.039 mmol, 0.1 equiv), cesium carbonate (251.34 mg, 0.772 mmol, 2.0 equiv) and dioxane (2 mL) at room temperature. The resulting mixture was stirred for 16h at 110°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. ammonium chloride (aq.) (10mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 10mL). The combined organic layers were 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 dichloromethane / methanol (5:1) to afford 3-(5-[(7- methoxyisoquinolin-3-yl) amino]-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (28.2 mg, 17.08%) as a yellow solid. [000359] LC-MS: (ES,m / z): [M+1]+=417.10 [000360]1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.18 (s, 1H), 9.00 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.74 – 7.64 (m, 2H), 7.48 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.29 (dd, J= 9.0, 2.6 Hz, 1H), 7.19 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (d, J = 16.7 Hz, 1H), 4.26 (d, J = 16.7 Hz, 1H), 3.87 (s, 3H), 2.92 (ddd, J = 17.8, 13.5, 5.3 Hz, 1H), 2.61 (d, J = 17.5 Hz, 1H), 2.40 (tt, J = 13.2, 6.6 Hz, 1H), 2.07 – 1.96 (m, 1H). [000361] Example 1.29. Synthesis of 3-(5-{[(6-methoxynaphthalen-2-yl)methyl]amino}-1- oxo-3H-isoindol-2-yl)piperidine-2,6-dione (I-64)[000362] Into a 25 mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (50 mg, 0.193 mmol, 1.0 equiv), MeOH (4 mL), 6-methoxynaphthalene-2- carbaldehyde (39.50 mg, 0.212 mmol, 1.1 equiv) and AcOH (0.02 mL, 0.349 mmol, 1.81 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added NaBH3CN (24.24 mg, 0.386 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for additional 4 h at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (20mL) at room temperature. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2x10 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 (0.1% FA), 0% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in 3-(5-{[(6-methoxynaphthalen-2-yl)methyl]amino}-1-oxo-3H- isoindol-2-yl)piperidine-2,6-dione (50 mg, 60.03%) as a white solid. [000363] LC-MS: (ES, m / z): [M+H]+= 430.10. [000364]1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.86 – 7.70 (m, 3H), 7.53 – 7.26 (m, 3H), 7.18 – 6.98 (m, 2H), 6.79 – 6.62 (m, 2H), 4.99 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 5.8 Hz, 2H), 4.32 – 4.04 (m, 2H), 3.86 (s, 3H), 2.88 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.63 – 2.54 (m, 1H), 2.30 (qd, J = 13.2, 4.4 Hz, 1H), 2.04 – 1.80 (m, 1H). [000365] Example 1.30. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-N-(6-methoxyquinolin-3- yl)-1-oxoisoindoline-5-carboxamide (I-1)[000366] The synthesis of Compound I-1 was completed following the procedure in Example 1.1 using 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid and 6- methoxyquinolin-3-amine. [000367] LC-MS: (ES, m / z): [M+H]+445.00 [000368]1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.85 (s, 1H), 8.89 (dd, J = 51.3, 2.4 Hz, 2H), 8.40 – 8.12 (m, 2H), 7.90 (dd, J = 14.4, 8.5 Hz, 2H), 7.46 – 7.16 (m, 2H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.70 – 4.39 (m, 2H), 3.91 (s, 3H), 2.96 (d, J = 12.9 Hz, 1H), 2.51-2.50 (m, 1H),2.49-2.47(m, 1H), 2.14 – 1.95 (m, 1H). [000369] Example 1.31. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-N-((6- methoxynaphthalen-2-yl)methyl)-1-oxoisoindoline-5-carboxamide (I-23)[000370] The synthesis of Compound I-23 was completed following the procedure in Example 1.1 using 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid and (6- methoxynaphthalen-2-yl)methanamine. [000371] LC-MS: (ES,m / z): [M+H]+:458.05 [000372]1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.32 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 8.06 (dd, J = 8.0, 1.4 Hz, 1H), 7.85-7.75 (m, 4H), 7.47 (dd, J = 8.5, 1.8 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 8.9, 2.6 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.54 (d, J = 17.6 Hz, 1H), 4.40 (d, J = 17.6 Hz, 1H), 3.87 (s, 3H), 2.93 (ddd, J = 17.7, 13.4, 5.3 Hz, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.41 (td, J = 13.3, 4.5 Hz, 1H), 2.03 (d, J = 12.5 Hz, 1H). [000373] Example 1.32. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-160)[000374] Into a 25 mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (200 mg, 0.771 mmol, 1 equiv), 1-methylpyrrolo[2,3-b]pyridine-5- carboxylic acid (135.90 mg, 0.771 mmol, 1 equiv), DIEA (299.11 mg, 2.313 mmol, 3 equiv), DMF (5 mL) and HATU (439.98 mg, 1.157 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture 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: 9% B to 29% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.43) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1- methylpyrrolo[2,3-b]pyridine-5-carboxamide (51.4 mg, 15.21%) as an off-white solid. [000375] LC-MS: (ES, m / z): [M+H]+: 418.00 [000376]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.62 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 5.11 (dd, J = 13.4, 5.0 Hz, 1H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 3.88 (d, J = 2.5 Hz, 3H), 2.99 – 2.87 (m, 1H), 2.61 (d, J = 17.3 Hz, 1H), 2.39 (dt, J = 14.5, 7.2 Hz, 1H), 2.02 (d, J = 11.1 Hz, 1H). [000377] Example 1.33. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-158)[000378] Synthesis of 6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine[000379] Into a 25mL round-bottom flask were added methylhydrazine sulfate (447.97 mg, 3.108 mmol, 1.1 equiv) and Et3N (314.48 mg, 3.108 mmol, 1.1 equiv) in MeOH at 0°C. The resulting mixture was stirred for 0.5h at 0°C under N2 atmosphere. To the above mixture was added 2,4-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol, 1 equiv) in portions. The resulting mixture was stirred for additional 1 h at 0°C. Then to the above mixture was added Et3N (314.48 mg, 3.108 mmol, 1.1 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional 2h at 0°C. Desired product could be detected by LCMS. The residue was concentrated under reduced pressure and purified he residue was purified by silica gel column chromatography, eluted with PE / EA(40%) to afford 6-chloro-1-methylpyrazolo[3,4-d]pyrimidine (305 mg, 64.04%) as a white solid. [000380] LCMS (ES, m / z): no mass signal [000381]1H-NMR: (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.44 (s, 1H), 4.02 (s, 3H). [000382] Synthesis of methyl 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate[000383] To a solution of 6-chloro-1-methylpyrazolo[3,4-d]pyrimidine (200 mg, 1.186 mmol, 1 equiv) in MeOH (10 mL) was added Pd(dppf)Cl2(17.36 mg, 0.024 mmol, 0.02 equiv) and Et3N (240.11 mg, 2.372 mmol, 2 equiv) in a pressure tank. The mixture was purged with nitrogen for 3 mins and then was pressurized to 5 atm with carbon monoxide at 100°C for 1 overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by silica gel column chromatography, eluted with EA / PE (100%) to afford as a methyl 1-methylpyrazolo[3,4-d]pyrimidine-6-carboxylate (182 mg, 79.83%) as a white solid. [000384] LC MS (ES, m / z): [M+H]+: 193.0 [000385]1H-NMR: (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.52 (s, 1H), 4.12 (s, 3H), 3.96 (s, 3H). [000386] Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid[000387] To a stirred mixture of methyl 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (120 mg, 0.624 mmol, 1 equiv) in MeOH (4mL) were added NaOH (24.97 mg, 0.624 mmol, 1 equiv) in H2O (4 mL) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with HCl(aq). 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 (1-methylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (90 mg, 81%) as a white solid. [000388] LC MS (ES, m / z): [M+H]+: 179.00 [000389] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidine-6-carboxamide[000390] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (90.23 mg, 0.348 mmol, 1 equiv), 2,6-dicarboxynaphthalene (41.69 mg, 0.193 mmol, 1 equiv), DIEA (89.96 mg, 0.696 mmol, 2 equiv), DMF (2 mL) and HATU (198.49 mg, 0.522 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture 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: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% B to 26 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1 (min): 16.917) to afford N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1-methylpyrazolo[3,4-d]pyrimidine-6- carboxamide (26.7 mg, 17.41%) as a yellow solid. [000391] LC MS (ES, m / z): [M+H]+: 420.00 [000392]1H-NMR: (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 11.00 (s, 1H), 9.54 (s, 1H), 8.54 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.00 (dd, J = 8.4, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.12 (dd, J= 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.19 (s, 3H), 2.93 (ddd, J = 17.3, 13.7, 5.4 Hz, 1H), 2.66 – 2.57 (m, 1H), 2.41 (qd, J = 13.0, 4.3 Hz, 1H), 2.10 – 1.98 (m, 1H). [000393] Example 1.34. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-157)[[000395] Into a 40 mL vial were added cyclobutyl-hydrazine hydrochloride (228.60 mg, 1.865 mmol, 1.1 equiv) and MeOH (10 mL) at room temperature. To the above mixture was added Et3N (566.06 mg, 5.593 mmol, 3.3 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 0.5 h at 0°C. Then, to the above mixture was added 2,4-dichloropyrimidine-5- carbaldehyde (300 mg, 1.695 mmol, 1 equiv) in MeOH (10 mL) and Et3N (566.06 mg, 5.593 mmol, 3.3 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 2 h at 0°C. 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 (2:1) to afford 6-chloro-1-cyclobutylpyrazolo[3,4-d]pyrimidine (250 mg, 70.68%) as a yellow solid. [000396] LC-MS (ES, m / z): [M+H]+: 209.05 [000397]1H-NMR: (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.48 (s, 1H), 5.42 – 5.29 (m, 1H), 2.73 – 2.57 (m, 2H), 2.48 – 2.39 (m, 2H), 1.96 – 1.83 (m, 2H). [000398] Synthesis of methyl 1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate[000399] Into a 50 mL pressure tank reactor were added 6-chloro-1-cyclobutylpyrazolo[3,4- d]pyrimidine (230 mg, 1.102 mmol, 1 equiv), Pd(dppf)Cl2(16.13 mg, 0.022 mmol, 0.02 equiv), TEA (223.10 mg, 2.204 mmol, 2 equiv) and MeOH (25 mL) at room temperature. The resulting mixture was stirred for overnight at 100°C under carbon monoxide (5 atm) atmosphere. Desired product could be detected by LCMS. The reaction was quenched with Water / Ice at room temperature and concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1 x 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 (1:4) to afford methyl 1-cyclobutylpyrazolo[3,4-d]pyrimidine-6-carboxylate (230 mg, 89.84%) as a brown yellow oil. [000400] LC-MS (ES, m / z): [M+H]+: 233.10 [000401]1H-NMR: (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.57 (s, 1H), 5.57 – 5.44 (p, J = 8.1 Hz, 1H), 3.96 (s, 3H), 2.77 – 2.63 (m, 2H), 2.51 – 2.42 (m, 2H), 2.02 – 1.86 (m, 2H). [000402] Synthesis of 1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid[000403] Into a 25 mL round-bottom flask were added methyl 1-cyclobutylpyrazolo[3,4- d]pyrimidine -6-carboxylate (100 mg, 0.431 mmol, 1 equiv), THF (2 mL), H2O (2 mL) and LiOH.H2O (27.10 mg, 0.646 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under air atmosphere. Desired product could be detected by LCMS. The mixture was neutralized to pH = 7 with HCl (aq.). 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), 0% to 15% gradient in 15 min; detector, UV 254 nm. This resulted in 1- cyclobutylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (90 mg, 95.79%) as a yellow solid.[000404] LC-MS (ES, m / z): [M+H]+: 219.10 [000405] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- pyrazolo[3,4-d]pyrimidine-6-carboxamide[000406] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (100 mg, 0.386 mmol, 1 equiv), 1-cyclobutylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (84.17 mg, 0.386 mmol, 1 equiv), DIEA (299.11 mg, 2.316 mmol, 6 equiv), DMF (4 mL) and HATU (219.99 mg, 0.579 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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), 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (78.8 mg, 43.84%) as an off-white solid. [000407] LC-MS (ES, m / z): [M+H]+: 460.20 [000408]1H-NMR: (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 11.00 (s, 1H), 9.54 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.99 (dd, J = 8.3, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.72 – 5.59 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.2 Hz, 1H), 4.37 (d, J = 17.3 Hz, 1H), 3.00 – 2.87 (m, 1H), 2.80 – 2.66 (m, 2H), 2.66 – 2.57 (m, 1H), 2.56 – 2.51 (m, 2H), 2.47 – 2.35 (m, 1H), 2.07 – 1.89 (m, 3H). [000409] Example 1.35. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrazolo[4,3-b]pyridine-5-carboxamide (I-155)[000410] Synthesis of methyl 1-methyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylate and methyl 2-methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylate[000411] Into a 40 mL vial were added 1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid (500 mg, 0.306 mmol, 1 equiv) and DMF (4 mL) at room temperature. To the above mixture was added K2CO3(468.06 mg, 3.386 mmol, 2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 0.5 h at 0°C. To the above mixture was added CH3I (480.71 mg, 3.386 mmol, 2 equiv) dropwise at 0°C. The resulting mixture was stirred for additional overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with DMF (2x3 mL). The filtrate was purified by reversed-phase flashchromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 30% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 1-methyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylate and methyl 2-methyl-2H-pyrazolo[4,3- b]pyridine-5 -carboxylate (300 mg, 92.66%, mixture) as an off-white solid. [000412] LC-MS (ES, m / z): [M+H]+: 191.95 [000413] Synthesis of 1-methyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid and 2-methyl- 2H-pyrazolo[4,3-b]pyridine-5-carboxylic acid[000414] Into a 40 mL vial were added methyl 1-methyl-1H-pyrazolo[4,3-b]pyridine-5- carboxylate and methyl 2-methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (300 mg, mixture), THF (3 mL), H2O (3 mL) and LiOH.H2O (65.84 mg, 1.569 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature. Desired product could be detected by LCMS. The mixture was acidified to pH = 7 with HCl (aq.). The resulting mixture was concentrated under reduced pressure and 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; Gradient: 2% B to 14% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 10.93) to afford 1-methylpyrazolo[4,3- b]pyridine-5-carboxylic acid (80 mg, 43.17%) as an off-white solid and 2-methyl-2H- pyrazolo[4,3-b]pyridine-5-carboxylic acid (30 mg, 16.19%) as an off-white solid. [000415] LC-MS (ES, m / z): [M+H]+: 178.15 [000416] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-methyl-1H- pyrazolo[4,3-b]pyridine-5-carboxamide[000417] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (80 mg, 0.309 mmol, 1 equiv), 1-methylpyrazolo[4,3-b]pyridine-5-carboxylic acid (54.67 mg, 0.309 mmol, 1 equiv), DIEA (239.29 mg, 1.854 mmol, 6 equiv), DMF (3 mL) and HATU (175.99 mg, 0.464 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at 60°C under nitrogen atmosphere. 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), 35% to 45% gradient in 15 min; detector, UV 254 nm. This resulted in N-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1-methylpyrazolo[4,3-b]pyridine-5- carboxamide (68.5 mg, 50.46%) as a white solid. [000418] LC-MS: (ES, m / z): [M+H]+: 419.10 [000419]1H-NMR: (400 MHz, DMSO-d6) δ 11.00 (d, J = 8.0 Hz, 2H), 8.50 (d, J = 0.9 Hz, 1H), 8.40 (dd, J = 8.9, 1.0 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 8.9 Hz, 1H), 8.04 (dd, J = 8.3, 1.9 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 4.17 (s, 3H), 3.00 – 2.86 (m, 1H), 2.66 – 2.56 (m, 1H), 2.48 – 2.34 (m, 1H), 2.06 – 1.97 (m, 1H). [000420] Example 1.36. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 2-methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxamide (I-154)[000421] Into a 10 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (30 mg, 0.116 mmol, 1 equiv), 2-methylpyrazolo[4,3-b]pyridine-5-carboxylic acid (20.50 mg, 0.116 mmol, 1 equiv), DIEA (89.73 mg, 0.696 mmol, 6 equiv), DMF (2 mL) and HATU (66.00 mg, 0.174 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred forovernight at room temperature under nitrogen atmosphere. 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), 20% to 35% gradient in 20 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-2-methylpyrazolo[4,3-b]pyridine-5- carboxamide (41.1 mg, 83.62%) as a white solid. [000422] LC-MS (ES, m / z): [M+H]+: 419.15 [000423]1H-NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 2H), 8.90 (s, 1H), 8.34 – 8.27 (m, 2H), 8.10 – 7.99 (m, 2H), 7.72 (d, J = 8.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 4.31 (s, 3H), 3.00 – 2.86 (m, 1H), 2.66 – 2.56 (m, 1H), 2.48 – 2.34 (m, 1H), 2.05 – 1.98 (m, 1H). [000424] Example 1.37. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (I-156)[000425] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (50 mg, 0.193 mmol, 1 equiv), 1-methylpyrazolo[3,4-b]pyridine-5-carboxylic acid (34.17 mg, 0.193 mmol, 1 equiv), DMF (2 mL), DIEA (149.55 mg, 1.158 mmol, 6 equiv) and HATU (109.99 mg, 0.289 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight 60°C. 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), 35% to 45% gradient in 10 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1- methylpyrazolo[3,4 -b]pyridine-5-carboxamide (26.0 mg, 31.35%) as a white solid. [000426] LC-MS (ES, m / z): [M+H]+:419.05 [000427]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.76 (s, 1H), 9.13 (d, J = 2.1 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 0.8 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.85 (dd, J = 8.3, 1.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.3 Hz,1H), 4.35 (d, J = 17.2 Hz, 1H), 4.13 (s, 3H), 3.00 – 2.86 (m, 1H), 2.66 – 2.57 (m, 1H), 2.47 – 2.33 (m, 1H), 2.07 – 1.97 (m, 1H). [000428] Example 1.38. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-indazole-5-carboxamide (I-153) and N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-2-methyl-2H-indazole-5-carboxamide (I-152)[000429] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (100 mg, 0.386 mmol, 1 equiv), the mixture of 1-methylindazole-5-carboxylic acid and 2- methyl-2H-indazole-5-carboxylic acid (67.95 mg, 0.386 mmol, 1 equiv), DIEA (299.11 mg, 2.316 mmol, 6 equiv), DMF (4 mL) and HATU (219.99 mg, 0.579 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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), 30% to 50% gradient in 20 min; detector, UV 254 nm. The mixture of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-methyl-1H-indazole-5-carboxamide and N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2-methyl-2H-indazole-5- carboxamide(45 mg, mixture) obtained. The mixture was separated by SFC to afford N-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-methyl-1H-indazole-5-carboxamide (16.6 mg, 10.14%) as a yellow solid & N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2-methyl-2H- indazole-5-carboxamide (14.6 mg, 8.92%) as an off-white solid. [000430] LC-MS (ES, m / z) (I-153): [M-H]-: 416.15 [000431]1H-NMR (I-153): (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.60 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.02 (dd, J = 8.9, 1.6 Hz, 1H), 7.87 (dd, J = 8.3, 1.8 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.2 Hz,1H), 4.34 (d, J = 17.2 Hz, 1H), 4.11 (s, 3H), 3.00 – 2.86 (m, 1H), 2.66 – 2.57 (m, 1H), 2.47 – 2.33 (m, 1H), 2.06 – 1.97 (m, 1H). [000432] LC-MS (ES, m / z) (I-152): [M-H]-: 416.20 [000433]1H-NMR (I-152): (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.52 (s, 1H), 8.54 – 8.49 (m, 1H), 8.31 – 8.24 (m, 2H), 8.07 – 7.97 (m, 2H), 7.82 – 7.74 (m, 1H), 7.60 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.1 Hz, 1H), 4.32 (d, J = 17.1 Hz, 1H), 4.11 (s, 3H), 2.99 – 2.85 (m, 1H), 2.66 – 2.57 (m, 1H), 2.48 – 2.35 (m, 1H), 2.09 – 1.98 (m, 1H). [000434] Example 1.39. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-151)[000435] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (200 mg, 0.771 mmol, 1 equiv), 3-methyl-1H-pyrrolo[2,3-b] pyridine-5- carboxylic acid (135.90 mg, 0.771 mmol, 1 equiv), DIEA (299.11 mg, 2.313 mmol, 3 equiv), DMF (10 mL) and HATU (439.98 mg, 1.157 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was purified directly 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: 12% B to28% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.32 / 12.08) to afford N-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3-methyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide (6.7 mg, 1.95%) as a white solid. [000436] LC-MS (ES, m / z):[M+H]+: 418.05 [000437]1H-NMR: (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.00 (s, 1H), 10.58 (s, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.18 (s, 1H), 7.87 (d, J = 9.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.41 (dd, J=18 Hz, 2H), 3.01-2.85 (m, 1H), 2.64 (s, 1H), 2.41 (d, J = 12.8 Hz, 1H), 2.34 (d, J = 1.1 Hz, 3H), 2.02 (s, 1H).[000438] Example 1.40. Synthesis of (R)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-150)[000439] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (200 mg, 0.771 mmol, 1 equiv), 3-methyl-1H-pyrrolo[2,3-b] pyridine-5- carboxylic acid (135.90 mg, 0.771 mmol, 1 equiv), DIEA (299.11 mg, 2.313 mmol, 3 equiv), DMF (10 mL) and HATU (439.98 mg, 1.157 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture 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: 12% B to28% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.32 / 12.08) to afford N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3-methyl-1H-pyrrolo[2,3-b] pyridine-5- carboxamide (40 mg, 1.95%) as a white solid. The product was was purified by PREP_CHIRAL_HPLC- with the following conditions (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile Phase A: MtBE: DCM=1: 2(0.1%TFA), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 288 / 224 nm; RT1 (min): 5.4; RT2 (min): 6.5; Sample Solvent: MeOH: DCM=1: 1(0.1% TFA); Injection Volume: 0.6 mL; Number Of Runs: 5) to afford N-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl}-3-methyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide (9.4 mg, 5.68%) as a white solid. [000440] LC-MS (ES, m / z):[M+H]+: 418.00 [000441]1H-NMR: (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.00 (s, 1H), 10.58 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 5.18 – 5.07 (m, 1H), 4.49 (d, J=18Hz, 1H), 4.37 (d, J=18Hz, 1H), 2.93 (s, 1H), 2.64 (s, 1H), 2.39 (s, 1H), 2.34 (d, J = 1.1 Hz, 3H), 2.02 (s, 1H). [000442] Example 1.41. Synthesis of (S)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-149)[000443] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (200 mg, 0.771 mmol, 1 equiv), 3-methyl-1H-pyrrolo[2,3-b] pyridine-5- carboxylic acid (135.90 mg, 0.771 mmol, 1 equiv), DIEA (299.11 mg, 2.313 mmol, 3 equiv), DMF (10 mL) and HATU (439.98 mg, 1.157 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture 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: 12% B to28% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.32 / 12.08) to afford N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3-methyl-1H-pyrrolo[2,3-b] pyridine-5- carboxamide (40 mg, 1.95%) as a white solid. The product was purified by PREP_CHIRAL_HPLC- with the following conditions (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile Phase A: MtBE: DCM=1: 2(0.1%TFA), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 288 / 224 nm; RT1(min): 5.4; RT2(min): 6.5; Sample Solvent: MeOH: DCM=1: 1(0.1% TFA); Injection Volume: 0.6 mL; Number Of Runs: 5) to afford N-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-3H-isoindol-5-yl}-3-methyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide (8.7 mg, 5.34%) as a white solid. [000444] LC-MS (ES, m / z):[M+H]+: 418.05 [000445]1H-NMR: (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.00 (s, 1H), 10.58 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 5.18 – 5.07 (m, 1H), 4.49 (d, J=18Hz, 1H), 4.37 (d, J=18Hz, 1H), 2.93 (s, 1H), 2.64 (s, 1H), 2.39 (s, 1H), 2.34 (d, J = 1.1 Hz, 3H), 2.02 (s, 1H). [000446] Example 1.42. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-147)[000447] Synthesis of methyl 1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000448] In a 50mL round-bottom flask, to a solution of methyl 1H-pyrrolo[2,3-b] pyridine-5- carboxylate (200 mg, 1.135 mmol, 1 equiv) in DMF (15 mL) was added Cs2CO3(1109.64 mg, 3.405 mmol, 3 equiv) at 0 °C. The mixture was stirred for 15 min. Then iodoethane (194.76 mg, 1.249 mmol, 1.1 equiv) was added and the mixture was allowed to warm to room temperature and stirred for 1 overnight. Desired product could be detected by LCMS. The reaction was quenched with ice water (50 mL) at 0 °C. The resulting mixture was extracted with EA (3x50 mL). The combined organic layers were 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, H2O in ACN, 36% to 40% gradient in 4 min; detector, UV 254 nm. This resulted in methyl 1- ethylpyrrolo[2,3-b] pyridine-5-carboxylate (162 mg, 69.87%) as a yellow oil. [000449] LC-MS (ES, m / z): [M+H]+: 205.05 [000450] Synthesis of 1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000451] Into a 25 mL round-bottom flask were added methyl 1-ethylpyrrolo[2,3-b] pyridine- 5-carboxylate (100 mg, 0.490 mmol, 1 equiv) in MeOH (1 mL) and NaOH (19.58 mg, 0.490 mmol, 1 equiv) in H2O (1 mL) dropwises at 0 °C under N2 atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with 1M HCl(aq). The resulting mixture was concentrated under reduced pressure. The crude product 1-ethylpyrrolo[2,3-b] pyridine-5-carboxylic acid (150 mg, crude) was used in the next step directly without further purification. [000452] LC-MS (ES, m / z): [M+H]+: 191.05 [000453] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide[000454] Into a 25mL round-bottom flask were added 1-ethylpyrrolo[2,3-b] pyridine-5- carboxylic acid (93 mg, 0.489 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine- 2,6-dione (126.77 mg, 0.489 mmol, 1 equiv), DIEA (189.59 mg, 1.467 mmol, 3 equiv), DMF (2 mL) and HATU (278.88 mg, 0.734 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was purified directly 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: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% B to 26 % B in 10 min; Wave Length: 254nm / 220nm nm; RT (min): 16.917) to afford N-[2-(2,6-dioxopiperidin-3- yl)-1-oxo-3H-isoindol-5-yl]-1-ethylpyrrolo[2,3-b] pyridine-5-carboxamide (17.4 mg, 8.20%) as a white solid. [000455] LC-MS (ES, m / z):[M+H]+: 432.05 [000456]1H-NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.62 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.86 (dd, J = 8.4, 1.8 Hz, 1H), 7.77 – 7.69 (m, 2H), 6.66 (d, J = 3.5 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.3 Hz, 1H), 4.41– 4.30 (m, 3H), 2.97-2.88 (m, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.49-2.34 (m, 1H), 2.06 – 1.98 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H). [000457] Example 1.43. Synthesis of 1-cyclopropyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-146)[000458] Synthesis of methyl 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000459] Into a 50mL round-bottom flask were added methyl 1H-pyrrolo[2,3-b] pyridine-5- carboxylate (200 mg, 1.135 mmol, 1 equiv), cyclopropylboronic acid (195.03 mg, 2.270 mmol, 2 equiv), Na2CO3(240.64 mg, 2.270 mmol, 2 equiv), Cu(OAc)2(206.20 mg, 1.135 mmol, 1 equiv), 2,2’-Bipyridine (177.30 mg, 1.135 mmol, 1 equiv) and DCE(5 mL) at room 140emperature. The mixture was stirred for 1 overnight at 110°C. Desired product could be detected by LCMS. The residue was purified directly by silica gel column chromatography, eluted with PE / EA (2 / 3) to afford methyl 1-cyclopropylpyrrolo[2,3-b] pyridine-5-carboxylate (150 mg, 61.10%) as a yellow oil. [000460] LC-MS (ES, m / z) :[M+H]+: 217.00 [000461] Synthesis of 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000462] Into a 25mL round-bottom flask were added methyl 1-cyclopropylpyrrolo[2,3-b] pyridine-5-carboxylate (100 mg, 0.462 mmol, 1 equiv) in MeOH (3 mL) and NaOH (18.50 mg, 0.462 mmol, 1 equiv) in H2O (3 mL) at 0 °C under N2atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The crude product 1-cyclopropylpyrrolo[2,3-b]pyridine-5-carboxylic acid (151 mg, crude) was used in the next step directly without further purification. [000463] LC-MS (ES, m / z): [M+H]+: 203.00 [000464] Synthesis of 1-cyclopropyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- pyrrolo[2,3-b]pyridine-5-carboxamide[000465] Into a 25mL round-bottom flask were added 1-cyclopropylpyrrolo[2,3-b] pyridine-5- carboxylic acid (100 mg, 0.495 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine- 2, 6-dione (128.21 mg, 0.495 mmol, 1 equiv), DIEA (191.75 mg, 1.485 mmol, 3 equiv), DMF (5 mL) and HATU (282.06 mg, 0.742 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture was purified directly 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: CAN; Flow rate: 60 mL / min mL / min; Gradient: 12% B to 27 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 16.779) to afford 1-cyclopropyl-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]pyrrolo[2,3-b]pyridine-5-carboxamide (64.9 mg, 29.06%) as a white solid. [000466] LC-MS (ES, m / z):[M+H]+: 444.05 [000467]1H-NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.63 (s, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 7.86 (dd, J = 8.3, 1.8 Hz, 1H), 7.73 (d, J =8.3 Hz, 1H), 7.62 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 3.68 (tt, J = 6.9, 4.1 Hz, 1H), 2.93 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.61 (ddd, J = 17.3, 4.5, 2.3 Hz, 1H), 2.41 (qd, J = 13.2, 4.4 Hz, 1H), 2.10 – 1.97 (m, 1H), 1.16 – 1.00 (m, 4H). [000468] Example 1.44. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-148)[000469] Synthesis of methyl 1-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000470] In a 100 mL round-bottom flask were added methyl 1H-pyrrolo[2,3-b] pyridine-5- carboxylate (300 mg, 1.703 mmol, 1 equiv) in DMF (25 mL) and Cs2CO3(1664.46 mg, 5.109 mmol, 3 equiv) at 0 °C. The mixture was stirred for 15 min. Then iodocyclobutane (340.92 mg, 1.873 mmol, 1.1 equiv) was added and the mixture was allowed to warm to RT and stirred for 1 overnight. Desired product could be detected by LCMS. The mixture was filtrated. The filtration was purified directly by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, H2O in ACN, 63% to 69% gradient in 8 min; detector, UV 254 nm. This resulted in methyl 1-cyclobutylpyrrolo[2,3-b]pyridine-5-carboxylate (181 mg, 46.16%) as a solid. [000471] LC-MS (ES, m / z): [M+ H]+:231.00[000472] 1H-NMR: (400 MHz, DMSO-d6) 8.82 (d, J = 2.0 Hz 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 3.6 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 5.43-5.30 (m, 1H), 3.89 (s, 3H), 2.61-2.54 (m, 1H), 2.48-2.39 (m, 2H), 1.86 (td, J = 10.0, 5.4 Hz, 2H). [000473] Synthesis of 1-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000474] Into a 25mL round-bottom flask were added methyl 1-cyclobutylpyrrolo[2,3-b] pyridine-5-carboxylate (100 mg, 0.434 mmol, 1 equiv) in MeOH (1 mL) and NaOH (17.37 mg, 0.434 mmol, 1 equiv) in H2O (1 mL) at 0 °C under N2 atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with HCl(aq). The resulting mixture was concentrated under reduced pressure. The crude product 1-cyclobutylpyrrolo[2,3-b] pyridine-5-carboxylic acid) was used in the next step directly without further purification. [000475] LC-MS (ES, m / z): [M+H]+:217.00 [000476] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- pyrrolo[2,3-b]pyridine-5-carboxamide[000477] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (50.75 mg, 0.196 mmol, 0.83 equiv), 1-cyclobutylpyrrolo[2,3-b] pyridine-5- carboxylic acid (51 mg, 0.236 mmol, 1.00 equiv), DIEA (91.45 mg, 0.708 mmol, 3 equiv), DMF (5 mL) and HATU (134.52 mg, 0.354 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture was purified directly 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: 35% B to 50% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.35) to afford 1-cyclobutyl-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol- 5-yl] pyrrolo[2,3-b] pyridine-5-carboxamide (21.5 mg, 19.53%) as an off-white solid. [000478] LC-MS (ES, m / z): [M+H]+:458.05[000479] 1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.61 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 3.6 Hz, 1H), 7.86 (dd, J = 8.3, 1.8 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 3.6 Hz, 1H), 5.44 – 5.30 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (dd, J=18 Hz, 2H), 2.93 (ddd, J = 17.2, 13.5, 5.4 Hz, 1H), 2.64-2.52 (m, 3H), 2.48 – 2.33 (m, 3H), 2.08-2.00 (m, 1H), 1.91-1.84 (m, 2H). [000480] Example 1.45. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (I-145)[000481] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (100 mg, 0.386 mmol, 1 equiv), 3-methylimidazo[4,5-b]pyridine-6-carboxylic acid (68.33 mg, 0.386 mmol, 1 equiv), DIEA (299.11 mg, 2.316 mmol, 6 equiv), DMF (4 mL) and HATU (219.99 mg, 0.579 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at 60°C. 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), 25% to 30% gradient in 10 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3- methylimidazo[4,5 -b]pyridine-6-carboxamide (9.6 mg, 5.88%) as a white solid. [000482] LC-MS (ES, m / z): [M+H]+: 419.00 [000483]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.69 (s, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 8.4, 1.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), 3.91 (s, 3H), 3.00 – 2.86 (m, 1H), 2.65 – 2.57 (m, 1H), 2.47 – 2.34 (m, 1H), 2.06 – 1.98 (m, 1H). [000484] Example 1.46. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 7-methoxyquinoline-3-carboxamide (I-144)[000485] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (100 mg, 0.386 mmol, 1.00 equiv), 7-methoxyquinoline-3-carboxylic acid (78.37 mg, 0.386 mmol, 1.00 equiv), DIEA (149.55 mg, 1.158 mmol, 3 equiv), DMF (5.00 mL, 64.659 mmol, 167.51 equiv) and HATU (219.99 mg, 0.579 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture 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: 10% B to25% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 15.73) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-7- methoxyquinoline-3-carboxamide (93.2 mg, 53.06%) as an off-white solid. [000486] LC-MS (ES,m / z):[M+H]+: 445.05 [000487]1H-NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.83 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 8.3, 1.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.38 (dd, J = 9.0, 2.5 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 3.98 (s, 3H), 2.93 (ddd, J = 17.2, 13.5, 5.3 Hz, 1H), 2.66 – 2.57 (m, 1H), 2.41 (qd, J = 13.3, 4.4 Hz, 1H), 2.06 – 1.99 (m, 1H). [000488] Example 1.47. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 6-methylquinoline-3-carboxamide (I-141)[000489] Into a 25 mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (50 mg, 0.193 mmol, 1 equiv) and 6-methylquinoline-3-carboxylic acid (54.15 mg, 0.289 mmol, 1.5 equiv) in DMF (3 mL, 38.765 mmol, 201.01 equiv) were added HATU (109.99 mg, 0.289 mmol, 1.5 equiv) and DIEA (49.85 mg, 0.386 mmol, 2 equiv) inportions at room temperature under air atmosphere. The resulting mixture was stirred for overnight at 60°C under nitrogen atmosphere. 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), 30% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]-6-methylquinoline-3-carboxamide (23.9 mg, 28.64%) as a white solid. [000490] LC-MS (ES, m / z): [M+H]+=429.15 [000491]1H-NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.89 (s, 1H), 9.30 (d, J = 2.2 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.88 (dd, J = 8.3, 1.8 Hz, 1H), 7.79 – 7.72 (m, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 2.95-2.90 (m, 1H), 2.62 (d, J = 17.8 Hz, 1H), 2.56 (s, 3H), 2.43-2.39 (m, 1H), 2.10 – 1.98 (m, 1H). [000492] Example 1.48. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-140)[000493] Synthesis of methyl 1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000494] Into a 25mL round-bottom flask were added methyl 3-methyl-1H-pyrrolo[2,3- b]pyridine-5-carboxylate (200 mg, 1.052 mmol, 1 equiv) in DMF (15 mL) and Cs2CO3(1109.64 mg, 3.405 mmol, 3 equiv) at 0 degrees C. The mixture was stirred for 15 min. Then 3- iodooxetane (229.74 mg, 1.249 mmol, 1.1 equiv) was dropwise at 0 ºC. The resulting mixturewas stirred for 1 overnight at 40 ºC under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction involves filtration, washing the filter cake with DMF (2 x 5mL). The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 75 to 80% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 1-(oxetan-3-yl)pyrrolo[2,3-b]pyridine-5- carboxylate (225 mg, 85.34%) as a white solid. [000495] LC-MS (ES, m / z) :[M+H]+: 233.05 [000496] Synthesis of 1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000497] Into a 25mL round-bottom flask were added methyl 1-(oxetan-3-yl)pyrrolo[2,3- b]pyridine-5-carboxylate (100 mg, 0.431 mmol, 1 equiv) in MeOH (2 mL) and NaOH (17.22 mg, 0.431 mmol, 1 equiv) in H2O (2 mL) was dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with HCl (aq). The resulting mixture was concentrated under reduced pressure and was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 75 to 80% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(oxetan-3- yl)pyrrolo[2,3-b]pyridine-5-carboxylic acid (62 mg, 66%) as a white solid. [000498] LC-MS (ES, m / z): [M+H]+: 219.00 [000499] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-(oxetan-3-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carboxamide[000500] Into a 25mL round-bottom flask were added 1-(oxetan-3-yl)pyrrolo[2,3-b]pyridine-5- carboxylic acid (182 mg, 0.834 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine- 2,6-dione (216.24 mg, 0.834 mmol, 1 equiv), DIEA (323.40 mg, 2.502 mmol, 3 equiv), DMF (5 mL) ) and HATU (475.70 mg, 1.251 mmol, 1.5 equiv) at room temperature. The resultingmixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture 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: 10% B to 30% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.6) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1-(oxetan-3-yl)pyrrolo[2,3- b]pyridine-5-carboxamide (26.0 mg, 6.73%) as a white solid. [000501] LC-MS (ES,m / z):[M+H]+: 460.10 [000502]1H-NMR: (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.65 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 7.86 (dd, J = 8.3, 1.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.05 (p, J = 7.2 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 5.05 (d, J = 7.2 Hz, 4H), 4.48 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 2.93 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.61 (d, J = 17.3 Hz, 1H), 2.40 (qd, J = 13.4, 4.5 Hz, 1H), 2.08 – 1.97 (m, 1H). [000503] Example 1.49. Synthesis of tert-butyl 3-(5-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate (I- 1[000504] Synthesis of methyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrolo[2,3- b]pyridine-5-carboxylate[000505] Into a 25mL round-bottom flask were added methyl 1H-pyrrolo[2,3-b]pyridine-5- carboxylate (200 mg, 1.135 mmol, 1 equiv) in DMF (5 mL) and Cs2CO3 (1109.64 mg, 3.405 mmol, 3 equiv) at 0 degrees C. The mixture was stirred for 15 min. Then tert-butyl 3- iodoazetidine-1-carboxylate (353.53 mg, 1.249 mmol, 1.1 equiv) was dropwise at 0 degrees C.The resulting mixture was stirred for 1 overnight at rt under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction involves filtration, washing the filter cake with DMF (2x3mL). The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 75 to 80% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 3-[5-(methoxycarbonyl)pyrrolo[2,3- b]pyridin-1-yl]azetidine-1-carboxylate (305 mg, 81.08%) as a white solid. [000506] LC-MS (ES, m / z) :[M+H]+: 332.00 [000507] Synthesis of 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5- carboxylic acid[000508] Into a 25mL round-bottom flask were added tert-butyl 3-[5- (methoxycarbonyl)pyrrolo[2,3-b]pyridin-1-yl]azetidine-1-carboxylate (100 mg, 0.302 mmol, 1 equiv) in THF (2 mL) and NaOH (12.07 mg, 0.302 mmol, 1 equiv) in H2O (2 mL) at 0°C. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with HCl(aq). The resulting mixture was concentrated under reduced pressure and was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 5 to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 1-[1-(tert- butoxycarbonyl)azetidin-3-yl]pyrrolo[2,3-b]pyridine-5-carboxylic acid (68 mg, 71%) as a white solid. [000509] LC-MS (ES, m / z): [M+H]+: 318.00 [000510] Synthesis of tert-butyl 3-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate[000511] Into a 25mL round-bottom flask were added 1-(oxetan-3-yl)pyrrolo[2,3-b]pyridine-5- carboxylic acid (182 mg, 0.834 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (163.40 mg, 0.630 mmol, 1 equiv), DIEA (244.37 mg, 1.890 mmol, 3 equiv), DMF (10 mL) and HATU (359.45 mg, 0.945 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60 C under nitrogen atmosphere. The mixture 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 H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 24% B to 42% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.07) to afford tert-butyl 3-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]carbamoyl}pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate (5.6 mg, 1.59%) as a white solid. [000512] LC-MS (ES, m / z):[M+H]+: 459.05 [000513]1H-NMR: (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.65 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 3.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 5.65 (s, -1H), 5.11 (d, J = 8.7 Hz, -1H), 4.66 – 4.20 (m, 6H), 2.91 (d, J = 12.3 Hz, -1H), 2.62 (d, J = 17.3 Hz, -1H), 2.42 (d, J = 12.5 Hz, -1H), 2.03 (s, -1H), 1.45 (s, 9H). [000514] Example 1.50. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 5-methyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxamide (I-132)[000515] Synthesis of methyl 5-methyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate[000516] Into a 30 mL pressure tank reactor were added 2-bromo-5-methylpyrrolo[2,3- b]pyrazine (900 mg, 4.244 mmol, 1 equiv) and Pd(dppf)Cl2(1552.79 mg, 2.122 mmol, 0.5 equiv), TEA (1288.47 mg, 12.732 mmol, 3 equiv) in MeOH(10 mL). The resulting mixture was stirred for overnight at 120°C under carbon monoxide atmosphere 5 atm. The reaction was monitored by LCMS. The mixture were collected by filtration and washed with MeOH (10 mL). The resulting mixture was concentrated under vacuum and dissolved in DMF (2 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 85% gradient in 35 min; detector, UV 254 nm to afford methyl 5-methylpyrrolo[2,3-b]pyrazine-2-carboxylate (750 mg, 92.43%) as a white solid. [000517] LC-MS (ES, m / z): [M +H]+:192.00 [000518]1H-NMR: (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.53 (d, J = 3.7 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H). [000519] Example 1.51. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 7-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-139)[000520] To a stirred solution of phenyl N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]carbamate (150 mg, 0.395 mmol, 1 equiv) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline (96.80 mg, 0.593 mmol, 1.5 equiv) in DMSO (2 mL) was added DIEA (153.31 mg, 1.185 mmol, 3 equiv) 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 crude product (150 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 mL / min; Gradient: 17% B to 37% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.32) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 3H-isoindol-5-yl]-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxamide (78.3 mg, 43.54%) as a white solid. [000521] LC-MS (ES, m / z): [M+H]+: 449.17[000522]1H NMR: (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.93 (s, 1H), 7.83 – 7.78 (m, 1H), 7.63 – 7.53 (m, 2H), 7.14 – 7.07 (m, 1H), 6.77 (d, J = 7.0 Hz, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (s, 2H), 4.40 (d, J = 17.1 Hz, 1H), 4.25 (d, J = 17.1 Hz, 1H), 3.72 (d, J = 10.2 Hz, 5H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.79 (t, J = 5.9 Hz, 2H), 2.64 – 2.54 (m, 1H), 2.45 – 2.30 (m, 1H), 2.03 – 1.94 (m, 1H). [000523] Example 1.52. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-138)[000524] To a stirred solution of phenyl N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]carbamate (150 mg, 0.395 mmol, 1 equiv) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (96.80 mg, 0.593 mmol, 1.5 equiv) in DMSO (2 mL) was added DIEA (153.31 mg, 1.185 mmol, 3 equiv) 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 crude product (250mg) 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; RT (min): 11.22) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- isoindol-5-yl]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxamide (63.6 mg, 34.93%) as an off-white solid. [000525] LC-MS (ES, / z): [M+H]+:449.2 [000526]1H NMR: (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.91 (s, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.13 – 7.07 (m, 1H), 6.82 – 6.75 (m, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (s, 2H), 4.39 (d, J = 17.1 Hz, 1H), 4.25 (d, J = 17.0 Hz, 1H), 3.71 (d, J = 13.8 Hz, 5H), 2.97 – 2.89 (m, 1H), 2.84 (t, J = 5.9 Hz, 2H), 2.59 (ddd, J = 17.3, 4.5, 2.3 Hz, 1H), 2.37 (qd, J = 13.2, 4.4 Hz, 1H), 1.98 (dtd, J = 12.5, 5.1, 2.1 Hz, 1H). [000527] Example 1.53. Synthesis of 1-cyclopropyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-163)[000528] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (150 mg, 0.58 mmol, 1 equiv) and 1-cyclopropylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (118.14 mg, 0.58 mmol, 1 equiv) in DMF (5 mL) were added DIEA (448.66 mg, 3.47 mmol, 6 equiv) and HATU (329.98 mg, 0.87 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at 60°C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with Water / Ice 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. The crude product (120mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 10% B to 26% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.35) to afford 1- cyclopropyl-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrazolo[3,4-d]pyrimidine- 6-carboxamide (81.8 mg, 31.74%) as a white solid. [000529] LC-MS (ES, m / z): [M+H]+: 446.05 [000530]1H-NMR: (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 11.00 (s, 1H), 9.52 (s, 1H), 8.49 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.4, 1.9 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.2 Hz, 1H), 4.37 (d, J = 17.2 Hz, 1H), 4.19 – 4.11 (m, 1H), 3.01 – 2.88 (m, 1H), 2.67 – 2.57 (m, 1H), 2.49 – 2.35 (m, 1H), 2.08 – 1.98 (m, 1H), 1.34 – 1.16 (m, 4H). [000531] Example 1.54. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 7H-pyrrolo[2,3-d]pyrimidine-2-carboxamide (I-137)[000532] Into a 8mL vial ; To a stirred mixture of 3-(5-amino-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (100 mg, 0.37mmol, 1 equiv) and 7H-pyrrolo[2,3-d]pyrimidine-2-carboxylic acid (62.92 mg, 0.37 mmol, 1 equiv) in DMF (3 mL) were added DIEA (99.70 mg, 0.77 mmol, 2 equiv) and HATU (219.99 mg, 0.58 mmol, 1.5 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 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 N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-7H-pyrrolo[2,3- d]pyrimidine-2-carboxamide (5.4 mg, 3.46%) as a white solid. [000533] LC-MS (ES, m / z): [M+H]+:405.1 [000534]1H-NMR: (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.01 (d, J = 14.9 Hz, 2H), 9.21 (s, 1H), 8.29 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 3.4 Hz, 1H), 5.16 – 5.08 (m, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.35 (d, J = 17.3 Hz, 1H), 2.93 (s, 1H), 2.78 (s, 1H) 2.61 (d, J = 16.7 Hz, 1H), 2.41 (d, J = 13.1 Hz, 1H). [000535] Example 1.55. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)thiazolo[5,4-b]pyridine-5-carboxamide (I-162)[000536] Into a 10 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (70 mg, 0.270 mmol, 1 equiv), [1,3]thiazolo[5,4-b]pyridine-5-carboxylic acid (48.65 mg, 0.270 mmol, 1 equiv) and DMF (2 mL, 25.843 mmol, 95.72 equiv) at room temperature. To the above mixture was added DIEA (209.38 mg, 1.620 mmol, 6 equiv) and HATU (153.99 mg, 0.405 mmol, 1.5 equiv) in portions over 1 min at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 3H-isoindol-5-yl]-[1,3]thiazolo[5,4-b]pyridine-5-carboxamide (11.5 mg, 9.25%) as a brown solid.[000537] LC-MS (ES, m / z): [M+H]+:421.90 [000538]1H-NMR: (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.99 (s, 1H), 9.79 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.04 (dd, J = 8.4, 1.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.2 Hz, 1H), 4.50 (d, J = 17.1 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), 2.93 (ddd, J = 17.7, 13.6, 5.3 Hz, 1H), 2.61 (d, J = 17.4 Hz, 1H), 2.44-2.37 (m, 1H), 2.10-1.98 (m, 1H). [000539] Example 1.56. Synthesis of 2-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (I-135)[000540] Synthesis of 2-((tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-5-carboxylic acid[000541] Into a 40 mL vial were added 2-amino-1H-1,3-benzodiazole-5-carboxylic acid (250 mg, 1.411 mmol, 1 equiv), Boc2O (615.96 mg, 2.822 mmol, 2 equiv), EtOH (4 mL) and Guanidine hydrochloride (26.96 mg, 0.282 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were 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 (10mmol / L NH4HCO3), 5% to 50% gradient in 20 min;detector, UV 254 nm. This resulted in 2-[(tert-butoxycarbonyl)amino]-1H-1,3-benzodiazole-5- carboxylic acid (105 mg, 26.84%) as a white solid. [000542] Synthesis of 2-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- benzo[d]imidazole-5-carboxamide[000543] Into a 50 mL round-bottom flask were added 2-[(tert-butoxycarbonyl)amino]-1H-1,3- benzodiazole -5-carboxylic acid (105 mg, 0.379 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol- 2-yl)piperidine-2,6-dione (98.18 mg, 0.379 mmol, 1 equiv), DIEA (293.66 mg, 2.274 mmol, 6 equiv), DMF (4 mL) and HATU (215.98 mg, 0.569 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at 60°C under nitrogen 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 mmol / L NH4HCO3), 5% to 50% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under vacuum. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 20% B to 35% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 9.465) to afford 2-amino-N-[2- (2,6-dioxopiperidin-3-yl) -1-oxo-3H-isoindol-5-yl]-1H-1,3-benzodiazole-5-carboxamide (5.2 mg, 2.86%) as an off-white solid. [000544] LC-MS (ES, m / z): [M+H]+: 419.00 [000545]1H NMR: (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.99 (s, 1H), 10.60 (s, 1H), 8.68 – 8.46 (m, 2H), 8.15 (s, 1H), 7.95 (s, 1H), 7.90 (dd, J = 8.2, 1.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.48 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 2.95 – 2.86 (m, 1H), 2.66 – 2.53 (m, 1H), 2.44 – 2.33 (m, 1H), 2.05 – 1.98 (m, 1H). [000546] Example 1.57. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-143)[000547] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (100 mg, 0.386 mmol, 1 equiv), 1-isopropylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (79.53 mg, 0.386 mmol, 1 equiv), DIEA (299.11 mg, 2.316 mmol, 6 equiv), DMF (4 mL) and HATU (219.99 mg, 0.579 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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), 35% to 45% gradient in 10 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1 - isopropylpyrazolo[3,4-d]pyrimidine-6-carboxamide (119.0 mg, 66.61%) as a white solid. [000548] LC-MS (ES, m / z): [M+H]+:448.05 [000549]1H-NMR: (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 11.00 (s, 1H), 9.53 (s, 1H), 8.55 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.00 (dd, J = 8.3, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.43 – 5.30 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.51 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.66 – 2.57 (m, 1H), 2.49 – 2.34 (m, 1H), 2.10 – 1.98 (m, 1H), 1.56 (d, J = 6.7 Hz, 6H). [000550] Example 1.58. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 2-hydroxybenzo[d]thiazole-6-carboxamide (I-159)[000551] Synthesis of 3-(tert-butoxycarbonyl)-2-oxo-2,3-dihydrobenzo[d]thiazole-6-carboxylic acid[000552] Into a 25mL round-bottom flask were added 2-hydroxy-1,3-benzothiazole-6- carboxylic acid (100 mg, 0.512 mmol, 1 equiv) in DMF (2 mL) and sodium hydride (60% in oil, 14.75 mg, 0.614 mmol, 1.2 equiv) at 0 ºC. The mixture was stirred for 2 h. Then Boc2O (167.72 mg, 0.768 mmol, 1.5 equiv) was added and the mixture was allowed to warm to RT and stirred for 16h. The reaction was quenched with water at 0 ºC. The mixture was neutralized to pH 7 with HCl. The resulting mixture was concentrated under reduced pressure and lyophilized. This resulted in 3-(tert-butoxycarbonyl)-2-oxo-1,3-benzothiazole-6-carboxylic acid (67 mg, crude) as a solid. [000553] LC-MS (ES, m / z): [M-Boc-H]-: 193.90 [000554] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2- hydroxybenzo[d]thiazole-6-carboxamide[000555] Into a 25mL round-bottom flask were added 3-(tert-butoxycarbonyl)-2-oxo-1,3- benzothiazole-6-carboxylic acid (67 mg, 0.227 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol- 2-yl)piperidine-2,6-dione (58.82 mg, 0.227 mmol, 1 equiv), DMF (3 mL), DIEA (87.97 mg, 0.681 mmol, 3 equiv) and HATU (129.40 mg, 0.341 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere. The mixture 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: 7% B to25% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 13.03) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-2-hydroxy- 1,3-benzothiazole-6-carboxamide (18.9 mg, 17.42%) as an off-white solid. [000556] LC-MS (ES, m / z): [M-H]-: 434.95[000557]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.49 (s, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.90 (dd, J = 8.3, 1.9 Hz, 1H), 7.82 (dd, J = 8.4, 1.8 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 2.92 (ddd, J = 16.9, 13.5, 5.3 Hz, 1H), 2.65 – 2.56 (m, 1H), 2.39 (qd, J = 13.5, 4.8 Hz, 1H), 2.05 – 1.97 (m, 1H). [000558] Example 1.59. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1,4-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-136)[000559] Synthesis of methyl 1,4-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000560] Into a 25 mL round-bottom flask were added methyl 4-methyl-1H-pyrrolo[2,3- b]pyridine-5-carboxylate (45 mg, 0.237 mmol, 1 equiv), DMF (16 mL) and K2CO3 (49.05 mg, 0.355 mmol, 1.5 equiv) at room temperature. To the above mixture was added MeI (33.58 mg, 0.237 mmol, 1 equiv) and DMF (16 mL) in portions at room temperature. The resulting mixture was stirred for additional overnight at room temperature. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 5% to 95% gradient in 30 min; detector, UV 254 nm. This resulted in methyl 1,4-dimethylpyrrolo[2,3-b]pyridine-5-carboxylate (270 mg) as a brown solid. [000561] Synthesis of 1,4-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000562] Into a 50 mL round-bottom flask were added methyl 1,4-dimethylpyrrolo[2,3- b]pyridine-5-carboxylate (140 mg, 0.686 mmol, 1 equiv) and THF (1.5 mL) at room temperature. To the above mixture was added LiOH (131.34 mg, 5.488 mmol, 8 equiv) and H2O (1.5 mL) at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was concentrated under vacuum and lyophilized This resulted in 1,4- dimethylpyrrolo[2,3-b]pyridine-5-carboxylic acid (400 mg, containing LiCl) as a white solid. [000563] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-dimethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide[000564] Into a 25 mL round-bottom flask were added 1,4-dimethylpyrrolo[2,3-b]pyridine-5- carboxylic acid (80 mg, 0.421 mmol, 1 equiv) , DMF (4 mL) , DIEA (0.44 mL, 2.526 mmol, 6 equiv) and HATU (239.89 mg, 0.631 mmol, 1.5 equiv) at 0°C. To the above mixture was added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (218.10 mg, 0.842 mmol, 2 equiv) at 0°C. The resulting mixture was stirred for 3 h at 90°C. The reaction was monitored by LCMS. The resulting was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 13% B to28% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 13.62) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1,4- dimethylpyrrolo[2,3-b]pyridine-5-carboxamide (11.9 mg, 6.40%) as an off-white solid. [000565] LC-MS (ES, m / z): [M+H]+ 432 [000566]1H NMR: (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.67 (s, 1H), 8.44 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.81 – 7.74 (m, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz,1H), 3.85 (s, 3H), 2.92 (ddd, J = 17.8, 13.4, 5.3 Hz, 1H), 2.64 (s, 3H), 2.59 (s, 0H), 2.44 – 2.33 (m, 1H), 2.01 (d, J = 12.8 Hz, 1H). [000567] Example 1.60. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 4-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-131)[000568] Synthesis of methyl 4-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000569] To a stirred mixture of methyl 4-fluoro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (150 mg, 0.773 mmol, 1 equiv) and K2CO3(160.15 mg, 1.159 mmol, 1.5 equiv) in DMF (6 mL) was added MeI (109.65 mg, 0.773 mmol, 1 equiv) 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 reaction was quenched with Water(50 ml) at room temperature. The resulting mixture was extracted with EtOAc (3 x50 mL). 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 dissolved in DMF (5 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 80% gradient in 30 min; detector, UV 254 nm. This resulted in methyl 4-fluoro-1-methylpyrrolo[2,3-b]pyridine-5-carboxylate (100 mg, 62.17%) as a yellow solid. [000570] LC-MS (ES, m / z): [M +H]+: 209.00[000571]1H-NMR: (400 MHz, DMSO-d6) δ 8.75 (d, J = 9.4 Hz, 1H), 7.68 (d, J = 3.5 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1H), 3.88 (d, J = 5.9 Hz, 6H). [000572] Synthesis of 4-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000573] A mixture of methyl 4-fluoro-1-methylpyrrolo[2,3-b]pyridine-5-carboxylate (160 mg, 0.769 mmol, 1 equiv) and NaOH (61.48 mg, 1.538 mmol, 2 equiv) in THF (8 mL) and H2O (8 mL) was stirred for overnight at room temperature under argon atmosphere. Desired product could be detected by LCMS. The mixture was acidified to pH 4 with 1N HCl. The resulting mixture was concentrated under reduced pressure and was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 5 to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 4-fluoro-1- methylpyrrolo[2,3-b]pyridine-5-carboxylic acid (160 mg, 57.19%) as a white solid. The crude product mixture was used in the next step directly without further purification. [000574] LC-MS (ES, m / z): [M +H]+: 195.00 [000575] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-fluoro-1-methyl- 1H-pyrrolo[2,3-b]pyridine-5-carboxamide[000576] A mixture of 4-fluoro-1-methylpyrrolo[2,3-b]pyridine-5-carboxylic acid (100 mg, 0.515 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (267.06 mg, 1.030 mmol, 2 equiv) and DIEA (199.70 mg, 1.545 mmol, 3 equiv), HATU (380.235 mg, 0.773 mmol, 1.5 equiv) in DMF (7.5 mL) was stirred overnight at 40°C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was dissolved in DMF (5 mL) and 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 nmto afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoro-1-methylpyrrolo[2,3- b]pyridine-5-carboxamide as a white solid. [000577] LC-MS (ES, m / z): [M +H]+:436.00 [000578]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.77 (s, 1H), 8.57 (d, J = 9.3 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.80 – 7.67 (m, 3H), 6.72 (d, J = 3.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 3.89 (s, 3H), 2.89 (s, 1H), 2.67 – 2.58 (m, 1H), 2.44 – 2.32 (m, 1H), 2.06 – 1.96 (m, 1H). [000579] Example 1.61. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-142)[000580] To a stirred mixture of 1,3-dimethylpyrrolo[2,3-b]pyridine-5-carboxylic acid (80 mg, 0.421 mmol, 1 equiv) and HATU (319.86 mg, 0.842 mmol, 2 equiv) in DMF (4 mL) were added DIEA (326.17 mg, 2.526 mmol, 6 equiv). The resulting mixture was stirred for 20 min at room temperature under argon atmosphere. To the above mixture was added 3-(5- amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (109.05 mg, 0.421 mmol, 1 equiv) in portions at room temperature. The resulting mixture was stirred for overnight 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 , 10% to 50% gradient in 20 min; detector, UV 254 nm.This resulted in N-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1,3-dimethylpyrrolo[2,3-b]pyridine-5- carboxamide (32.2 mg, 16.91%) as an off-white solid. [000581] LC-MS (ES, m / z): [M+H]+: 432.16 [000582]1H NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.59 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 1.3 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 3.82 (s, 3H), 2.93 (ddd, J = 17.8, 13.5, 5.3 Hz, 1H), 2.66 – 2.57 (m, 1H), 2.41 (dd, J = 13.1, 4.5 Hz, 1H), 2.06 – 1.98 (m, 1H).[000583] Example 1.62. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-133)[000584] Synthesis of 5-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine[000585] Into a 100 mL 3-necked round-bottom flask were added 5-bromo-3-(trifluoromethyl)- 1H-pyrrolo[2,3-b]pyridine (900 mg, 3.396 mmol, 1 equiv) and K2CO3(938.63 mg, 6.792 mmol, 2 equiv), MeI (723.00 mg, 5.094 mmol, 1.50 equiv) in DMF(10 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for overnight at 25°C under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of Water (50 mL) at room temperature. The mixture was extracted with EtOAc (3x50mL) and the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The resulting mixture was dissolved in DMF (5 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 5-bromo-1-methyl-3- (trifluoromethyl)pyrrolo[2,3-b]pyridine (790 mg, 82.53%) as a white solid. [000586] LC-MS (ES, m / z): [M +H]+: 279.00 [000587]1H-NMR: (400 MHz, Chloroform-d) δ 8.38 (d, J = 2.1 Hz, 1H), 8.09 (dd, J = 2.1, 1.0 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 3.85 (s, 3H).[000588] Synthesis of methyl 1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate[000589] Into a 30 mL pressure tank reactor were added 5-bromo-1-methyl-3- (trifluoromethyl)pyrrolo[2,3-b]pyridine (690 mg, 2.473 mmol, 1 equiv) and Pd(dppf)Cl2(904.61 mg, 1.236 mmol, 0.50 equiv), TEA (750.63 mg, 7.419 mmol, 3 equiv) in MeOH(10 mL). The resulting mixture was stirred for 2 days at 120°C under carbon monoxide atmosphere 10 atm. The reaction was monitored by LCMS. The mixture were collected by filtration and washed with MeOH (10 mL)). The resulting mixture was concentrated under vacuum and dissolved in DMF(4 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 85% gradient in 35 min; detector, UV 254 nm to afford methyl 1-methyl-3-(trifluoromethyl)pyrrolo[2,3-b]pyridine- 5-carboxylate as a white solid. [000590] LC-MS (ES, m / z): [M +H]+: 259.00 [000591] Synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000592] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-methyl-3- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide[000593] A mixture of 1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (85 mg, crude), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (74.33 mg, 0.287 mmol, 1 equiv) and DIEA (222.32 mg, 1.722 mmol, 6 equiv), HATU (120 mg, 0.316 mmol, 1.1 equiv) in DMF (4 mL) was stirred 2 hours at 50°C under argon atmosphere. The reaction was monitored by LCMS. 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 80% gradient in 25 min; detector, UV 254 nm, The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 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): 12.37) to afford to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 3H-isoindol-5-yl]-1-methyl-3-(trifluoromethyl)pyrrolo[2,3-b]pyridine-5-carboxamide (18.8 mg, 12.9%) as a white solid. [000594] LC-MS (ES, m / z): [M -H]-: 484.10 [000595]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.77 (s, 1H), 9.05 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 – 8.39 (m, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 8.4, 1.9 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.35 (d, J = 17.3 Hz, 1H), 3.95 (s, 3H), 3.00 – 2.86 (m, 1H), 2.61 (ddd, J = 16.9, 4.3, 2.3 Hz, 1H), 2.40 (tt, J = 13.2, 6.5 Hz, 1H), 2.10 – 1.97 (m, 1H). [000596] Example 1.63. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-indazole-5-carboxamide (I-124)[000597] Synthesis of methyl 1-cyclobutyl-1H-indazole-5-carboxylate[000598] Into a 40 mL vial were added methyl 1H-indazole-5-carboxylate (500 mg, 2.838 mmol, 1 equiv), Cs2CO3(1849.41 mg, 5.676 mmol, 2 equiv), DMF (5 mL) and iodocyclobutane (568.20 mg, 3.122 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction involves filtration, washing the filter cake with DMF (2x3mL). The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 75% to 85% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 1-cyclobutylindazole-5-carboxylate (300 mg, 45.91%) as an off-white solid. [000599] LC-MS (ES, m / z): [M+H]+: 231.10 [000600]1H-NMR: (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.32 (s, 1H), 7.94 (dd, J = 8.9, 1.5 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 5.38 – 5.26 (m, 1H), 3.88 (s, 3H), 2.72 – 2.57 (m, 2H), 2.51 – 2.42 (m, 2H), 1.95 – 1.82 (m, 2H). [000601] Synthesis of 1-cyclobutyl-1H-indazole-5-carboxylic acid[000602] Into a 50 mL round-bottom flask were added methyl 1-cyclobutylindazole-5- carboxylate (150 mg, 0.651 mmol, 1 equiv), THF (3 mL), H2O (3 mL) and LiOH.H2O (32.80mg, 0.781 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was neutralized to pH = 7 with Cationic resin. T The resulting mixture was concentrated under reduced pressure and was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 5 to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 1-cyclobutylindazole-5-carboxylic acid (120 mg, 85.19%) as an off-white solid. [000603] LC-MS (ES, m / z): [M+H]+: 217.10 [000604]1H-NMR: (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.22 (s, 1H), 7.96 (dd, J = 8.9, 1.5 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 5.35 – 5.22 (m, 1H), 2.72 – 2.56 (m, 2H), 2.50 – 2.40 (m, 2H), 1.96 – 1.80 (m, 2H). [000605] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- indazole-5-carboxamide[000606] Into a 50 mL round-bottom flask were added 1-cyclobutylindazole-5-carboxylic acid (140 mg, 0.647 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (167.86 mg, 0.647 mmol, 1 equiv), DIEA (502.07 mg, 3.882 mmol, 6 equiv), DMF (7 mL) and HATU (369.26 mg, 0.971 mmol, 1.5 equiv) at room temperature. The resulting mixture wasstirred for overnight at 60 C under nitrogen atmosphere. Desired product could be detected byLCMS. 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), 45% to 55% gradient in 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]indazole-5-carbox amide (104.9 mg, 35.03%) as a white solid. [000607] LC-MS (ES, m / z): [M+H]+: 458.05 [000608]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.58 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.00 (dd, J = 8.9, 1.7 Hz, 1H), 7.87 (dd, J = 8.4, 1.8Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 5.41 – 5.28 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.73 – 2.56 (m, 3H), 2.54 – 2.51 (m, 1H), 2.49 – 2.32 (m, 2H), 2.07 – 1.97 (m, 1H), 1.96 – 1.83 (m, 2H). [000609] Example 1.64. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-128)[000610] Synthesis of 6-chloro-1-cyclobutyl-3-methyl-1H-pyrazolo[3,4-d]pyrimidine[000611] To a stirred mixture of 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.966 mmol, 1 equiv) and cyclobutanol (641.60 mg, 8.898 mmol, 3 equiv) and PPh3 (1166.92 mg, 4.449 mmol, 1.5 equiv) in THF (6 mL) was added DIAD (899.62 mg, 4.449 mmol, 1.5 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred for overnight at 60 °C 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 10mL). The combined organic layers were washed with brine (1x20 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 6-chloro-1- cyclobutyl-3-methylpyrazolo[3,4-d]pyrimidine as an off-white solid. 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 6-chloro-1-cyclobutyl-3-methylpyrazolo[3,4-d]pyrimidine (360 mg, 54.51%) as a yellow solid. [000612] LC-MS (ES, m / z): [M+H]+:223 [000613]1H NMR: (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 5.40 – 5.27 (m, 1H), 2.86 – 2.70 (m, 2H), 2.62 (s, 3H), 2.58 – 2.26 (m, 2H), 2.06 – 1.83 (m, 2H). [000614] Synthesis of methyl 1-cyclobutyl-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- carboxylate[000615] To a stirred mixture of 6-chloro-1-cyclobutyl-3-methylpyrazolo[3,4-d]pyrimidine (310 mg, 1.392 mmol, 1 equiv) and Pd(dppf)Cl2 (203.73 mg, 0.278 mmol, 0.2 equiv) in MeOH (14 mL) was added TEA (0.58 mL, 4.176 mmol, 3 equiv). The resulting mixture was stirred for overnight at 120°C under carbon monoxide atmosphere 5 atm. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x20 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, 10% to 95% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 1-cyclobutyl-3-methylpyrazolo[3,4-d]pyrimidine-6-carboxylate (300 mg) as a yellow solid. [000616] LC-MS (ES, m / z): [M+H]+:247 [000617]1H NMR: (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 5.41 (q, J = 8.4 Hz, 1H), 3.94 (s, 3H), 2.75 – 2.65 (m, 2H), 2.65 (s, 3H), 2.48 – 2.38 (m, 2H), 1.89 (td, J = 9.9, 5.6 Hz, 2H). [000618] Synthesis of 1-cyclobutyl-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid[000619] To a stirred solution of methyl 1-cyclobutyl-3-methylpyrazolo[3,4-d]pyrimidine-6- carboxylate (300 mg, 1.218 mmol, 1 equiv) in H2O (0.02 mL)and THF (0.10 mL) was added NaOH (97.45 mg, 2.436 mmol, 2.00 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at room temperature under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and lyophilized. The crude resulting mixture was used in the next step directly without further purification. [000620] LC-MS (ES, m / z): [M+H]+:233 [000621] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide[000622] To a stirred solution of 1-cyclobutyl-3-methylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (47 mg, 0.202 mmol, 1 equiv) and 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (52.47 mg, 0.202 mmol, 1 equiv) in DMF (1.5 mL) were added HATU (115.42 mg, 0.303 mmol, 1.5 equiv) and DIEA (0.11 mL, 0.606 mmol, 3 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 30 °C under argon atmosphere. The reaction was monitored by LCMS. The residue was dissolved in DMSO (2mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 20% to 70% gradient in 13 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5- yl]-3-methylpyrazolo[3,4-d]pyrimidine-6-carboxamide (34.8 mg, 32.79%) as a yellow solid. [000623] LC-MS (ES, m / z): [M+H]+:474 [000624]1H NMR: (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.99 (s, 1H), 9.50 (s, 1H), 8.25 (s, 1H), 8.00 (dd, J = 8.3, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.57 (p, J = 8.4 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 2.93 (ddd, J = 18.2, 9.6, 3.8 Hz, 1H), 2.82 – 2.56 (m, 6H), 2.56 – 2.36 (m, 3H), 2.08 – 1.82 (m, 3H).[000625] Example 1.65. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-129)[000626] Synthesis of methyl 1-cyclobutyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000627] Into a 40 mL vial were added 3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (200 mg, 1.135 mmol, 1 equiv), Cs2CO3(685.21 mg, 2.104 mmol, 2 equiv), DMF (5 mL) and iodocyclobutane (229.66 mg, 1.262 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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 (10mmol / L NH4HCO3), 60% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-3-methylpyrrolo[2,3-b]pyridine -5- carboxylic acid (190 mg, 72.68%) as an off-white solid. [000628] LC-MS (ES, m / z): [M+H]+: 245.05 [000629]1H-NMR: (300 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 5.40 – 5.22 (m, 1H), 3.89 (s, 3H), 2.60 – 2.52 (m, 1H), 2.49 – 2.34 (m, 3H), 2.31 (d, J = 1.1 Hz, 3H), 1.92 – 1.75 (m, 2H). [000630] Synthesis of 1-cyclobutyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000631] Into a 40 mL vial were added methyl 1-cyclobutyl-3-methylpyrrolo[2,3-b]pyridine-5- carboxylate (190 mg, 0.778 mmol, 1 equiv), THF (4 mL), H2O (4 mL) and LiOH (27.94 mg, 1.167 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was neutralized to pH = 7 with HCl (aq.). The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0:1) to afford 1-cyclobutyl-3-methylpyrrolo[2,3 - b]pyridine-5-carboxylic acid (120 mg, 67.01%) as an off-white solid. [000632] LC-MS (ES, m / z): [M+H]+: 231.10 [000633]1H-NMR: (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 1.3 Hz, 1H), 5.37 – 5.24 (m, 1H), 2.54 (dd, J = 9.4, 2.7 Hz, 1H), 2.49 – 2.45 (m, 1H), 2.44 – 2.35 (m, 2H), 2.30 (d, J = 1.1 Hz, 3H), 1.89 – 1.76 (m, 2H). [000634] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide[000635] Into a 40 mL vial were added 1-cyclobutyl-3-methylpyrrolo[2,3-b]pyridine-5- carboxylic acid (80 mg, 0.347 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine- 2,6-dione (90.07 mg, 0.347 mmol, 1 equiv), DIEA (269.42 mg, 2.082 mmol, 6 equiv), DMF (5 mL) and HATU (198.15 mg, 0.520 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-3- methylpyrrolo [2,3-b]pyridine-5-carboxamide (28.4 mg, 17.28%) as a white solid. [000636] LC-MS (ES, m / z): [M+H]+: 472.10 [000637]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.58 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.8 Hz, 1H), 7.76 – 7.69 (m, 2H), 5.39 – 5.26 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 2.99 – 2.86 (m, 1H), 2.66 – 2.52 (m, 3H), 2.47 – 2.37 (m, 3H), 2.36 (d, J = 1.1 Hz, 3H), 2.07 – 1.96 (m, 1H), 1.91 – 1.79 (m, 2H). [000638] Example 1.66. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxamide (I-130)[000639] Synthesis of methyl 1H-pyrazolo[3,4-b]pyrazine-5-carboxylate[000640] Into a 30 mL pressure tank reactor were added 6-chloro-1-cyclobutylpyrazolo[3,4- d]pyrimidine (20 mg, 0.096 mmol, 1 equiv), Pd(dppf)Cl2(14.71 mg, 0.020 mmol, 0.02 equiv), TEA (203.39 mg, 2.010 mmol, 2 equiv) and MeOH (10 mL) at room temperature. The resulting mixture was stirred for overnight at 100°C under carbon monoxide (10 atm) 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 silica gel columnchromatography, eluted with PE / EA (0:1) to afford methyl 1H-pyrazolo[3,4-b]pyrazine-5- carboxylate (8.5 mg, 47.48%) as a pink solid. [000641] LC-MS (ES, m / z): [M+H]+: 179.00 [000642]1H-NMR: (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 9.18 (s, 1H), 8.66 (s, 1H), 3.96 (s, 3H). [000643] Synthesis of methyl 1-cyclobutyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate[000644] Into a 20 mL vial were added methyl 1H-pyrazolo[3,4-b]pyrazine-5-carboxylate (75 mg, 0.421 mmol, 1 equiv), Cs2CO3(274.33 mg, 0.842 mmol, 2 equiv), DMF (3 mL) and iodocyclobutane (114.93 mg, 0.631 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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 (10 mmol / L NH4HCO3), 35% to 55% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 1-cyclobutylpyrazolo[3,4-b]pyrazine-5- carboxylate (60 mg, 61.37%) as an off-white solid. [000645] LC-MS (ES, m / z): [M+H]+: 233.00 [000646] Synthesis of 1-cyclobutyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid[000647] Into a 20 mL vial were added methyl 1-cyclobutylpyrazolo[3,4-b]pyrazine-5- carboxylate (60 mg, 0.258 mmol, 1 equiv), THF (1.5 mL), H2O (1.5 mL) and LiOH.H2O (16.26 mg, 0.387 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was neutralized to pH = 7 with cationic resin.The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0:1) to afford 1-cyclobutylpyrazolo[3,4-b]pyrazine-5 - carboxylic acid (45 mg, 79.82%) as a white solid. [000648] LC-MS (ES, m / z): [M+H]+: 219.10 [000649]1H-NMR: (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.65 (s, 1H), 5.53 – 5.44 (m, 1H), 2.79 – 2.69 (m, 2H), 2.50 – 2.42 (m, 2H), 1.98 – 1.89 (m, 2H). [000650] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- pyrazolo[3,4-b]pyrazine-5-carboxamide[000651] Into a 40 mL vial were added 1-cyclobutylpyrazolo[3,4-b]pyrazine-5-carboxylic acid (40 mg, 0.183 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (47.52 mg, 0.183 mmol, 1 equiv), DIEA (142.15 mg, 1.098 mmol, 6 equiv), DMF (3 mL) and HATU (104.55 mg, 0.274 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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), 45% to 55% gradient in 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrazolo[3,4-b]pyrazine- 5-carboxamide (29.3 mg, 34.34%) as a white solid. [000652] LC-MS (ES, m / z): [M+H]+: 460.00 [000653]1H-NMR: (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.98 (s, 1H), 9.31 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.03 (dd, J = 8.3, 1.6 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 5.63 – 5.45 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 3.02 – 2.86 (m, 1H), 2.85 – 2.61 (m, 3H), 2.61 – 2.52 (m, 2H), 2.46 – 2.33 (m, 1H), 2.05 – 1.87 (m, 3H). [000654] Example 1.67. Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (I-115)[000655] Synthesis of methyl 1-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate[000656] Into a 40 mL vial were added methyl 1H-pyrazolo[3,4-b]pyridine-5-carboxylate (300 mg, 1.693 mmol, 1 equiv), Cs2CO3(827.59 mg, 2.540 mmol, 1.5 equiv), DMF (7 mL) and bromocyclobutane (228.61 mg, 1.693 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction involves filtration, washing the filter cake with DMF (2x3mL). The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 65% to 75% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 1-cyclobutylpyrazolo[3,4- b]pyridine-5-carboxylate (230 mg, 58.73%) as an off-white solid. [000657] LC-MS (ES, m / z): [M+H]+: 232.10 [000658]1H-NMR: (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 5.58 – 5.45 (m, 1H), 3.93 (s, 3H), 2.78 – 2.63 (m, 2H), 2.52 – 2.40 (m, 2H), 1.98 – 1.86 (m, 2H). [000659] Synthesis of 1-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid[000660] Into a 50 mL round-bottom flask were added methyl 1-cyclobutylpyrazolo[3,4- b]pyridine-5 -carboxylate (200 mg, 0.865 mmol, 1 equiv), THF (4 mL), H2O (4 mL) andLiOH.H2O (54.43 mg, 1.297 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was neutralized to pH = 7 with cationic resin. The resulting mixture was concentrated under reduced pressure and was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 5 to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 1-cyclobutylpyrazolo[3,4-b]pyridine-5-carboxylic acid (175 mg, 93.15%) as an off-white solid. [000661] LC-MS (ES, m / z): [M+H]+: 218.20 [000662]1H-NMR: (400 MHz, DMSO-d6) δ 9.06 (d, J = 1.9 Hz, 1H), 8.71 (d, J = 1.9 Hz, 1H), 8.28 (s, 1H), 5.57 – 5.44 (m, 1H), 2.77 – 2.62 (m, 2H), 2.48 – 2.37 (m, 2H), 1.95 – 1.83 (m, 2H). [000663] Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide[000664] Into a 40 mL vial were added 1-cyclobutylpyrazolo[3,4-b]pyridine-5-carboxylic acid (170 mg, 0.783 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (202.90 mg, 0.783 mmol, 1 equiv), DIEA (606.88 mg, 4.698 mmol, 6 equiv), DMF (7 mL) and HATU (446.35 mg, 1.175 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at 60°C under nitrogen atmosphere. 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), 45% to 55% gradient in 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrazolo[3,4 -b]pyridine-5-carboxamide (55.5 mg, 15.10%) as a white solid. [000665] LC-MS (ES, m / z): [M+H]+: 459.05 [000666]1H-NMR: (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.75 (s, 1H), 9.11 (d, J = 2.1 Hz, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.42 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.85 (dd, J = 8.3, 1.8 Hz,1H), 7.74 (d, J = 8.3 Hz, 1H), 5.61 – 5.48 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.80 – 2.66 (m, 2H), 2.66 – 2.57 (m, 1H), 2.50 – 2.33 (m, 3H), 2.07 – 1.86 (m, 3H). [000667] Example 1.68. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-isopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-127)[000668] Synthesis of methyl 1-isopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[000669] Into a 40 mL vial were added methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (500 mg, 2.838 mmol, 1 equiv), NaH (102.16 mg, 4.257 mmol, 1.5 equiv), DMF (5 mL) and 2- iodopropane (530.70 mg, 3.122 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. 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), 60% to 75% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 1-isopropylpyrrolo[2,3- b]pyridine-5-carboxylate (320 mg, 51.66%) as a gray solid. [000670] LC-MS (ES, m / z): [M+H]+: 219.00 [000671]1H-NMR: (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 5.23 – 5.08 (m, 1H), 3.90 (s, 3H), 1.49 (d, J = 6.8 Hz, 6H). [000672] Synthesis of 1-isopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid[000673] Into a 50 mL round-bottom flask were added methyl 1-isopropylpyrrolo[2,3- b]pyridine-5-carboxylate (270 mg, 1.237 mmol, 1 equiv), THF (3 mL), H2O (3 mL) and LiOH.H2O (77.86 mg, 1.856 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was neutralized to pH = 7 with cationic resin. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 10 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 (10 mmol / L NH4HCO3), 40% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 1-isopropylpyrrolo[2,3-b]pyridine-5-carboxylic acid (220 mg, 87.08%) as a white solid. [000674] LC-MS (ES, m / z): [M+H]+: 205.05 [000675]1H-NMR: (400 MHz, DMSO-d6) δ 8.85 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 3.6 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 5.18 – 5.03 (m, 1H), 1.46 (d, J = 6.8 Hz, 6H). [000676] Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1-isopropyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide[000677] Into a 40 mL vial were added 1-isopropylpyrrolo[2,3-b]pyridine-5-carboxylic acid (100 mg, 0.490 mmol, 1 equiv), 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (126.95 mg, 0.490 mmol, 1 equiv), DIEA (379.71 mg, 2.940 mmol, 6 equiv), DMF (5 mL) and HATU (279.27 mg, 0.735 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with thefollowing conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-[2-(2,6-dioxopiperidin-3-yl)- 1-oxo-3H-isoindol-5-yl]-1-isopropylpyrrolo[2,3-b]pyridine-5-carboxamide (31.0 mg, 13.79%) as a white solid. [000678] LC-MS (ES, m / z): [M+H]+: 446.15 [000679]1H-NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.60 (s, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.90 – 7.80 (m, 2H), 7.72 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 5.21 – 5.07 (m, 2H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.65 – 2.57 (m, 1H), 2.48 – 2.33 (m, 1H), 2.10 – 1.97 (m, 1H), 1.51 (d, J = 6.7 Hz, 6H). [000680] Example 1.69. Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-y...

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, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 –OR, -N(R)2, -O(CH2)2OR, -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; or: L is a C1-4aliphatic chain wherein one or more methylene units of the aliphatic chain are optionally and independently replaced by a group selected from –N(Ry)-, -C(=O)-, -O-, - S(O)2-, and -CF2-; each Ryis selected from hydrogen, C1-3alkyl and lower haloalkyl; Ring C is a bivalent group comprising, wherein 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; 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 L is.

4. The compound according to claim 3, wherein L is, wherein * indicates the point of attachment to Ring A.

5. The compound according to claim 3, wherein L is, wherein * indicates the point of attachment to Ring A.

6. The compound according to any one of claims 1-5, wherein Ring A is selected from:

7. The compound according to any one of claims 1-6, wherein the compound is not a compound set forth in Table 2.

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

9. A pharmaceutical composition comprising a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

10. A method of treating a cancer, the method comprising administering a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9.

11. The method according to claim 10, wherein the cancer is a CK1α-mediated cancer.

12. The method according to claim 11, wherein the cancer is a WNT-mediated cancer.

13. The method according to claim 11, wherein the cancer is a p53-mediated cancer.

14. A method of modulating an oncogenic pathway, the method comprising contacting a biological sample or administering to a patient in need thereof a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9.

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