Dioxopiperidine-indolone-methylene-carbamate compounds as degraders of cyclin-dependent kinase 2

Abstract

The present application provides bicyclic compounds of formula (I), formula (II), and formula (III), and pharmaceutically acceptable salts thereof, that are degraders of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

Description

CROSS REFERENCE TO RELATED APPLICATION [1] This application claims priority to U.S. Provisional Application Serial No. 63 / 578,549 filed on August 24, 2023. The entire text of that provisional application is incorporated by reference into this application. BACKGROUND [2] The field of the disclosure relates generally to cyclin dependent kinase 2 degrader compounds. [3] The ubiquitin-proteasome pathway (UPP) is a critical pathway that controls protein metabolism in cells by degrading / eliminating misfolded and abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases, such as cancer. [4] Cyclin dependent kinases (CDKs) are a family of serine / threonine kinases that, when heterodimerized with cyclin regulatory subunits, become activated and regulate key cellular processes including cell cycle progression and cell division. Deregulation of CDK activity is implicated with abnormal regulation of cell-cycle, and is detected in virtually all forms of human cancers which are characterized by uncontrolled cell proliferation. As such, therapeutic agents that leverage UPP mediated protein degradation to target cancer-associated proteins such as cyclin-dependent kinase 2 (“CDK2”) are believed to be chemo-therapeutic agents. Accordingly, there remains a need to find compounds that are CDK2 degraders useful as therapeutic agents. BRIEF DESCRIPTION [5] In one aspect, provided herein are compounds of formula (I):, wherein each R1is independently selected from halogen, cyano, C1-6 alkyl, hydroxy, and C1- 6 haloalkyl, C1-6 alkoxy, O-C1-6 haloalkyl, and -N(Ra)(Rb);p is an integer selected from 0, 1, 2, and 3; each Raand Rbis independently selected from H and optionally substituted C1-6 alkyl, or Raand Rbtogether with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocycloalkyl; each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6 alkyl, C1-6 alkoxy, hydroxy, C1-6 haloalkyl, O-C1-6 haloalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, and optionally substituted O-C3-6 cycloalkyl; q is an integer selected from 0, 1, 2, and 3; R3is hydrogen or C1-4alkyl; each R4is independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted 3-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl; m is 1 or 2; and A is selected from: (i) 5-membered monocyclic heteroaryl; and (ii) 6-10-membered fused bicyclic heteroaryl; or a pharmaceutically acceptable salt thereof. [6] In another aspect, also provided herein are compounds of formula (II):, wherein Y is optionally substituted monocyclic C3-6cycloalkyl or optionally substituted monocyclic 3-5 membered heterocycloalkyl; each R1is independently selected from halogen, cyano, C1-6 alkyl, hydroxy, and C1-6haloalkyl; p is an integer selected from 0, 1, 2, and 3; each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6 alkyl, C1-6 alkoxy, hydroxy, C1-6 haloalkyl, O-C1-6 haloalkyl, optionallysubstituted C3-8cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, O-C3-6 cycloalkyl, and NR2aR2b; q is an integer selected from 0, 1, 2, and 3; each R2aand R2bis independently selected from H and optionally substituted C1-6alkyl, or R2aand R2btogether with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocycloalkyl; R3is hydrogen or C1-4alkyl; L3is a bond or a linker selected from optionally substituted -C1-4 alkylene-, optionally substituted -O-C1-4 alkylene-, optionally substituted -C(O)O-C1-4 alkylene-, and -C(O)-; and B is selected from: (i) C6-10 aryl; (ii) 5-10 membered heteroaryl; and (iii) 5-10 membered fused bicyclic heterocycloalkyl; or a pharmaceutically acceptable salt thereof, with the proviso that q is 1, 2, or 3 when (i) L3is a bond and (ii) B is phenyl. [7] In another aspect, also provided herein are compounds of formula (III):, wherein Y is optionally substituted monocyclic C3-6cycloalkyl or optionally substituted monocyclic 3-5 membered heterocycloalkyl; each R1is independently selected from halogen, cyano, C1-6alkyl, hydroxy, and C1-6haloalkyl; p is an integer selected from 0, 1, 2, and 3; each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6alkyl, C1-6alkoxy, hydroxy, C1-6haloalkyl, O-C1-6haloalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, O-C3-6 cycloalkyl; q is an integer selected from 0, 1, 2, and 3;R3is hydrogen or C1-4alkyl; L3is a bond or a linker selected from optionally substituted -C1-4 alkylene-, optionally substituted -O-C1-4 alkylene-, optionally substituted -C(O)O-C1-4 alkylene-, and -C(O)-; C is a 3 to 6 membered heterocycloalkyl having a nitrogen heteroatom attached to L3, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION [8] Provided herein are degraders of CDK2, e.g., degraders of formulae (I), (II), and (III) or a pharmaceutically acceptable salt thereof. Further provided are pharmaceutical compositions thereof, and methods for their use, e.g., for treating CDK2- mediated diseases such as cancer. Also provided are methods of making the CDK2 degraders described herein such as degraders of formulae (I), (II), and (III). [9] The cell cycle plays a critical and central role in control of cell growth and proliferation. Every cell cycle step is a well-regulated process controlled by CDKs defined by serine / threonine-protein kinases, and their associated cyclin partners. It is known that CDK2 controls cell division and is central to oncogenic signaling. (See, e.g., Chi, et. al., “A novel landscape of nuclear human CDK2 substrates revealed by in situ phosphorylation”, Sci. Adv.2020, vol 6, issue 16.) Cyclin is activated by cyclin E and cyclin A, where E-CDK2 complexes regulate cell cycle reentry, G1 progression, and S phase entry, and where cyclin A–CDK2 complexes coordinate S phase progression and function in G2 and M phase cells. (Id.) Thus, CDK2 inhibition could be an effective therapy to arrest or inhibit proliferation of cancer cells.

[0010] Without being bound to any particular theory, it is believed that the compounds of the present disclosure function as CDK2 degrader compounds that induce protein-protein interactions (aggregation) and that, in the context of an ubiquitin ligase, promote ubiquitination and degradation of CDK2. The compounds provided herein can achieve degradation selectivity against GSPT1 (G1 to S phase transition 1), a reported protein being degraded by similar class of compounds. GSPT1 is a translation termination factor that is commonly essential. Depletion of GSPT1 could lead to downstream effects on a large number of proteins and on cellular functions, as such, achieving degradationselectivity against GSPT1 is critical to avoid broad toxicity. The compounds provided herein can effectively degrade CDK2 with desirable selectivity over GSPT1.

[0011] Definitions

[0012] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. In addition, any method or material similar or equivalent to a method or material described herein can be used. For purposes as described herein, the following terms are defined.

[0013] “A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0014] The term “alkyl”, by itself or as part of another substituent, is used in its conventional sense, and refers to a straight or branched chain hydrocarbon radical. The number of carbons may suitably be from 1 to 20, from 1 to 12, from 1 to 8, from 1 to 6, or from 1 to 4. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl. The term “alkenyl” refers to an unsaturated alkyl radical having one or more double bonds. Similarly, the term “alkynyl” refers to an unsaturated alkyl radical having one or more triple bonds. Non-limiting examples of such unsaturated alkyl groups include linear and branched groups including vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0015] The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”), an amino group (“amino”) or thio group, and further include mono- and poly-halogenated variants thereof. Additionally, for dialkylamino groups, the alkyl portions can be the same or different.

[0016] The terms “halo” or “halogen,” by themselves or as part of another substituent, are used in their conventional sense, and refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, for instance C1-6 haloalkyl and C1-4haloalkyl, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4haloalkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, difluoromethyl, and the like.

[0017] The terms “cycloalkyl” and “cycloalkylene” are used in their conventional sense and refer to a saturated or partially saturated carbocyclic moiety having mono- or bicyclic rings and 3 to 10 carbon atoms in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In particular embodiments cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular embodiments cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Non- limiting examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially saturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl). In some aspects, bicyclic cycloalkyl rings are limited to fused rings sharing two carbon atoms. In some aspects, bicyclic cycloalkyl rings exclude bridged bicyclic and spiro bicyclic ring structures.

[0018] The terms “heterocycle”, “heterocycloalkyl”, and “heterocycloalkylene” are used in their conventional sense and refer to a 3, 4, 5, 6 or 7-membered monocyclic or a 6, 7, 8, 9 and 10-membered bicyclic heterocyclic moiety that is saturated or partially saturated, and has one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. In some embodiments, bicyclic heterocyclic rings are limited to fused rings sharing two carbon atoms. In some embodiments, bicyclic heterocyclic rings are fused rings sharing one or more heteroatoms selected from oxygen, nitrogen and sulfur. In some embodiments, bicyclic heterocyclic rings exclude bridged bicyclic and spiro bicyclic ring structures. In some embodiments, one ring of a bicyclic heterocyclic ring structure comprises one or more heteroatoms. In some embodiments, both rings of a bicyclic ring structure comprise one or more heteroatoms.

[0019] The term “aryl” refers to a cyclic aromatic hydrocarbon moiety having a mono- or bi-cyclic aromatic ring of 5 to 10 carbon ring atoms. Bicyclic aryl ring systemsinclude fused bicyclics having two fused five-membered aryl rings, having a five- membered aryl ring and a fused six-membered aryl ring, and having two fused six- membered aryl rings. The aryl group can be optionally substituted as defined herein.

[0020] The term "heteroaryl" is used in its conventional sense and refers to a monovalent aromatic radical of a 5-,6-, or 7-membered ring and includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups may be optionally substituted independently with one or more substituents described herein. 5 or 6 membered heteroaryl can be selected from the group consisting of optionally substituted pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinone and benzimidazolyl

[0021] The term “fused bicyclic heteroaryl” means a structure having atoms arranged in two rings fused together with at least two atoms common to each ring, and at least one of the rings being a heteroaryl ring. Non limiting examples of bicyclic heteroaryl comprise bicyclic heteroaryl groups comprising 1, 2, 3 or 4 heteroatom(s) independently selected from N, S or O.

[0022] The term “heteroatom,” refers to an atom other than hydrogen or carbon. Non-limiting examples of heteroatoms include N, O, and S.

[0023] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers). Racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0024] The term “chiral” refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0025] The term “chiral purity” refers to the mole% of one chiral compound based on the total moles of chiral compounds.

[0026] The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0027] The term E / Z refers to the IUPAC isomerism convention where the substituents at each end of a double bond are assigned priority based on their atomic number. If the high-priority substituents are on the same side of the bond it is assigned Z, and if they are on opposite sides of the bond it is assigned E.

[0028] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the disclosure. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0029] The term “spiro” refers to bicyclic molecules for which the two constitutive cyclic moieties have one carbon atom in common.

[0030] The term “bridged” refers to bicyclic molecules for which the two constitutive cyclic moieties have two non-adjacent carbon atoms in common.

[0031] The term “fused” refers to bicyclic molecules for which the two constitutive cyclic moieties have two adjacent carbon atoms in common.

[0032] The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term "substituted" denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitution, i.e., replacement of one hydrogen up to replacement of all hydrogens bysubstituents. Examples of substituents include, but are not limited to, hydroxy, alkyl, alkoxy, halo, haloalkyl, oxo, cyano, nitro, amino, monoalkylamino, dialkylamino, 3-10- membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered aryl, and 5-10 membered heteroaryl.

[0033] In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0034] The term “salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases (e.g., those salts that are pharmaceutically acceptable), depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate andthe like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0035] Neutral forms of the compounds of the present disclosure can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0036] The term “subject” refers to refers to animals such as mammals, including but not limited to, humans.

[0037] The terms “treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination

[0038] The term “solid tumor” refers to a solid mass of cancer cells that grow in organ systems and can occur anywhere in the body, for example breast cancer.

[0039] The term “liquid tumor” refers to tumors that occur in the blood, bone marrow, or lymph nodes and includes types of leukemia, lymphoma, and myeloma.

[0040] The term "pharmaceutically acceptable" refers to an anion, cation, carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0041] The terms “effective dosage”, “effective amount” and “therapeutically effective amount” of a compound or pharmaceutical composition of the present disclosure is an amount sufficient to affect any one or more beneficial or desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. Fortherapeutic use, a “therapeutically effective amount” refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dose of other medications required to treat the disease, (6) enhancing the effect of another medication, and / or (7) delaying the progression of the disease in a patient.

[0042] An effective dosage can be administered in one or more administrations. For the purposes of the present disclosure, an effective dosage of a compound or a pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.

[0043] The term “additional anticancer therapeutic agent” as used herein means any one or more therapeutic agent, other than a compound of the disclosure, that is or can be used in the treatment of cancer.

[0044] The term "co-administering" refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including a chemotherapeutic agent. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

[0045] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound as described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, provided is a single unit dosageform comprising a compound of formulae (I), (II), or (III), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0046] The term “IC50” refers to the half maximal inhibitory concentration of a substance required to inhibit a specific biological or biochemical function as measured by an appropriate assay method.

[0047] The term “DC50” refers to the concentration of a substance required to achieve half maximal protein degradation as measured by an appropriate assay method.

[0048] The term “Dmax” refers to the maximum level of protein degradation observed across a titration of substance, as measured by an appropriate assay method and a defined time point.

[0049] Compounds of formula (I)

[0050] Some embodiments of the present disclosure are directed to compounds of formula (I):

[0051] Each R1is independently selected from: halogen; cyano; C1-6 alkyl; hydroxy; C1-6 haloalkyl; C1-6 alkoxy; O-C1-6 haloalkyl; and -N(Ra)(Rb). In some embodiments, each R1is independently selected from: -CH3; -F; -Cl; and -OH. In some embodiments, each R1is halogen. In some embodiments, each R1is independently selected from -F and -Cl. In some embodiments, each R1is C1-6 alkyl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl.

[0052] Each Raand Rbis independently selected from H and optionally substituted C1-6 alkyl, or Raand Rbtogether with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocycloalkyl. In some embodiments, both Raand Rbare hydrogen. In some embodiments, Rais hydrogen and Rbis C1-6alkyl (e.g., methyl). In some embodiments, both Raand Rbare C1-6 alkyl (e.g., methyl).

[0053] p is an integer selected from 0, 1, 2, and 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In someembodiments, p is 1 and R1is -F or -Cl. In some embodiments, p is 2 and each R1is independently selected from -F and -Cl.

[0054] Each R2is independently selected from: halogen; cyano; oxo; optionally substituted C1-6alkyl; C1-6alkoxy; hydroxy; C1-6haloalkyl; O-C1-6haloalkyl; optionally substituted C3-8cycloalkyl; optionally substituted 3-8 membered heterocycloalkyl; optionally substituted aryl; optionally substituted 5-6 membered heteroaryl; and O-C3-6 cycloalkyl. In some embodiments, each R2is independently selected from: halogen; haloalkyl; optionally substituted C1-4alkyl; C3-6cycloalkyl; and C5-6aryl. In some embodiments, each R2is independently selected from: fluoro; chloro; methyl; isopropyl; fluoromethyl; difluoromethyl; trifluoromethyl; methoxy; cyclohexyl; and phenyl.

[0055] q is an integer selected from 0, 1, 2, and 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0056] R3is selected from hydrogen and C1-4alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0057] Each R4is independently selected from: hydrogen; optionally substituted C1-6 alkyl; optionally substituted C3-6 cycloalkyl; optionally substituted C6-10 aryl; optionally substituted 3-6 membered heterocycloalkyl; and optionally substituted 5-6 membered heteroaryl. In some embodiments, R4is hydrogen. In some embodiments, R4is optionally substituted C6-10 aryl. In some embodiments, R4is optionally substituted phenyl.

[0058] m is an integer selected from 1 and 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, when m is 2, at least one of R4is H.

[0059] A is selected from: (i) a 5-membered monocyclic heteroaryl; and (ii) a 6-10- membered fused bicyclic heteroaryl. In some embodiments, A is a 5-membered monocyclic heteroaryl. In some embodiments, A is a 6-10-membered fused bicyclic heteroaryl.

[0060] In some embodiments, A is selected from:

[0062] In some embodiments, A is selected from:

[0063] In some embodiments, A is selected from:

[0064] In some embodiments, A is selected from:

[0065] In some embodiments, A is selected from:

[0066] In some embodiments, A is selected from:

[0067] In some embodiments, A is selected from:

[0068] In some embodiments, A is selected from: [, . embodiment, A is. In a specific embodiment,and is substituted with 1 or 2 R2, each R2is independently selected from: fluoro; chloro; methyl; isopropyl; fluoromethyl; difluoromethyl; trifluoromethyl; methoxy; cyclohexyl; and phenyl. In a specific embodiment, A isand is substituted with 1 or 2 R2, each R2is independently selected from: fluoro; chloro; and methyl. In a specific embodiment,

[0070] In one embodiment, A is. In a specific embodiment, A issubstituted with 1 or 2 R2, each R2is independently selected from: fluoro; chloro; methyl; isopropyl; fluoromethyl; difluoromethyl; trifluoromethyl; fluoroethyl; difluoroethyl;

[0071] In some embodiments, the compound of formula (I) is a compound of.

[0072] In some embodiments, the compound of formula (I) is a compound of formula

[0073] In some embodiments, the compound of formula (I) is a compound of formula (I-a). In some embodiments, R1is selected from: -CH3; -F; -Cl; and –OH. In some embodiments, R1is – F or –Cl. In one embodiment, R1is –F. In another embodiment, R1is –Cl.

[0074] In some embodiments, the compound of formula (I) is a compound of formula (I-b). In some embodiments, R1is selected from: -CH3; -F; -Cl; and –OH. In some embodiments, R1is – F or –Cl. In one embodiment, R1is –F. In another embodiment, R1is –Cl.

[0075] In some embodiments, the compound of formula (I) is a compound of formula (I-c). In some embodiments, R1is selected from: -CH3; -F; -Cl; and –OH. In some embodiments, R1is –F or –Cl. In one embodiment, R1is –F. In another embodiment, R1is –Cl.

[0076] In some embodiments, the compound of formula (I) is a compound of formula (. In some embodiments, each R1is independently selected from: -CH3; -F; -Cl; and -OH. In some embodiments, each R1is independently selected from –F and –Cl. In one embodiment, each R1is –F. In another embodiment, each R1is –Cl. In one embodiment, one R1is -F and the other R1is - Cl.

[0077] In some embodiments, the compound of formula (I) is selected from:Compound 29 Compound 15Compound 8 Compound 13Compound 23 Compound 31Compound 35 Compound 36Compound 26 Compound 14Compound 65 Compound 66Compound 67 Compound 68Compound 73 Compound 74Compound 77 Compound 78Compound 81 Compound 82Compound 89 Compound 90Compound 93 Compound 94Compound 97 Compound 98Compound 107 Compound 108Compound 111 Compound 112

[0078] In some embodiments, the disclosure comprises compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0079] In some embodiments, compounds of formula (I) (or a pharmaceutically acceptable salt thereof) are characterized by IC50 values measured at 6 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, or less than 0.025 µM, and any range constructed therefrom, such as from about 10 µM to about 0.025 µM, from about 1 µM to about 0.025 µM, or from about 0.5 µM to about 0.025 µM,. In some such embodiments, 6 hours IC50values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, or less than 0.025 µM. Dmax values measured at 6 hours by CDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%, and any range constructed therefrom, such as from about 25% to about 70%, or from about 45% to about 70%. In some such embodiments, 6 hour Dmax values can be at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%.

[0080] In some embodiments, compounds of formula (I) (or a pharmaceutically acceptable salt thereof) are characterized by IC50 values measured at 18 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM, and any range constructed therefrom, such as from about 10 µM to about 0.025 µM, from about 1 µM to about 0.025 µM, or from about 0.5 µM to about 0.025 µM. In some such embodiments, 18 hour IC50values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM. Dmax values measured at 18 hours by CDK2 HiBiT assaycan be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%, and any range constructed therefrom, such as from about 25% to about 60%, or from about 40% to about 60%. In some such embodiments, 18 hour Dmax values can be at least 50%, at least 55%, or at least 60%.

[0081] In some embodiments, compounds of formula (I) (or a pharmaceutically acceptable salt thereof) are characterized by a CDK2 DC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

[0082] In some embodiments, the HiBiT assay is conducted in HEK293 cells.

[0083] Compounds of formula (II)

[0084] Some embodiments of the present disclosure are directed to compounds of formula (II):.

[0085] Y is optionally substituted monocyclic C3-6cycloalkyl or optionally substituted monocyclic 3-5 membered heterocycloalkyl. In some embodiments, Y is monocyclic C3-6 cycloalkyl. In some embodiments, Y is cyclobutyl. In some embodiments, Y is cyclopentyl. In some embodiments, Y is monocyclic 3-5 membered heterocycloalkyl. In some embodiments, Y is azetidinyl. In any such embodiments, Y is optionally substituted, for instance with hydroxy or halo. In some embodiments, Y is optionally mono-substituted with hydroxy or halo.

[0086] Each R1is independently selected from: halogen; cyano; C1-6alkyl; hydroxy; and C1-6 haloalkyl. In some embodiments, each R1is independently selected from: -CH3; - F; -Cl; and –OH. In some embodiments, each R1is halogen. In some embodiments, each R1is selected from -F and -Cl. In some embodiments, each R1is C1-6alkyl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl.

[0087] p is an integer selected from 0, 1, 2, and 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In someembodiments, p is 1 and R1is -F or –Cl. In some embodiments, p is 2 and each R1is independently selected from -F and –Cl.

[0088] Each R2is independently selected from: halogen; cyano; oxo; optionally substituted C1-6alkyl; C1-6alkoxy; hydroxy; C1-6haloalkyl; O-C1-6haloalkyl; optionally substituted C3-8cycloalkyl; optionally substituted 3-8 membered heterocycloalkyl; optionally substituted aryl; optionally substituted 5-6 membered heteroaryl; and O-C3-6 cycloalkyl, NR2aR2b. In some embodiments, each R2is independently selected from: halogen; haloalkyl; O-C1-6haloalkyl; optionally substituted C1-4alkyl; C3-6cycloalkyl; oxo; and C1-4 alkoxy; and N(C1-6 alkyl)2. In some embodiments, each R2is independently selected from: fluoro; chloro; trifluoromethyl; cyclopropyl; and methoxy. In some embodiments, each R2aand R2bis independently selected from H and optionally substituted C1-6 alkyl, or R2aand R2btogether with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocycloalkyl;

[0089] q is an integer selected from 0, 1, 2, and 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0090] R3is hydrogen or C1-4 alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0091] L3is a bond or a linker selected from: optionally substituted -C1-4 alkylene-; optionally substituted -O-C1-4 alkylene-; optionally substituted -C(O)O-C1-4 alkylene-; and -C(O)-. L3is a bond or a linker selected from: unsubstituted -C1-4alkylene-; unsubstituted -O-C1-4 alkylene-; and unsubstituted -C(O)O-C1-4 alkylene-. L3is selected from: unsubstituted -C1-4 alkylene-; unsubstituted -O-C1-4 alkylene-; and unsubstituted -C(O)O- C1-4alkylene-. In some embodiments, L3is a bond. In some embodiments, L3is unsubstituted -C1-4alkylene-. In some embodiments, L3is methylene. In some embodiments, L3is unsubstituted -O-C1-4 alkylene-. In some embodiments, L3is O- methylene. In some such L3embodiments, -O-C1-4 alkylene- is in the orientation . In some embodiments, -O-C1-4 alkylene- is in the opposite orientation. In some embodiments, L3is unsubstituted -C(O)O-C1-4alkylene-. In some embodiments, L3is -C(O)O-methylene-. In some embodiments, L3is -C(O)-. In some L3embodiments, -C(O)O-C1-4 alkylene- is in the orientation. In some embodiments, -C(O)O-C1-4 alkylene- is in the opposite orientation. In any such embodiment, L3is optionally substituted.

[0092] B is selected from: (i) C6-10aryl; (ii) 5-10 membered heteroaryl; and (iii) 5- 10 membered fused bicyclic heterocycloalkyl. In some embodiments, B is selected from:[

[0094] In some embodiments, B is selected from:

[0095] In some embodiments, B is selected from:some embodiments, R2is haloalkyl (e.g., -CF3). In some embodiments, q is 1. In some embodiments, R2is haloalkyl (e.g., -CF3) and q is 1.

[0096] In some embodiments, B is selected from:one embodiment, B is In another embodiment, B is. In another embodiment, B is. In another embodiment, B is. In some embodiments, R2is haloalkyl (e.g., -CF3). In some embodiments, q is 1. In some embodiments, R2is haloalkyl (e.g., -CF3) and q is 1.

[0097] In some embodiments,. one embodiment, B is. In another embodiment,. some embodiments, R2is haloalkyl (e.g., -CF3). In some embodiments, q is 1. In some embodiments, R2is haloalkyl (e.g., -CF3) and q is 1.

[0098] In some embodiments, B is selected from:

[0099] In some embodiments, B is selected from:In some such embodiments, each R2is independently selected from: halogen; cyano; optionally substituted C1-6 alkyl; C1-6 alkoxy; hydroxy; C1-6 haloalkyl; O-C1-6 haloalkyl; optionally substituted aryl; and optionally substituted C3-8cycloalkyl; In some such embodiments, each R2is independently selected from: halogen; C1-4haloalkyl; cyano; O- C1-4 haloalkyl; optionally substituted C1-4 alkyl; optionally substituted aryl; and optionallysubstituted C3-6cycloalkyl. In some embodiments, each R2is independently selected from: fluoro; chloro; O-trifluoromethyl; methyl; fluoro; chloro; cyano; difluoromethyl; trifluoromethyl; cyclopropyl; and aryl.

[0100] In some embodiments, -B-(R2)q is selected from:

[0101] In some embodiments, -B-(R2)q is selected from:

[0103] In some embodiments, -B-(R2)q is selected from:

[0104] In some embodiments, -B-(R2)q is selected from:

[0105] In some embodiments, -B-(R2)q is selected from:

[0106] In some embodiments, -B-(R2)q is selected from:

[0109] In some embodiments, -B-(R2)q is selected from:

[0111] In some embodiments, -B-(R2)q is selected from:

[0113] In some embodiments, -B-(R2)q is selected from:

[0115] For compound formula (II), q is 1, 2, or 3 when (i) L3is a bond and (ii) B is phenyl. In some embodiments, when (i) L3is a bond and (ii) B is phenyl, then B is substituted phenyl. In some other embodiments, when (i) L3is a bond and (ii) B is phenyl, B is a para-substituted phenyl. In some other embodiments, when (i) L3is a bond and (ii) B is phenyl, B is a meta-substituted phenyl. In some other embodiments, when (i) L3is a bond and (ii) B is phenyl, B is an ortho-substituted phenyl.

[0116] In some embodiments, the compound of formula (II) is a compound of formula. In some embodiments, R1is selected from: -CH3; -F; and -Cl. In some embodiments, R1is –F or –Cl. In one embodiment, R1is –F. In another embodiment, R1is –Cl.

[0117] In some embodiments, the compound of formula (II) is a compound of formula (. In some embodiments, R1is selected from: -CH3; -F; and -Cl. In some embodiments, R1is –F or –Cl. In one embodiment, R1is –F. In another embodiment, R1is –Cl.

[0118] In some embodiments, the compound of formula (II) is a compound of. In some embodiments, R1is

[0119] selected from: -CH3; -F; and -Cl. In some embodiments, R1is –F or –Cl. In one embodiment, R1is –F. In another embodiment, R1is –Cl.

[0120] In some embodiments, the compound of formula (II) is a compound of formula. In some embodiments, each R1is independently selected from: -CH3; -F; and -Cl. In some embodiments, each R1is independently selected from –F and –Cl. In one embodiment, each R1is –F. In another embodiment, each R1is –Cl. In one embodiment, one R1is -F and the other R1is -Cl.

[0121] In some embodiments, the compound of formula (II) is selected from:Compound 44 Compound 42Compound 51 Compound 52Compound 57 Compound 41Compound 49 Compound 39

[0122] In some embodiments, compounds of formula (II) are pharmaceutically acceptable salts thereof.

[0123] In some embodiments, compounds of formula (II) (or a pharmaceutically acceptable salt thereof) are characterized by IC50values measured at 6 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, or less than 0.025, or less than 0.020 µM, and any range constructed therefrom, such as from about 10 µM to about 0.020 µM, from about 1 µM to about 0.020 µM, or from about 0.5 µM to about 0.020 µM. In some such embodiments, 6 hours IC50 values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, less than 0.025 µM, or less than 0.020 µM. In some embodiments, Dmaxvalues measured at 6 hours byCDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or at least 65%, and any range constructed therefrom, such as from about 25% to about 65%, or from about 40% to about 65%. In some such embodiments, 6 hour Dmaxvalues can be at least 50%, at least 55%, at least 60%, or at least 65%.

[0124] In some embodiments, compounds of formula (II) (or a pharmaceutically acceptable salt thereof) are characterized by IC50 values measured at 18 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM, and any range constructed therefrom, such as from about 10 µM to about 0.05 µM, from about 1 µM to about 0.05 µM, or from about 0.5 µM to about 0.05 µM. In some such embodiments, 18 hour IC50 values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM. Dmax values measured at 18 hours by CDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%, and any range constructed therefrom, such as from about 25% to about 60%, or from about 40% to about 60%. In some such embodiments, 18 hour Dmax values can be at least 50%, at least 55%, or at least 60%.

[0125] In some embodiments, compounds of formula (II) (or a pharmaceutically acceptable salt thereof) are characterized by a CDK2 DC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

[0126] In some embodiments, the HiBiT assay is conducted in HEK293 cells.

[0127] In some embodiments, compounds of formula (II) are characterized by a CDK2 Dmaxof at least 50%, at least 60%, or at least 70% when measured by HiBiT assay.

[0128] In some embodiments, compounds of formula (II) are characterized by a CDK2 DC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

[0129] In some embodiments, the HiBiT assay is conducted in HEK293 cells.

[0130] Compounds of formula (III)

[0131] Some embodiments of the present disclosure are directed to compounds of formula (III):

[0132] Y is optionally substituted monocyclic C3-6 cycloalkyl or optionally substituted monocyclic 3-5 membered heterocycloalkyl.

[0133] Each R1is independently selected from halogen, cyano, C1-6 alkyl, hydroxy, and C1-6 haloalkyl.

[0134] p is an integer selected from 0, 1, 2, and 3.

[0135] Each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6 alkyl, C1-6 alkoxy, hydroxy, C1-6 haloalkyl, O-C1-6 haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, O-C3-6 cycloalkyl.

[0136] q is an integer selected from 0, 1, 2, and 3.

[0137] R3is hydrogen or C1-4alkyl.

[0138] L3is a bond or a linker selected from optionally substituted -C1-4 alkylene-, optionally substituted -O-C1-4 alkylene-, optionally substituted -C(O)O-C1-4 alkylene-, and - C(O)-.

[0139] C is a 3 to 6 membered heterocycloalkyl having a nitrogen heteroatom attached to L3.

[0140] In some embodiments of formula (III), Y is monocyclic C3-6cycloalkyl. In some embodiments, Y is cyclobutyl.

[0141] In some embodiments of formula (III), L3is selected from a bond and - C(O)-.

[0142] In some embodiments of formula (III), L3is a bond. In some embodiments, L3is a bond and Y is cyclobutyl. In some embodiments, L3is a bond and C issubstituted with -(R2)q. In some embodiments, L3is a bond, Y is cyclobutyl, and C issubstituted with -(R2)q.

[0143] In some embodiments of formula (III), L3is -C(O)-.

[0144] In come embodiments of formula (III), C is selected from

[0145] In some embodiments of formula (III), each R2is independently selected from halogen, oxo, and C1-6 haloalkyl. In some embodiments, each R2is halogen. In some embodiments, each R2is oxo. In some embodiments, each R2is C1-6 haloalkyl.

[0146] In some embodiments of formula (III), C-(R2)qis selected from:.

[0147] In some embodiments, the compound of formula (III) is selected from:

[0148] In some embodiments, the compound of formula (III) is selected from:

[0149] In some embodiments, the compound of formula (III) is selected from:

[0150] In some embodiments, compounds of formula (III) are pharmaceutically acceptable salts thereof.

[0151] In some embodiments, compounds of formula (III) (or a pharmaceutically acceptable salt thereof) are characterized by IC50 values measured at 6 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, or less than 0.025, or less than 0.020 µM, and any range constructed therefrom, such as from about 10 µM to about 0.020 µM, from about 1 µM to about 0.020 µM, or from about 0.5 µM to about 0.020 µM. In some such embodiments, 6 hours IC50 values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, less than 0.025 µM, or less than 0.020 µM. In some embodiments, Dmax values measured at 6 hours by CDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or at least 65%, and any range constructed therefrom, suchas from about 25% to about 65%, or from about 40% to about 65%. In some such embodiments, 6 hour Dmax values can be at least 50%, at least 55%, at least 60%, or at least 65%.

[0152] In some embodiments, compounds of formula (III) (or a pharmaceutically acceptable salt thereof) are characterized by IC50values measured at 18 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM, and any range constructed therefrom, such as from about 10 µM to about 0.05 µM, from about 1 µM to about 0.05 µM, or from about 0.5 µM to about 0.05 µM. In some such embodiments, 18 hour IC50 values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM. Dmaxvalues measured at 18 hours by CDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%, and any range constructed therefrom, such as from about 25% to about 60%, or from about 40% to about 60%. In some such embodiments, 18 hour Dmaxvalues can be at least 50%, at least 55%, or at least 60%.

[0153] In some embodiments, compounds of formula (III) (or a pharmaceutically acceptable salt thereof) are characterized by a CDK2 DC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

[0154] In some embodiments, the HiBiT assay is conducted in HEK293 cells.

[0155] In some embodiments, compounds of formula (III) are characterized by a CDK2 Dmax of at least 50%, at least 60%, or at least 70% when measured by HiBiT assay.

[0156] In some embodiments, compounds of formula (III) are characterized by a CDK2 DC50of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

[0157] In some embodiments, the HiBiT assay is conducted in HEK293 cells.

[0158] Pharmaceutical Compositions

[0159] In some embodiments, pharmaceutical compositions of compounds of formula (I), formula (II), and formula (III) are provided. In such embodiments, the pharmaceutical compositions comprise (i) compounds of formula (I) or a pharmaceutically acceptable salt thereof; (ii) compounds of formula (II) or a pharmaceutically acceptable saltthereof; or (iii) compounds of formula (III) or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

[0160] In some embodiments, pharmaceutical compositions of compound formula (I) and compounds of formula (II) are provided. In such embodiments, the pharmaceutical compositions comprise (i) compounds of formula (I) or a pharmaceutically acceptable salt thereof or (ii) compounds of formula (II) or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

[0161] The pharmaceutical compositions of the present disclosure can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. In the practice of methods of the present disclosure, a therapeutically effective amount of any one of the compounds of this disclosure or a combination of any of the compounds of this disclosure or a pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art. For instance, compounds or compositions of the present disclosure can be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.

[0162] Suitable excipients are known to those skilled in the art and are described in detail in, e.g.: (i) Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; (ii) Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and (iii) Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Examples of pharmaceutically acceptable excipients include, without limitation, carriers, diluents, adjuvants, and vehicles. Non-limiting examples include, buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, and flavoring agents.

[0163] The compositions comprising compounds of formulae (I), (II), or (III) may be formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice. A typical formulation is prepared by mixing a compound of the present disclosure and one or more excipients.

[0164] When a pharmaceutical composition according to the present disclosure is prepared as a formulation for oral administration, the carrier and / or diluent to be used may include, for instance and without limitation: cellulose and cellulose derivatives (e.g., microcrystalline cellulose); calcium silicate; corn starch; saccharides (e.g., lactose, sucrose, dextrose, mannitol, and combinations thereof); calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agents, emulsifying agents, diluents, and combinations thereof. Formulations for oral administration may also include, for instance and without limitation: polymers (for instance hydrophilic polymers such as polyvinylpyrrolidone); antioxidants; preservatives; wetting agents; lubricating agents; glidants; processing aids; granulating agents; dispersing agents; colorants; and flavoring agents.

[0165] Compressed tablets can be prepared in a suitable tableting device by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with or more of a carrier, binder, lubricant, inert diluent, preservative, surface active, dispersing agent, and an inert liquid diluent. The tablets can optionally be coated or scored. Tablets may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay coating material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0166] When the pharmaceutical composition according to the present disclosure is prepared as a formulation for injections, the carrier to be used may include, for instance and without limitation, water, saline, an aqueous glucose solution, an aqueous sugar-like solution, alcohols, glycols (e.g., polyethylene glycol 400), ethers, oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents, and combinations thereof.

[0167] The pharmaceutical compositions may further comprise pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.

[0168] In some embodiments, pharmaceutical compositions comprising compounds of formula (I), compounds of formula (II), or compounds of formula (III) or a pharmaceutically acceptable salt thereof, further comprise an additional therapeutic agent.

[0169] Combination Therapy

[0170] The compounds of the present disclosure may be administered in combination with other additional therapeutic agents, such as for instance and without limitation, standard of care agents appropriate for a particular cancer.

[0171] The compounds as described herein or pharmaceutically acceptable salts thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound as described herein such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a chemotherapeutic agent to treat proliferative diseases and cancer.

[0172] Those additional agents may be administered separately from the compound or pharmaceutically acceptable salt thereof described herein, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound as described herein in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0173] The amount of both an inventive compound and 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. In some embodiments, compositions as described herein are formulated such that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive can be administered.

[0174] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6thedition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0175] In some embodiments, the treatment method includes the co-administration of a compound as described herein or a pharmaceutically acceptable salt thereof and at least one chemotherapeutic agent. The term “chemotherapeutic agent” is an agent useful in the treatment of cancer, and includes, but is not limited to, cytotoxic agents such as radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212and radioactive isotopes of Lu); growth inhibitory agents; anti- microtubule agents; platinum analogs; topoisomerase II inhibitors; anti-metabolites; topoisomerase I inhibitors; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; nitrogen mustards; alkylating agents; toxoids or taxanes; aromatase inhibitors; chromoprotein enediyne antibiotic chromophores; mitomycins; anti- hormonal agents; anti-androgens; protein kinase inhibitors; lipid kinase inhibitors; antisense oligonucleotides; tyrosine kinase inhibitors; Raf-1 inhibitors; EGFR inhibitors; camptothecins; anthracycline antibiotics; nucleoside metabolic inhibitors, and other CDK inhibitors.

[0176] Methods of Treatment

[0177] In some embodiments, the compounds of the present disclosure may be administered as single agents. In some embodiments, the compounds of the present disclosure may be administered in combination with at least one additional therapeutic agent.

[0178] In some embodiments, provided herein are methods of treating a disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0179] In some embodiments, provided herein are methods of treating a CDK2- mediated disorder in a subject in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0180] In some embodiments, provided herein are methods of degrading CDK2 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0181] In some embodiments, provided herein are methods of selectively reducing the level of CDK2 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, wherein the level of GSPT1 in the subject is not reduced.

[0182] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject in need thereof.

[0183] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a CDK2-mediated disorder in a subject in need thereof.

[0184] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for degrading CDK2 in a subject.

[0185] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for selectively reducing the level of CDK2 in a subject, wherein the level of GSPT1 in the subject is not reduced.

[0186] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a disease, disorder or condition in a subject in need thereof.

[0187] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a CDK2-mediated disorder in a subject in need thereof.

[0188] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in degrading CDK2 in a subject.

[0189] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in selectively reducing the level of CDK2 in a subject, wherein the level of GSPT1 in the subject is not reduced.

[0190] In some embodiments, provided herein are methods of treating a disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (III) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0191] In some embodiments, provided herein are methods of treating a CDK2- mediated disorder in a subject in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0192] In some embodiments, provided herein are methods of degrading CDK2 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0193] In some embodiments, provided herein are methods of selectively reducing the level of CDK2 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (III) or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as described herein, wherein the level of GSPT1 in the subject is not reduced.

[0194] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject in need thereof.

[0195] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a CDK2-mediated disorder in a subject in need thereof.

[0196] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for degrading CDK2 in a subject.

[0197] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for selectively reducing the level of CDK2 in a subject, wherein the level of GSPT1 in the subject is not reduced.

[0198] The compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a disease, disorder or condition in a subject in need thereof.

[0199] The compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a CDK2-mediated disorder in a subject in need thereof.

[0200] The compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in degrading CDK2 in a subject.

[0201] The compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in selectively reducing the level of CDK2 in a subject, wherein the level of GSPT1 in the subject is not reduced.

[0202] In some embodiments, the disorder is cancer. In some embodiments, the cancer is selected from bladder cancer; bone cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; prostate cancer; esophagus cancer; eye cancer; head cancer; kidney cancer; liver cancer; lymph node cancer; lung cancer; upper aerodigestive tract cancer; oral cancer; oropharynx cancer; larynx cancer; hypopharynx cancer; salivary gland cancer; neck cancer; thyroid cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; uterine cancer; neuroblastoma; meningioma; hemangiopericytoma; leiomyoma; leukemia; lymphoma; and myeloma.

[0203] In some embodiments, the cancer is selected from: hormone-receptor positive breast cancer; estrogen receptor positive breast cancer; triple negative breast cancer; multiple brain metastase; glioblastoma multiforms; glioblastoma; brain stem glioma; malignant glioma; anaplastic astrocytoma; anaplastic oligodendroglioma; neuroendocrine cancer; metastatic hepatocellular carcinoma; Kaposi's sarcoma; malignant melanoma; malignant mesothelioma; malignant pleural effusion mesothelioma syndrome; peritoneal carcinoma; papillary serous carcinoma; gynecologic sarcoma; soft tissue sarcoma; scleroderma; cutaneous vasculitis; Langerhans cell histiocytosis; leiomyosarcoma; hormone refractory prostate cancer; resected high-risk soft tissue sarcoma; unresectable hepatocellular carcinoma; fallopian tube cancer; androgen independent prostate cancer; androgen dependent stage IV non-metastatic prostate cancer; hormone-insensitive prostate cancer; papillary thyroid carcinoma; follicular thyroid carcinoma; medullary thyroid carcinoma; diffuse large B-cell lymphoma; B-cell immunoblastic lymphoma; small non-cleaved cell lymphoma; human lymphotropic virus- type 1 leukemia / lymphoma; adult T-cell lymphoma; peripheral T-cell lymphoma; cutaneous T-cell lymphoma; mantle cell lymphoma; Hodgkin’s lymphoma; non-Hodgkin’s lymphoma; AIDS-related lymphoma; follicular lymphoma; small lymphocytic lymphoma; T-cell / histiocyte rich large B-cell lymphoma; transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma; splenic marginal zone lymphoma; Richter's transformation; nodal marginal zone lymphoma; ALK-positive large B-cell lymphoma; indolent lymphoma; acute myelogenous leukemia; acute lymphocytic leukemia; adult T- cell leukemia; chronic lymphocytic leukemia; small lymphocytic lymphoma; hairy cell leukemia; myelodysplasia; myeloproliferative disorders; chronic myelogenous leukemia;acute monocytic leukemia; myelodysplastic syndrome; human lymphotropic virus- type 1 leukemia; mastocytosis, B-cell acute lymphoblastic leukemia; and multiple myeloma.

[0204] Exemplary cancers include, but are not limited to, leukemia (e.g., acute myelocytic leukemia), bladder cancer, brain cancer, breast cancer (e.g., hormone receptor positive breast cancer, triple negative breast cancer, HER2+ breast cancer), cervical cancer, colorectal cancer (e.g., including colon cancer and / or rectal cancer), endometrial cancer, esophageal cancer, gastric cancer (e.g. stomach adenocarcinoma), kidney cancer (e.g., renal cell carcinoma), liver cancer (e.g., hepatocellular cancer), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), neuroblastoma, ovarian cancer (e.g., serous ovarian cancer), prostate cancer, skin cancer (e.g., melanoma), thyroid cancer, and uterine cancer (e.g., uterine carcinosarcoma).

[0205] In certain embodiments, the cancer is ovarian cancer, gastric cancer, uterine cancer, esophageal cancer, lung cancer, or breast cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is uterine cancer. In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is lung cancer.

[0206] In certain embodiments, the cancer is breast cancer. In certain embodiments, the breast cancer is HR+, and the subject in need thereof has progressed on CDK4 / 6 inhibitors. In certain embodiments, the breast cancer is HER2+ and the subject has progressed on trastuzumab.

[0207] In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is NSCLC and the subject has progressed on an epidermal growth factor receptor (EGFR) inhibitor.

[0208] In certain embodiments, treatment may be administered after one or more symptoms have developed. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0209] Administration of the compounds of the disclosure may be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0210] The dosage regimen may be adjusted to provide the optimum desired response. For instance, a single dose may be administered, several doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Each unit dose may contain a predetermined quantity of a compound of formula (I), a compound of formula (II), or a compound of formula (III) calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are influenced by (i) the unique characteristics of the particular active compound formula, (ii) and the particular therapeutic or prophylactic effect to be achieved, and (iii) pharmacokinetic factors associated with the drug and associated excipients, and the disease to be treated.

[0211] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen may be adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined. Dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose- escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0212] The amount of the compound of the disclosure administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg perkg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, for instance by dividing such larger doses into several small doses for administration throughout the day.

[0213] While certain dose and administration regimens are disclosed herein, said disclosure does not limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0214] In some embodiments, a method of degrading CDK2 in a subject suffering from cancer is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) the compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising the compound of formula (I), formula (II), or formula (III) as described elsewhere herein.

[0215] In some embodiments, a method of cancer treatment in a subject suffering from cancer is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) the compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising the compound of formula (I), formula (II), or formula (III) as described elsewhere herein.

[0216] In some embodiments, a method of treating a solid tumor is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) the compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising the compound of formula (I), formula (II), or formula (III) as described elsewhere herein.

[0217] In some embodiments, a method of treating a liquid tumor is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compoundof formula (II) or a pharmaceutically acceptable salt thereof; (iii) the compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising the compound of formula (I), formula (II), or formula (III) as described elsewhere herein.

[0218] Examples

[0219] Table 1 below lists compounds of formula (I) were prepared and characterized by NMR and / or mass spectrometry, where “Ex” refers to example compound number.

[0220] Table 1

[0221] Table 2 below lists compounds of formula (II) were prepared and characterized by NMR and / or mass spectrometry, where “Ex” refers to example compound number.

[0222] Table 2

[0223] The NMR and / or mass spectrometry results for formula (I) compounds 65- 97, 99-107, 109-114, and 212, for formula (II) compounds 116 to 151, 153-183, 185-191, 193-203, 213-219, and 221-229, and for formula (III) compounds 204 to 211 are presented in the examples that follow.

[0224] Compounds Synthesis

[0225] Example 1

[0226] Preparation of intermediate 1A

[0227] General scheme for preparing intermediate 1A (“Int-1A”)

[0228] Step 1: Preparation of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6- dione

[0229] To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (350 g, 1.14 mol, 1.00 eq) in MeCN (2.45 L) was added DIEA (587 g, 4.55 mol, 791 mL, 4.00 eq) and 3-aminopiperidine-2,6-dione hydrogen chloride (280 g, 1.70 mol, 1.50 eq). The mixture was stirred at 80.0 °C for 12 hrs. The filter cake was concentrated under pressure to give a residue to afford the title compound (250 g, 773 mmol, 68.0% yield) as a crude gray solid.

[0230] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5- carbonitrile

[0231] A mixture of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 g, 309 mmol, 1.00 eq), Zn(CN)2(36.8 g, 313 mmol, 1.01 eq) in DMF (700 mL) was degassed and purged with N2 for 3 times, then was added palladium triphenylphosphine (34.9 g, 30.2 mmol, 0.10 eq). The mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (2100 ml) and extracted with EtOAc (200 ml x 3). The organic phase was washed with brine (200 ml), dried Na2SO4 and concentrated under pressure to afford the title compound (35.0 g, 129 mmol, 42.0% yield) as a crude gray solid.

[0232] Step 3: Preparation of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0233] A mixture of 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-carbonitrile (65.0 g, 241 mmol, 1.00 eq) in MeOH (420 mL) and HCl (12 M, 60.3 mL) was added Raney-Ni (4.14 g, 48.2 mmol) and purged with H2for 3 times. The mixture was stirred at 25 °C for 12 hrs under H2atmosphere (50 Psi). The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (65.0 g, 238 mmol, 98.7% yield) as a crude green solid.

[0234] Step 4: Preparation of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)methyl)carbamate (Int-1A)

[0235] A mixture of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (65 g, 237 mmol, 1.00 eq), TEA (72.2 g, 713 mmol, 99.3 mL, 3.00 eq), Boc2O (62.2 g, 285 mmol, 65.5 mL, 1.20 eq) in MeOH (70.0 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 25 °C for 12 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate = 10 : 1 to 0 : 1). After combining with other lots (51.3 g) the product was submitted to further purification. The combined material was purified by reversed-phase HPLC to afford the title compound (25.0 g, 62.8 mmol, 46.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.60 (s, 1H), 7.58 - 7.48 (m, 3H), 5.10 (dd, J = 4.8, 13.2 Hz, 1H), 4.45-4.27 (m, 2H), 4.21 (d, J = 6.0 Hz, 2H), 2.94 - 2.87 (m, 1H), 2.54 (d, J = 28.0 Hz, 1H), 2.41 - 2.38 (m, 1H), 2.02 - 2.00 (m, 1H), 1.39 (s, 9H). LCMS (ESI): m / z 374.2 (M+H)+.

[0236] Example 2

[0237] Preparation of formula (I) compounds 1-4, 7, 9-16, 18, 19, 21-32 and formula (II) compounds 40, 41, 43-47, and 51-53. Compound “I-C” was prepared according to the following scheme. For formula (I) compounds 1-4, 7, 9-16, 18, 19, 21-32, the “R” moiety of compound I-C in the following scheme corresponds toin formula (I). For formula (II) compounds 40, 41, 43-47, and 51-53, the “R” moiety of compound I-C in the following scheme corresponds toformula (II).

[0238] General scheme where “Int-2B” refers to intermediate 2B, “Int1” refers to intermediate 1, and “Int-2B” refers to intermediate 2B.

[0239] Step 1: Preparation of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione hydrogen chloride (Int-1B)

[0240] To a solution of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)methyl)carbamate (37 mg, 0.100 mmol, 1.00 eq) in DCM (1 mL) was added HCl- Dioxane (1 mL, 4 M). The mixture was stirred at 30oC for 16 hrs. The reaction mixturewas concentrated under reduced pressure to afford the title compound as a crude residue that was carried on to the next step.

[0241] Step 2: Preparation of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (Int1)

[0242] 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen was dissolved (31 mg, 0.100 mmol, 1.00 eq) in CH3CN (1 mL), the pH of the solution was adjusted to pH=7 with DIEA. Then additional DIEA (0.300 mmol, 3.00 eq) was added to afford a solution of the title compound that was carried on to the next step.

[0243] Step 3a / b: Preparation of compound I-C

[0244] To a solution of alcohol I-A (0.300 mmol, 3.00 eq) in DCM (1 mL) was added TEA or pyridine (0.600 mmol, 6.00 eq), then a solution of 4-nitrophenyl chloroformate (0.300 mmol, 3.00 eq) in DCM (0.5 mL) at 0oC. The reaction mixture was stirred at 30oC for 2-16 hrs. The reaction mixture was concentrated under reduced pressure to afford crude carbonate I-B. A solution of Int-1B in CH3CN (1 mL) was then added and stirred at 30oC for 2-16 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford the tittle compound.

[0245] Example 3

[0246] Preparation of 3-(p-tolyl)cyclobutyl ((2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)methyl)carbamate (Compound 39)

[0247] Step 1: Preparation of 1-(3-(benzyloxy)cyclobutyl)-4-methylbenzene

[0248] To a suspension of p-tolylboronic acid (1.09 g, 8.02 mmol, 1 eq) and cesium carbonate (7.89 g, 24.05 mmol, 3 eq) in 1,4-dioxane (50mL) was added N-[(3- benzyloxycyclobutylidene)amino]-4-methyl-benzenesulfonamide (4.14 g, 12.03 mmol, 1.5 eq). The reaction was stirred at 100 °C for 16 hrs under N2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (0 - 10% EtOAc in Petroleum ether) to afford the title compound as a yellow oil (898 mg, 44% yield).1H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.30 (m, 5H), 7.16 - 7.07 (m, 4H), 4.04 (s, 2H), 4.42 - 4.38 (m, 0.7H), 4.05 - 3.92 (m, 0.3H), 3.55 - 3.44 (m, 0.7H), 3.00 - 2.85 (m, 0.3H), 2.66 - 2.56 (m, 0.7H), 2.45 - 2.35 (m, 1.3H), 2.34 - 2.26 (m, 1.3H), 2.27 (s, 3 H), 1.96 - 1.83 (m, 0.7H).

[0249] Step 2: Preparation of 3-(p-tolyl)cyclobutan-1-ol

[0250] To a solution of 1-(3-(benzyloxy)cyclobutyl)-4-methylbenzene (0.89 g, 3.53 mmol, 1 eq) in 1,4-dioxane (20 mL) was added 10% Pd / C (0.38 g) and 20% Pd / (OH)2(0.5 g). The suspension was stirred at 25 °C for 16 hrs under H2. Then the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0 - 15% EtOAc in petroleum ether) to afford the title compound as a yellow oil (300 mg, 52% yield).

[0251] Step 3: Preparation of 4-nitrophenyl (3-(p-tolyl)cyclobutyl) carbonate

[0252] To a solution of 3-(p-tolyl)cyclobutan-1-ol (100.0 mg, 0.62 mmol, 1 eq.), 4-dimethylaminopyridine (7.53 mg, 0.06 mmol, 0.1 eq.) and pyridine (0.15 mL, 1.85 mmol, 3 eq.) in DCM (5mL) was added 4-nitrophenyl carbonochloridate (161.52 mg, 0.80 mmol, 1.3 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hrs under N2. The reaction mixture was diluted with water (10 mL) and extracted with DCM ( 20 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (201.77mg, crude) as a yellow oil. It was directly used in the next step without further purification.

[0253] Step 4: Preparation of 3-(p-tolyl)cyclobutyl ((2-(2,6-dioxopiperidin-3-yl)- 3-oxoisoindolin-5-yl)methyl)carbamate

[0254] To a solution of 4-nitrophenyl (3-(p-tolyl)cyclobutyl) carbonate (201.77 mg, 0.62 mmol, 1 eq.) in DMF (3mL) was added 3-[6-(aminomethyl)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (168.46 mg, 0.62 mmol, 1 eq.) and Et3N (0.26 mL, 1.85 mmol, 3 eq.). Then mixture was stirred at 25oC for 16 hrs. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by pre-HPLC (Xtimate C18150*40mm*10um, water (0.225% FA)-ACN, 58-88%) to afford the title compound as a white solid (53 mg, 41% yield). LCMS (ESI): m / z 484.1 (M+Na)+. 1H NMR (400MHz, DMSO-d6) δ 10.98 (s, 1H), 7.88 - 7.84 (m, 1H), 7.61 (s,1H), 7.58 - 7.49 (m, 2H), 7.19 - 7.06 (m, 4H), 5.14 - 5.09 (m, 1H), 5.06 - 4.77 (m, 1H), 4.48 - 4.22 (m, 4H), 2.97 - 2.86 (m, 1H), 2.73 - 2.56 (m, 2H), 2.45 - 2.36 (m, 4H), 2.26 (s, 3H), 2.01 - 1.99 (m, 1H).

[0255] Example 4

[0256] Preparation of [3-(o-tolyl)cyclobutyl] N-[[2-(2,6-dioxo-3-piperidyl)-3-oxo- isoindolin-5-yl]methyl]carbamate (Compound 42)

[0257] Step 1: Preparation of 1-(3-benzyloxycyclobutyl)-2-methyl-benzene

[0258] To a solution of 2-methylphenylboronic acid (1.0 g, 7.36 mmol, 1.00 eq.) in 1,4-dioxane (30 mL) was added N-[(3-benzyloxycyclobutylidene)amino]-4-methyl- benzenesulfonamide (5.07 g, 14.71 mmol, 2.00 eq.) and Cs2CO3 (4.82g, 14.71mmol, 2.00 eq.) at 25 ℃ under N2. Then the mixture was stirred at 100 ℃ for 16 hrs under N2. After that, the reaction mixture was concentrated under vacuum. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to afford the title compound (700 mg, 38% yield) as a white solid.

[0259] Step 2: Preparation of 3-(o-tolyl)cyclobutanol

[0260] To a stirred solution of 1-(3-benzyloxycyclobutyl)-2-methyl-benzene (600.0 mg, 2.38 mmol, 1 eq.) in 1,4-Dioxane (20 mL), 10% Pd / C (120.0 mg) was added, and the reaction mixture was stirred at 25oC for 3 hrs under H2 (15 psi). After filtration,the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to afford title compound (330mg, 86%) as a light oil.

[0261] Step 3: Preparation of (4-nitrophenyl) [3-(o-tolyl)cyclobutyl] carbonate

[0262] To a solution of 3-(o-tolyl)cyclobutanol (100.0 mg, 0.62 mmol 1.00 eq.) in DCM (2 mL) was added 4-dimethylaminopyridine (7.53 mg, 0.06 mmol, 0.1 eq.) and pyridine (0.15 mL, 1.85 mmol, 3.00 eq.). Then 4-nitrophenyl carbonochloridate (124.24 mg, 0.62 mmol, 1.00 eq.) was added at 0 ℃. The resulting reaction mixture was stirred at 25oC for 16 hrs. After that, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers was washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated to give the crude title compound (120 mg, crude) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0263] Step 4: Preparation of [3-(o-tolyl)cyclobutyl] N-[[2-(2,6-dioxo-3-piperidyl)- 3-oxo-isoindolin-5-yl]methyl]carbamate

[0264] To a solution of (4-nitrophenyl) [3-(o-tolyl)cyclobutyl] carbonate (90.0 mg, 0.27 mmol, 1.00 eq.) in DMF (2 mL) was added Et3N (0.08 mL, 0.55 mmol, 2.00 eq.) and 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (112.71 mg, 0.41 mmol, 1.50 eq.) at 25oC. After stirring at 25oC for 16 hrs, the reaction mixture was concentrated. The resulting residue was purified by prep-HPLC (Welch Xtimate C18 150*30mm*5um / water(FA)-CAN, 0-60%) to afford the title compound (38.6 mg, 30% yield) as a white solid. LCMS (ESI): m / z 462.3 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.84 - 7.82 (m, 1H), 7.57 - 7.54 (m, 1H), 7.48 - 7.43 (m, 1H), 7.31 (d, J = 7.6Hz, 1H), 7.23 - 7.19 (m, 1H), 7.16 - 7.12 (m, 3H), 5.26 - 5.04 (m, 3H), 4.50 - 4.47 (m, 3H), 4.36 - 4.32 (m, 1H), 3.80 - 3.78 (m, 1H), 2.95 - 2.54 (m, 3H), 2.59 - 2.52 (m, 3H), 2.42 - 2.29 (m, 1H), 2.24 (d, J = 13.2 Hz, 4H).

[0265] Example 5

[0266] Preparation of (4-chlorobenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 5)

[0267] Step 1: Preparation of (4-chlorobenzo[d]thiazol-2-yl)methanol

[0268] A mixture of 2-bromo-4-chlorobenzo[d]thiazole (1.0 g, 4.02 mmol, 1.00 eq.), (tributylstannyl)methanol (1.1 g, 4.43 mmol, 1.10 eq.) and Pd(PPh3)4 (372.0 mg, 0.32 mmol, 0.08 eq.) and CuI (153.0 mg, 0.80 mmol, 0.2 eq.) in 1,4-dioxane (10 mL) was stirred at 100oC for 16 hrs under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by column chromatography (0 - 30% EtOAc in petroleum ether) to afford the title compound (180.0 mg, 22% yield) as a white solid.1H NMR (400MHz, DMSO-d6)δ8.08 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.36 (t, J = 6.0 Hz, 1H), 4.90 (d, J = 6.0 Hz, 2H).

[0269] Step 2: Preparation of (4-chlorobenzo[d]thiazol-2-yl)methyl (4- nitrophenyl) carbonate

[0270] To a mixture of 4-chlorobenzo[d]thiazol-2-yl)methanol (50.0 mg, 0.25 mmol, 1.00 eq.) in DCM (5 mL) was added DMAP (3.0 mg, 0.03 mmol, 0.10 eq.) and pyridine (0.06 mL, 0.76 mmol, 3.00 eq.). Then 4-nitrophenyl carbonochloridate (61.0 mg, 0.30 mmol, 1.20 eq.) was added into the mixture. The mixture was stirred at 25oC for 16 hrs. The reaction was concentrated to afford the title compound (90.0 mg, 98% yield) as a yellow oil. The crude product would be directly used in the next step without purification. LCMS (ESI): m / z 365.0 (M+H)+.

[0271] Step 3: Preparation of (4-chlorobenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0272] To a mixture of (4-chlorobenzo[d]thiazol-2-yl)methyl (4-nitrophenyl) carbonate (90.0 mg, 0.25 mmol, 1.00 eq.) in DMF (2 mL) was added 3-(6-(aminomethyl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (67.0 mg, 0.25 mmol, 1.00 eq.) and Et3N (0.1 mL, 0.74 mmol, 3.00 eq.), the mixture was stirred at 20oC for 16 hrs. The mixture was purified by pre-HPLC (Xtimate C18150*40mm*10um; water(FA)-ACN; 33 / 63) to afford the title product (29.0 mg, 23% yield) as white solid. LCMS (ESI): m / z 499.0 (M+H)+. 1H NMR (400MHz, DMSO-d6) δ 10.98 (s, 1H), 8.32 (t, J = 6.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 5.50 (s, 2H), 5.12 (dd, J = 4.8, 13.2 Hz, 1H), 4.49 - 4.28 (m, 4H), 2.98 - 2.84 (m, 1H), 2.67 - 2.58 (m, 1H), 2.43 - 2.32 (m, 1H), 2.05 - 1.96 (m, 1H).

[0273] Example 6

[0274] Preparation of (6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 6)

[0275] Step 1: Preparation of 2-bromo-4-phenylcyclohexan-1-one

[0276] To a solution of bromine (0.95mL, 17.23mmol) in MeOH(30mL) was added 4-phenylcyclohexan-1-one (3.0g, 17.23mmol). The resulting mixture was stirred at - 10oC for 0.5 hour, then the mixture was stirred at 25°C for 16 hours. The reaction mixture was extracted with EtOAc (50 mLX3) and washed by brine (70 mL × 2). The organic layer was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (2 g, crude) as a yellow oil. The crude product was directly used in the next step without further purification.

[0277] Step 2: Preparation of ethyl 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate

[0278] To a solution of 2-bromo-4-phenyl-cyclohexanone (2000.0 mg, 7.9 mmol) in EtOH(10 mL) was added ethyl amino(thioxo)acetate (1052 mg, 7.9 mmol). The resulting reaction mixture was stirred at 90oC for 3hrs under N2. After cooling to room temperature, the reaction mixture was poured into ice-water (25 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (100 mL), dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-25% (75% ethyl acetate in ethanol) in petroleum ether) to afford ethyl 6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2-carboxylate (550 mg, 24% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.31 (m, 4H), 7.30 (d, J = 4.4 Hz, 1H), 4.41 - 4.30 (m, 2H), 3.18 (dd, J = 4.8, 16.2 Hz, 1H), 3.12 - 3.04 (m, 1H), 3.01 - 2.86 (m, 3H), 2.11 - 2.01 (m, 2H), 1.35 - 1.28 (m, 3H).

[0279] Step 3: Preparation of (6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0280] To a solution of ethyl 6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2- carboxylate (450.0 mg, 1.57 mmol) in MeOH (5 mL) was degassed with N2for three times and then cooled to 0℃. NaBH4(118 mg, 3.13 mmol) was added and the reaction mixture was stirred at 25oC for 2 h. The reaction was quenched with NH4Cl solution (5 mL) at 0oC. The mixture was extracted with EtOAc (10 mL × 3), the combined organic layer waswashed with brine (10 mL), filtered and concentrated to afford the title compound (300 mg, crude) as yellow oil. The crude product was directly used in the next step without further purification.

[0281] Step 4: Preparation of 4-nitrophenyl ((6-phenyl-4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl)methyl) carbonate

[0282] To a solution of (6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2- yl)methanol (150.0 mg, 0.6100 mmol) in DCM (2mL) was added pyridine (0.15 mL, 1.83 mmol) and N,N-dimethylpyridin-4-amine (0.01 mL, 0.06 mmol). Then 4-nitrophenyl carbonochloridate (246.47mg, 1.22mmol) was added at 0 ℃. The mixture was stirred at 25oC for 2 h. After that, the reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The organics were washed with brine (20 mL × 3), dried over sodium sulfate, filtered and concentrated to afford the title compound (200 mg, 80% yield) as a yellow oil. The crude product was directly used in the next step without further purification.

[0283] Step 5: Preparation of (6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0284] To a mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione;hydrochloride (150.9 mg, 0.490 mmol) in DMF (0.60 mL) was added DIEA (0.25 mL, 1.46 mmol) at 25oC. After stirring at 25oC for 10 min, (4-nitrophenyl) (6-phenyl- 4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)methyl carbonate (200.0mg, 0.4900mmol) was added. The resulting mixture was stirred at 25oC for 1 h under N2. The reaction mixture was purified by pre-HPLC (acetonitrile 58-88 / 0.225% FA in water) to afford the title compound (14.5 mg, 5.4% yield) as a yellow solid. LCMS (ESI): m / z 545.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.13 (t, J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.58 - 7.51 (m, 2H), 7.32 - 7.30 (m, 4H), 7.26 - 7.20 (m, 1H), 5.23 (s, 2H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.46 - 4.28 (m, 4H), 3.08 - 2.99 (m, 2H), 2.96 - 2.80 (m, 3H), 2.62 - 2.55 (m, 1H), 2.43 - 2.36 (m, 1H), 2.08 - 1.89 (m, 4H).

[0285] Example 7

[0286] Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 8)

[0288] To a solution of 4,4-difluorocyclohexan-1-one (1.00 g, 7.46 mmol, 1.00 eq.) in MeOH (20.00 mL) was added Br2(0.41 mL, 7.46 mmol, 1.00 eq.) at -10 °C under N2. The mixture was stirred at -10oC for 0.5 hour, then the mixthre was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with water (25 mL) and extracted with DCM (25 mL × 3). The combined organic phase was washed with brine (25 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound (1.00 g, crude) as yellow oil.

[0289] Step 2: Preparation of ethyl 6,6-difluoro-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate

[0290] To a solution of 2-bromo-4,4-difluoro-cyclohexanone (800.00 mg, 3.76 mmol, 1.00 eq.) in EtOH (13.00 mL) was added ethyl amino(thioxo)acetate (500.10 mg, 3.76 mmol, 1.00 eq.) under N2. The reaction was stirred at 90oC for about 3 hrs under N2. The reaction mixture was extracted with DCM (25 mL × 3) and washed by brine (25 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The resulting residue was purified by pre-HPLC (acetonitrile 38-68 / 0.225% FA in water) to afford the title compound (190 mg, 20.5% yield) as a white solid. LCMS (ESI): m / z 248.0 (M+H)+.

[0291] Step 3: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0292] To a solution of ethyl 6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate (162.00 mg, 0.66 mmol, 1.00 eq.) in THF (2.00 mL) and MeOH (2.00 mL) was added sodium borohydride (51.00 mg, 1.35 mmol, 2.05 eq.) slowly at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h. Then the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound (100.00 mg, quant.) as yellow oil. LCMS (ESI): m / z 205.8 (M+H)+ 1H NMR (400 MHz, CD3OD) δ 5.45 (s, 1H), 4.73 (s, 2H), 2.93 - 2.85 (m, 2H), 2.28 (tt, J = 6.8, 14.0 Hz, 2H), 1.28 - 1.18 (m, 2H).

[0293] Step 4: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl (4-nitrophenyl) carbonate

[0294] To a solution of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (100.00 mg, 0.49 mmol, 1.00 eq.) in DCM (2.00 mL) was added 4- dimethylaminopyridine (5.90 mg, 0.05mmol, 0.10 eq.) and pyridine (0.12 mL, 1.46 mmol,3.00 eq.). Then 4-nitrophenylchloroformate (196.40 mg, 0.97 mmol, 2.00 eq.) was added at 0 °C under N2. The reaction mixture was stirred at 25oC for 5 hrs. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic phase was washed with brine (5 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound (287.00 mg, crude) as yellow oil. LCMS (ESI): m / z 371.0 (M+H)+.

[0295] Step 5: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl (4-nitrophenyl) carbonate

[0296] To a solution of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl (4-nitrophenyl) carbonate (47.80 mg, 0.13 mmol, 2.00 eq.) and 3-[6- (aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride (20.00 mg, 0.06 mmol, 1.00 eq.) in DMF (1.00 mL) was added DIPEA (0.03 mL, 0.19 mmol, 3.00 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hrs under N2. The resulting residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um / water(FA)-ACN) to afford the title compound (4.50 mg, 13% yield) as a white solid. LCMS (ESI): m / z 505.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.15 ( t, J = 6.0 Hz, 1H), 7.63 (s, 1H), 7.54 (q, J = 8.0 Hz, 2H), 5.24 (s, 2H), 5.11-5.0 (m, 1H), 4.46 - 4.26 (m, 4H), 3.42 ( s, 2H), 2.93 - 2.83 (m, 3H), 2.62 - 2.57 (m, 1H), 2.41 - 2.24 (m, 3H), 2.04 - 1.94 (m, 1H).

[0297] Example 8

[0298] Preparation of 3-(2-methoxyphenyl)cyclobutyl ((2-(2,6-dioxopiperidin-3- yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 48)

[0299] Step 1: Preparation of 3-phenylcyclopentan-1-one

[0300] To a mixture of N-[(3-benzyloxycyclobutylidene)amino]-4-methyl- benzenesulfonamide (9.1 g, 26.32 mmol, 2.00 eq.), (2-methoxyphenyl)boronic acid (2.0 g, 13.16 mmol, 1.00 eq.) in 1,4-dioxane (4 mL) was added Cs2CO3 (12.9 g, 39.48 mmol, 3.00 eq.) at 25oC. Then the mixture was stirred at 100oC for 16 hours under N2. After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 mL × 3) and washed by brine (30 mL × 2). The organic layer was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography (2% ethyl acetate in petroleum ether) to afford the title compound (800 mg, 23% yield) as a white oil.

[0301] Step 2: Preparation of 3-phenylcyclopentan-1-ol

[0302] To a solution of Pd / C (169 mg, 0.16 mmol, 0.40 eq.) in 1,4-dioxane (5 mL) was added 1-(3-(benzyloxy)cyclobutyl)-2-methoxybenzene (100.0 mg, 0.40 mmol, 1.00 eq.), then the mixture was stirred at 25oC for 3 hrs under H2(15 psi). After that, the mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (0-5% EtOAc in petroleum ether) to afford the tittle compound (51.6 mg, 80% yield) as a white oil.1H NMR (400 MHz, CDCl3) δ 7.26-7.13 (m, 2H), 6.95 (t, J =7.2 Hz, 1H), 6.88 - 6.82 (m, 1H), 4.54 - 4.25 (m, 1H), 3.90 - 3.77 (m, 4H), 2.82 - 2.71 (m, 1H), 2.52 - 2.34 (m, 3H), 2.02 - 1.92 (m, 1H).

[0303] Step 3: Preparation of 3-(2-methoxyphenyl)cyclobutyl (4-nitrophenyl) carbonate

[0304] To a solution of 3-(2-methoxyphenyl)cyclobutan-1-ol (50 mg, 0.31 mmol, 1.00 eq.) in DCM (2 mL) was added pyridine (73.14 mg, 0.92 mmol, 3.00 eq.) and DMAP (3.77 mg, 0.03 mmol, 0.10 eq.), then 4-nitrophenyl carbonochloridate (93.18 mg, 0.46 mmol, 1.50 eq.) was added at 0oC. The mixture was stirred at 25oC for 2 hours. After that, the reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The organics were washed with brine (10 mL × 3), dried over sodium sulfate, filtered and concentrated to afford the crude title compound (80 mg, crude). The crude product would be directly used in the next step without further purification.

[0305] Step 4: Preparation of 3-(2-methoxyphenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0306] To a solution of the 3-(2-methoxyphenyl)cyclobutyl (4-nitrophenyl) carbonate (80.0 mg, 0.23 mmol, 1.00 eq.) in DMF (2 mL) was added 3-(6-(aminomethyl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (254.7 mg, 0.93 mmol, 4.00 eq.) and Et3N (0.06 mL, 0.47 mmol, 2.00 eq.) at 25oC. The mixture was stirred at 25oC for 16 hours under N2 atmosphere. After that, the mixture was purified by pre-HPLC (water (0.225% FA)-ACN, 37-67%) to afford the title compound (14.9 mg, 13% yield) as a white solid. LCMS (ESI): m / z 478.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.93 -7.78 (m, 1H), 7.64 -7.59 (m, 1H), 7.58 - 7.49 (m, 2H), 7.31 - 7.15 (m, 2H), 6.98 - 6.86 (m, 2H), 5.11 (dd, J = 13.2, 5.2 Hz, 1H), 5.01-4.81 (m, 1H), 4.47 - 4.24 (m, 4H), 3.76 (s, 3H), 3.42 - 3.33 (m, 1H), 2.97 - 2.85 (m, 1H), 2.68 - 2.56 (m, 2H), 2.44 - 2.31 (m, 4H), 2.01 - 1.97 (m, 1H).

[0307] Example 9

[0308] Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 49)

[0309] Step 1: Preparation of 1-(3-(benzyloxy)cyclobutyl)-2- (trifluoromethyl)benzene

[0310] A mixture of 1-bromo-2-(trifluoromethyl)benzene (140 mg, 0.62 mmol, 1.5 eq.) and NiCl2.glyme (9.1 mg, 0.04 mmol, 0.10 eq.) in DME (2 mL) was stirred for 5 mins. Then it was transferred to a mixture of (TMS)3SiH (103.1 mg, 0.41 mmol, 1.00 eq.), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (46.5 mg, 0.04 mmol, 1.00 eq.), ((3- bromocyclobutoxy)methyl)benzene (100.0 mg, 0.41 mmol, 1.00 eq.) and dtbbpy (11.1 mg, 0.04 mmol) in DME (1 mL) dropwise at 20oC. All the above operations were operated in glove box. Then the reaction mixture was stirred at 20oC under a Lumidox Screen Kit for 16 hours. After that, added water (10 mL) into it and extracted it with ethyl acetate (10 mL × 3), combined the organic phase and washed it with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0 - 2% ethyl acetate in petroleum ether) to afford the tittle compound (130 mg, crude) as yellow oil.1H NMR (400 MHz, CD3OD) δ 7.74 - 7.54 (m, 1H), 7.44 -7.19 (m, 8H), 4.51- 4.42 (m, 2H), 4.11 - 4.03 (1H), 3.95 - 3.86 (m, 1H), 3.01 - 2.64 (m, 2H), 2.45 - 2.04 (m, 2H).

[0311] Step 2: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobutan-1-ol

[0312] To a solution of Pd / C (20 mg, 0.02 mmol, 0.03 eq.) and Pd(OH)2 (20 mg, 0.03 mmol, 0.05 eq.) in 1,4-dioxane (5 mL) DMF (3 mL) was added 1-(3- (benzyloxy)cyclobutyl)-2-(trifluoromethyl)benzene (170.0 mg, 0.56 mmol, 1.00 eq.), then the mixture was stirred at 25oC for 16 hours under H2 (15 psi). The residue was purified by column chromatography (0 -5% EtOAc in petroleum ether) to afford the tittle compound (36 mg, 30% yield) as a white oil.

[0313] Step 3: Preparation of 4-nitrophenyl (3-(2- (trifluoromethyl)phenyl)cyclobutyl) carbonate

[0314] To a solution of 3-(2-(trifluoromethyl)phenyl)cyclobutan-1-ol (36 mg, 0.17 mmol, 1.00 eq.) in DCM (2 mL) was added pyridine (39.5 mg, 0.50 mmol, 3.00 eq.) and DMAP (2.08 mg, 0.02 mmol, 0.10 eq.). Then 4-nitrophenyl carbonochloridate (50.34 mg, 0.25 mmol, 1.50 eq.) was added at 0oC. The resulting reaction mixture was stirred at 25oC for 2 hours. After that, the reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The organics were washed with brine (10 mL × 3), dried over sodium sulfate, filtered and concentrated to give a crude compound. The crude product was directly used in the next step without further purification.

[0315] Step 4: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0316] To a solution of the 4-nitrophenyl (3-(2-(trifluoromethyl)phenyl)cyclobutyl) carbonate (50.0 mg, 0.13 mmol, 1.00 eq.) in DMF (2 mL) was added 3-(6-(aminomethyl)- 1-oxoisoquinolin-2(1H)-yl)piperidine-2,6-dione (71.7 mg, 0.26 mmol, 2.00 eq.) and Et3N(39.8 mg, 0.47 mmol, 2.00 eq.) at 25oC. The resulting reaction mixture was stirred at 25oC for 16 hours under N2 atmosphere. After that, the reaction mixture was purified by pre- HPLC (water (0.225% FA)-ACN, 39-69%)) to afford the title compound (4.6 mg, 6% yield) as a white solid. LCMS (ESI): m / z 516.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.99 - 7.82 (m, 1H), 7.81 - 7.63 (m, 3H), 7.62 (s, 1H), 7.57 - 7.50 (m, 2H), 7.46 - 7.40 (m, 1H), 5.11 (dd, J = 13.2, 5.2 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.48 - 4.33 (m, 4H), 2.96 - 2.85 (m, 2H), 2.77 - 2.65 (m, 2H), 2.64 - 2.56 (m, 1H), 2.48 - 2.28 (m, 2H), 2.19 - 2.13 (m, 1H), 2.03 - 1.97 (m, 1H).

[0317] Example 10

[0318] Preparation of 3-(4-(trifluoromethyl)phenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 50)

[0319] Step 1: Preparation of N'-(3-(benzyloxy)cyclobutylidene)-4- methylbenzenesulfonohydrazide

[0320] To a solution of TosNHNH2 (10.57 g, 56.75 mmol, 1.00 eq.) in MeOH (100 mL) was added 3-(benzyloxy)cyclobutan-1-one (10.0 g, 56.75 mmol, 1.00 eq.) at 25oC. The crude product was produced immediately. After stirring at 25oC for 10 mins, the reaction mixture was concentrated. The residue was dried in vacuo to afford the title compound (19 g, crude) as a yellow solid.

[0321] Step 2: Preparation of 1-(3-(benzyloxy)cyclobutyl)-4- (trifluoromethyl)benzene

[0322] To a solution of (4-(trifluoromethyl)phenyl)boronic acid (1.0 g, 5.27 mmol, 1.00 eq.) in 1,4-dioxane (30 mL) was added N'-(3-(benzyloxy)cyclobutylidene)-4- methylbenzenesulfonohydrazide (3.63 g, 10.53 mmol, 2.00 eq.) and Cs2CO3(3.45 g, 10.53 mmol, 2.00 eq.) at 25oC under N2. Then the mixture was stirred at 100oC for 16 hrs under N2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to afford title compound (230 mg, 14%) as a white solid.

[0323] Step 3: Preparation of 3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol

[0324] To a stirred solution of 1-(3-(benzyloxy)cyclobutyl)-4- (trifluoromethyl)benzene (200.0 mg, 0.65 mmol, 1.00 eq.) in 1,4-dioxane (5 mL), was added 10% Pd / C (40.0 mg), and the reaction mixture was stirred at 25oC for 16 hrs under H2 (15 psi). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to afford title compound (100 mg, 71%) as a light oil.1H NMR (400 MHz, DMSO- d6) δ 7.65 (d, J = 8.0 Hz, 2H), 7.50 - 7.43 (m, 2H), 5.16 - 5.12 (m, 1H), 4.36 - 4.02 (m, 1H), 3.61 - 3.54 (m, 1H), 2.66 - 2.60 (m, 1H), 2.34 (d, J = 6.4 Hz, 2H), 1.93 - 1.87 (m, 1H).

[0325] Step 4: Preparation of 4-nitrophenyl (3-(4- (trifluoromethyl)phenyl)cyclobutyl) carbonate

[0326] To a solution of 3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (100.0 mg, 0.46 mmol, 1.00 eq.) in DCM (3 mL) was added 4-dimethylaminopyridine (5.65 mg, 0.05 mmol, 0.1 eq.) and pyridine (0.11 mL, 1.39 mmol, 3.00 eq.). Then 4-nitrophenylcarbonochloridate (121.2 mg, 0.60 mmol, 1.20 eq.) was added at 0 ℃. The mixture was stirred at 25oC for 4 h. The reaction was diluted with H2O (10 mL) and extracted with DCM (10 mL × 3). The organics were washed with brine (10 mL × 3), dried over Na2SO4, filtered and concentrated to give the crude title compound (170 mg, crude) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0327] Step 5: Preparation of 3-(4-(trifluoromethyl)phenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0328] To a solution of 4-nitrophenyl (3-(4-(trifluoromethyl)phenyl)cyclobutyl) carbonate (170.0 mg, 0.45 mmol, 1.00 eq.) in DMF (3 mL) was added Et3N (0.19 mL, 1.34 mmol, 3.00 eq.) and 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (165.72 mg, 0.54 mmol, 1.20 eq.) at 25oC. Then the solution was stirred at 25oC for 16 h. The resulting residue was purified by pre-HPLC (Welch Xtimate C18 150*30mm*5um / water(FA)-CAN, 0-60%) to afford the title compound (109.5 mg, 46% yield) as a white solid. LCMS (ESI): m / z 516.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.84 (s, 1H), 7.59 - 7.53 (m, 3H), 7.47 - 7.45 (m, 1H), 7.37 - 7.33 (m, 2H), 5.26 - 5.20 (m, 2H), 5.14 - 5.01 (m, 1H), 4.52 - 4.48 (m, 3H), 4.37 - 4.33 (m, 1H), 3.75 - 3.71 (m, 1H), 2.97 - 2.80 (m, 3H), 2.66 - 2.54 (m, 3H), 2.40 - 2.32 (m, 1H), 2.25 - 2.22 (m, 1H).

[0329] Example 11

[0330] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 17)

[0331] Step 1: Preparation of 2-bromo-4,4-dimethylcyclohexan-1-one

[0332] To a solution of 4,4-dimethylcyclohexan-1-one (10.00 g, 79.24 mmol, 1.00 eq.) in MeOH (75.00 mL) was added Br2 (4.35 mL, 7.46 mmol, 1.00 eq.) at -10 °C under N2. The mixture was stirred at -10oC for 0.5 hr, then the mixture was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic phase was washed with brine (80 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound (12.50 g, quant.) as yellow oil. LCMS (ESI): m / z 206.9 (M+H)+.

[0333] Step 2: Preparation of ethyl 6,6-dimethyl-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate

[0334] To a solution of 2-bromo-4,4-dimethylcyclohexan-1-one (1.00 g, 4.88 mmol, 1.00 eq.) in EtOH (10.00 mL) was added 2-amino-2-thioxo-acetate (649.30 mg, 4.88 mmol, 1.00 eq.) under N2. The reaction was stirred at 90oC for 3 hrs under N2. After cooling to room temperature, the reaction mixture was extracted with DCM (25 mL × 3) and washed by brine (25 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (0.85 g, quant.) as a white solid.

[0335] Step 3: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0336] To a solution of ethyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate (1.73 g, 7.23 mmol, 1.00 eq.) in THF (7.00 mL) and MeOH (7.00 mL) was added sodium borohydride (0.52 g, 13.75 mmol, 1.90 eq.) slowly at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The solution was purified by column chromatography (0-60% EtOAc in petroleum ether) to afford the title compound (1.30 g, 91% yield) as a white solid. LCMS (ESI): m / z 197.9 (M+H)+.

[0337] Step 4: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl (4-nitrophenyl) carbonate

[0338] To a solution of (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2- yl)methanol (200.0 mg, 1.01 mmol, 1.00 eq.) in DCM (4.0 mL) was added pyridine (0.25 mL, 3.04 mmol, 3.00 eq.) and DMAP (12.38 mg, 0.10 mmol, 0.10 eq.). Then 4- nitrophenylchloroformate (245.18 mg, 1.22 mmol, 1.20 eq.) was added to the above reaction mixture at 0 °C. The mixture was stirred at 25oC for 2 hrs under N2. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The organics were washed with brine (20 mL × 3), dried over sodium sulfate, filtered and concentrated to give the title compound (367 mg, 99% yield) as yellow oil. The crude product was directly used in the next step without further purification.

[0339] Step 5: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0340] To a solution of 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (226.23 mg, 0.83 mmol, 1.50 eq.) in DMF (2.0 mL) were added Et3N ( 0.31 mL, 2.21 mmol, 4.00 eq) and (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2-yl)methyl(4- nitrophenyl)carbonate (200.0 mg, 0.55 mmol, 1.00 eq) at 0 °C. Then the solution was stirred at 25oC for 16 hrs. The mixture was purified by pre-HPLC (acetonitrile 58- 88 / 0.225% FA in water) to afford the title compound (115.8 mg, 41% yield) as a white solid. LCMS (ESI): m / z 497.2 (M+H)+.1H NMR (400MHz, DMSO-d6) 10.96 (s, 1H), 8.08 - 8.06 (m, 1H), 7.63 (s, 1H), 7.58 - 7.50 (m, 2H), 5.21 (s, 2H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.26 (m, 4H), 2.97 - 2.85 (m, 1H), 2.68 - 2.65 (m, 2H), 2.62 - 2.60 (m, 1H), 2.58 - 2.54 (m, 2H), 2.45 - 2.32 (m, 1H), 2.05 - 1.94 (m, 1H), 1.57 (J = 6.4 Hz, 2H), 0.98 (s, 6H).

[0341] Example 12

[0342] Preparation of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 20)

[0343] Step 1: Preparation of 2-bromo-4-isopropylcyclohexan-1-one

[0344] To a solution of 4-isopropylcyclohexan-1-one (3.0 g, 21.39 mmol, 1.00 eq) in MeOH (60 mL) was added Br2(3.4 g, 21.39 mmol, 1.00 eq) dropwise at -10oC. The mixture was stirred at -10oC for 0.5 hour, then the mixture was stirred at 25 °C for 16 hours. After that, the reaction mixture was extracted with EtOAc (90 mL x 3) and washed by brine (90 mL × 3). The organic layer was combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title compound (4.8 g, crude) as a yellow oil. The crude product would be directly used in the next step without purification.

[0345] Step 2: Preparation of ethyl 6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazole-

[0346] To a solution of 2-bromo-4-isopropylcyclohexan-1-one (4.8 g, 21.91 mmol, 1.00 eq) in EtOH (73 mL) was added ethyl amino(thioxo)acetate (2.92 g, 21.91 mmol, 1.00 eq) at 25oC. The resulting reaction mixture was stirred at 90oC for 3 hours under N2. After cooling to room temperature, the reaction mixture was extracted with DCM (90 mL × 3) and washed with brine (90 mL × 2). The organic layer was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by pre-HPLC (water (0.225% FA)-ACN, 63-93%) to afford the title compound (554 mg, 10% yield) as a white solid. LCMS (ESI): m / z 254.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 4.39 - 4.30 (m, 2H), 3.02 - 2.82 (m, 2H), 2.76 - 2.64 (m, 1H), 2.63 - 2.54 (m, 1H), 2.02 - 1.93 (m, 1H), 1.73 - 1.51 (m, 2H), 1.50 - 1.39 (m, 1H), 1.36 - 1.26 (m, 3H), 0.99 - 0.88 (m, 6H).

[0347] Step 3: Preparation of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0348] To a solution of ethyl 6-isopropyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2- carboxylate (450.0 mg, 1.78 mmol, 1.00 eq) in THF (5 mL) was added LiAlH4(134.8 mg, 3.55 mmol, 2.00 eq) at 0oC. After stirring at 25oC for 2 hrs, the reaction was quenched with NaSO4.10H2O at 0oC until no bubbles were formed. Then the reaction mixture was extracted with EtOAc (10 mL x 3). The organic layer was combined, washed by brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (30 mg, 8% yield) as a yellow oil.1H NMR (400 MHz, CD3OD) δ 4.74 (s, 2 H) 2.90 - 2.78 (m, 2 H) 2.71 - 2.59 (m, 1 H) 2.54 - 2.44 (m, 1 H) 2.07 - 2.00 (m, 1 H) 1.68 - 1.48 (m, 3 H) 1.00 (t, J = 6.0 Hz, 6 H).

[0349] Step 4: Preparation of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl (4-nitrophenyl) carbonate

[0350] To a solution of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (30.0 mg, 0.14 mmol, 1.00 eq) in DCM (2 mL) was added 4-nitrophenyl carbonochloridate (42.9 mg, 0.21 mmol, 1.50 eq), pyridine (33.7 mg, 0.43 mmol, 3.00 eq) and DMAP (1.7 mg, 0.01 mmol, 0.1 eq) at 25oC. The resulting reaction mixture was stirred at 25oC for 3 hours. After that, the reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic layer was washed with brine (10 mL × 3), dried over sodium sulfate, filtered and concentrated to afford the title compound (50 mg, 94% yield) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0351] Step 5: Preparation of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0352] To a solution of the (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl (4-nitrophenyl) carbonate (50.0 mg, 0.13 mmol, 1 eq) in DMF (2 mL) was added Et3N (40.3 mg, 0.40 mmol, 3 eq) and 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (82.3 mg, 0.27 mmol, 2 eq) at 25oC. The resulting mixture was stirred at 25oC for 16 hours under N2 atmosphere. Then the mixture was purified by pre- HPLC (water (0.225% FA)-ACN, 48-78%) to afford the title compound (33.5 mg, 45% yield) as a white solid. LCMS (ESI): m / z 511.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.10 (t, J = 6.4 Hz, 1H), 7.63 (s, 1H), 7.57-7.50 (m, 2H), 5.20 (s, 2H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.47 - 4.27 (m, 4H), 2.95-2.74 (m, 3H), 2.67 - 2.56 (m, 2H), 2.47 - 2.37 (m, 2H), 2.05 - 1.90 (m, 2H), 1.64 - 1.49 (m, 2H), 1.47 - 1.35 (m, 1H), 0.92 (t, J = 6.4 Hz, 6H).

[0353] Example 13

[0354] Preparation of N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)-2-((1r,3r)-3-(2-(trifluoromethyl)phenyl)cyclobutyl) acetamide and of N-((2- (2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)-2-((1s,3s)-3-(2- (trifluoromethyl)phenyl)cyclobutyl)acetamide (Compounds 54 and 55)

[0355] Step 1: Preparation of 1-(3-(benzyloxy)cyclobutyl)-2- (trifluoromethyl)benzene

[0356] To the stirred mixture of ((3-bromocyclobutoxy)methyl)benzene (200 mg, 0.83 mmol, 1.00 eq), 1-bromo-2-(trifluoromethyl)benzene (279 mg, 1.24 mmol, 1.50 eq) and Na2CO3(175 mg, 1.66 mmol, 2.00 eq) in 1,2-Dimethoxyethane (4 mL) was addedIr[dF(CF3)ppy]2(dtbbpy)PF6(93 mg, 0.08 mmol, 0.10 eq), and 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (206 mg, 0.83 mmol, 1.00 eq). In a second vial, the mixture of NiCl2 glyme (18 mg, 0.08 mmol, 0.10 eq) and 4,4'-di-tert-butyl-2,2'-bipyridine (22 mg, 0.08 mmol, 0.10 eq) in 1,2-Dimethoxyethane (2 mL) was stirred at 25oC for 5 mins. Then the mixture was transferred to the first vial and the reaction mixture was stirred at 25oC under a 24W blue LED for 16 hours. The solution was diluted with water (10 mL) and extracted with ether acetate (10 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by pre-TLC (10 % ethyl acetate in petroleum ether, Rf = 0.6) to give the title compound (60 mg, 75% yield).1H NMR (400 MHz, CD3OD) δ 7.68 - 7.61 (m, 3H), 7.39 - 7.24 (m, 6H), 4.49 - 4.42 (m, 2H), 4.13 - 3.85 (m, 2H), 3.00 - 2.90 (m, 1H), 2.72 - 2.63 (m, 1H), 2.46 - 2.30 (m, 1H), 2.17 - 2.07 (m, 1H).

[0357] Step 2: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobutan-1-ol

[0358] To a solution of 1-(3-(benzyloxy)cyclobutyl)-2-(trifluoromethyl)benzene (600 mg, 1.96 mmol, 1.00 eq) in 1,4-dioxane (10 mL) was added Pd / C (600 mg, 0.56 mmol, 0.3 eq) and Pd(OH)2on carbon (240 mg, 0.34 mmol, 0.20 eq) at 25 °C. Then the solution was stirred at 25 °C for 4 hours under H2. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (0-20% ethyl acetate in petroleum ether) to afford the title compound (200 mg, 47% yield).1H NMR (400 MHz, CD3OD) δ 7.69 - 7.59 (m, 3H), 7.37 - 7.33 (m, 1H), 4.24 - 4.16 (m, 1H), 4.05 - 3.97 (m, 1H), 3.02 - 2.94 (m, 1H), 2.72 - 2.66 (m, 1H), 2.50 - 2.40 (m, 1H), 2.10 - 2.02 (m, 1H).

[0359] Step 3: Preparation of N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)-2-((1r,3r)-3-(2-(trifluoromethyl)phenyl)cyclobutyl) acetamideand of N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)-2-((1s,3s)-3- (2-(trifluoromethyl)phenyl)cyclobutyl)acetamide

[0360] To a solution of 3-(2-(trifluoromethyl)phenyl)cyclobutan-1-ol (40 mg, 0.19 mmol, 1.00 eq) in THF (1 mL) was added CDI (30 mg, 0.19 mmol, 1.00 eq), then the mixture was stirred at 25 °C for 2 hrs. The resulting solution was added to a mixture of 3- (6-(aminomethyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60 mg, 0.19 mmol, 1.00 eq), DBU (0.03 mL, 0.19 mmol, 1.00 eq), and trimethylamine (0.05mL, 0.37 mmol, 2.00 eq) in DMF (1 mL). The mixture was stirred at 25 °C for 12 hrs. After that, the reaction mixture was purified by pre-HPLC (C18150*30mm, water (HCl)-ACN, 40-70%) to give N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)-2-((1r,3r)-3- (2-(trifluoromethyl)phenyl) cyclobutyl)acetamide (tentatively assigned) (4.5 mg, 4.5% yield) as yellow solid. LCMS (ESI): m / z 534.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.92 (t, J = 6.0 Hz, 1H), 7.78 - 7.76 (m, 1H), 7.71 - 7.67 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 5.07 (dd, J = 4.8, 13.2 Hz, 1H), 4.89 – 4.83 (m, 1H), 4.48 - 4.26 (m, 4H), 2.94 - 2.86 (m, 1H), 2.71 - 2.55 (m, 3H), 2.40 - 2.24 (m, 2H), 2.18 - 2.08 (m, 2H), 2.02 - 1.97 (m, 1H) and to further give N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)-2-((1s,3s)-3-(2-(trifluoromethyl)phenyl) cyclobutyl)acetamide (tentatively assigned) (1.7 mg, 1.6% yield) as yellow solid. LCMS (ESI): m / z 534.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.92 (t, J = 5.6 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.58 (t, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 5.07 (dd, J = 4.8, 13.2 Hz, 2H), 4.47 – 4.27 (m, 4H), 2.95 - 2.86 (m, 1H), 2.71 - 2.55 (m, 3H), 2.43 - 2.33 (m, 4H), 2.05 - 1.97 (m, 1H).

[0361] Example 14

[0362] Preparation of 3-(1-methyl-1H-indol-4-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 56)

[0363] Step 1: Preparation of 4-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H- indole

[0364] To a mixture of 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (4.84 g, 12.24 mmol, 2 eq) in 1,4-dioxane (40 mL) was added 3-((tert- butyldimethylsilyl)oxy)cyclobutan-1-ol (1.86 g, 9.2 mmol, 1.5 eq), the mixture reaction was stirred at 20oC under N2 for 5 min and then pyridine (0.79 mL, 9.8 mmol, 1.6 eq) was added. The mixture reaction was stirred at 20oC under N2 for 10 min. Then the solution was added into the mixture of 4-bromo-1H-indole (1.2 g, 6.12 mmol, 1 eq), quinuclidine (1.19 g, 10.72 mmol, 1.75 eq), Ir(ppy)2(dtbbpy) PF6 (83.91 mg, 0.092 mmol, 0.015 eq) and NiBr2.dtbbpy (149 mg, 0.31 mmol, 0.05 eq) in DMA (40 mL), the mixture was stirred at 900 rpm stir rate and irradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hrs. The reaction mixture was extracted with ethyl acetate (50 mL × 3) and washed by brine (30 mL × 2). The organic layer was combined, dried with anhydrous Na2SO4and concentrated under vacuum. The residue was purified by column chromatography (0-6% ethyl acetate in petroleum ether) to afford the title compound (1.74 g, 94% yield) as a brown oil. LCMS (ESI): m / z 302.0 (M+H)+.

[0365] Step 2: Preparation of 3-(1H-indol-4-yl)cyclobutan-1-ol

[0366] To solution of 4-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H-indole (1.7 g, 5.64 mmol, 1 eq) in THF (15 mL) was added 1 M TBAF in THF (6.2 mL, 6.2 mmol, 1.1 eq), the resulting solution was stirred at 20oC for 1 hr. The reaction mixture was concentrated and purified by column chromatography (0-30% (75% ethyl acetate in Ethanol) in petroleum ether) to afford the title compound (370 mg, 1.98 mmol, 35% yield) as a brown oil. LCMS (ESI): m / z 187.9 (M+H)+.

[0367] Step 3: Preparation of 3-(1-methyl-1H-indol-4-yl)cyclobutan-1-ol

[0368] To a solution of 3-(1H-indol-4-yl)cyclobutan-1-ol (190.0 mg, 1.01 mmol, 1 eq) in DMF (3 mL) was added KI (33.69 mg, 0.20 mmol, 0.2 eq), K2CO3 (154.27 mg, 1.12 mmol, 1.1 eq) and MeI (69.49 uL, 1.12mmol, 1.1 eq). The mixture was stirred at 25oC for 16 hrs. After that, the mixture was diluted with ethyl acetate (20 mL) and wash with H2O (10 mL × 3). The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by pre-TLC (30 % ethyl acetate in petroleum ether) to afford the title compound (40 mg, 20% yield) (mixture of cis & trans isomers) as a white solid. LCMS (ESI): m / z 202.1 (M+H)+.

[0369] Step 4: Preparation of 3-(1-methyl-1H-indol-4-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0370] To a solution of 3-(1-methyl-1H-indol-4-yl)cyclobutan-1-ol (40.0 mg, 0.20 mmol, 1 eq) in THF (1 mL), was added CDI (41.9 mg, 0.26 mmol, 1.3 eq), the solution was stirred at 25oC for 2 hrs. The resulting solution was added to a mixture of 3-(6- (aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; hydrochloride (80 mg, 0.26 mmol, 1.3 eq) , Et3N (0.06 mL, 0.40 mmol, 2 eq), and DBU (0.04 mL, 0.26 mmol, 1.3 eq) in DMF (1mL). The resulting reaction mixture was stirred at 25oC for 16 hrs. After that, the reaction mixture was concentrated under reduced pressure. The crude product was purified by pre-HPLC (Xtimate C18150*40mm*5um, water (HCl)-ACN, 27-57%) toafford the title compound (35 mg, 35% yield) as a white solid. LCMS (ESI): m / z 501.2 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 11.00 (s, 1H), 7.81-7.94 (m, 1H), 7.63 (d, J = 4.8 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.33 - 7.25 (m, 2H), 7.15 - 7.09 (m, 1H), 7.02 - 6.85 (m, 1H), 6.47 - 6.34 (m, 1H), 5.12 (dd, J = 4.4, 12.8 Hz, 1H), 5.08 - 4.95 (m, 1H), 4.48 - 4.25 (m, 4H), 3.99 - 3.87 (m, 0.5H), 3.78 - 3.76 (m, 3H), 3.37 - 3.45 (m, 0.5H), 2.99 - 2.79 (m, 2H), 2.54-2.59 (m, 2H), 2.42 -2.33 (m, 2H), 2.24 - 2.11 (m, 1H), 2.06 - 1.96 (m, 1H).

[0371] Example 15

[0372] Preparation of (1R,3S)-3-(2-(trifluoromethyl)phenyl)cyclohexyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 57)

[0373] Step 1: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclohexan-1-one

[0374] To a solution of 1-bromo-2-(trifluoromethyl)benzene (5.0 g, 22.22 mmol, 1.00 eq) in THF (50 mL) was added isopropylmagnesium chloride (22.22 mL, 44.44 mmol, 2.00 eq) (2 M in THF) at -78oC under N2, then the solution was stirred at room temperature for 16 hrs, then CuI (2.12 g, 11.11 mmol, 0.50 eq) was added. After stirring at room temperature for 1 min, cyclohex-2-en-1-one (2.58 mL, 26.67 mmol, 1.20 eq) was added and stirred for 30 mins. The mixture was diluted with water (40 mL). The aqueous phase was concentrated and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography(petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to afford the title compound (800 mg, 15% yield) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.0 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.39 - 7.31 (m, 1H), 3.47 - 3.36 (m, 1H), 2.60 - 2.48 (m, 3H), 2.43 - 2.35 (m, 1H), 2.23 - 2.14 (m, 1H), 2.05 - 2.01 (m, 1H), 1.90 - 1.78 (m, 2H).

[0375] Step 2: Preparation of (1S,3R)-3-(2-(trifluoromethyl)phenyl) cyclohexan-1-

[0376] To a solution of 3-(2-(trifluoromethyl)phenyl)cyclohexan-1-one (800.0 mg, 3.3 mmol, 1.00 eq) in MeOH (8 mL) was added sodium borohydride (1.06 g, 28.02 mmol, 8.00 eq) slowly at 0℃. The mixture was stirred at 0℃ for 5 mins. The mixture was stirred at 25oC for 16 hrs. The reaction was quenched by addition of saturated NH4Cl solution (15 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to afford the title compound (500 mg, 62% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.32 - 7.28 (m, 1H), 3.86 - 3.72 (m, 1H), 3.01 (t, J = 12.0 Hz, 1H), 2.16 - 2.07 (m, 2H), 1.96 - 1.86 (m, 1H), 1.83 - 1.74 (m, 1H), 1.55 - 1.45 (m, 2H), 1.41 - 1.30 (m, 2H).

[0377] Step 3: Preparation of (1R,3S)-3-(2-(trifluoromethyl)phenyl) cyclohexyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0378] To a solution of (1S,3R)-3-(2-(trifluoromethyl)phenyl)cyclohexan-1-ol (100.0 mg, 0.410 mmol, 1.00 eq) in THF (2 mL) was added CDI (86.3 mg, 0.53 mmol), the solution was stirred at 25oC for 2 hrs. The resulting solution was added to a mixture of 3- (6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (123 mg, 0.45 mmol, 1.10 eq ), DBU (0.12 mL, 0.82 mmol, 2.00 eq) and triethylamine (0.11 mL, 0.82 mmol, 2.00 eq) inDMF (2 mL). After that, the reaction mixture was stirred at 25oC for 16 hrs. Then was purified by pre-HPLC (acetonitrile 40-70% / 0.225% hydrochloric acid in water) to get the title compound (54 mg, 24% yield) as a white solid. LCMS (ESI): m / z 544.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.75 (t, J = 5.6 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.59 (s, 1H), 7.56 - 7.47 (m, 2H), 7.45 - 7.36 (m, 1H), 5.15 - 5.06 (m, 1H), 4.63 - 4.54 (m, 1H), 4.49 - 4.25 (m, 4H), 2.97 - 2.85 (m, 2H), 2.65 - 2.55 (m, 1H), 2.41 - 2.32 (m, 1H), 2.04 - 1.93 (m, 3H), 1.89 - 1.82 (m, 1H), 1.68 - 1.58 (m, 2H), 1.50 - 1.35 (m, 3H).

[0379] Example 16

[0380] Preparation of 3-(2-fluorophenyl)cyclobutyl ((2-(2,6-dioxopiperidin-3-yl)- 3-oxoisoindolin-5-yl)methyl)carbamate (Compound 58)

[0381] Step 1: Preparation of 3-(2-fluorophenyl)cyclobutan-1-ol

[0382] To a mixture of cyclobutane-1,3-diol (177 mg, 2.00 mmol, 1.75 eq), 5,7- ditert-butyl-3-phenyl-1,3-benzoxazol-3-ium;trifluoroborane;fluoride (904 mg, 2.29 mmol, 2.0 eq) in 1,4-dioxane (4 mL) was added pyridine (0.15 mL, 1.83 mmol, 1.6 eq), the mixture was stirred at 20 °C under nitrogen for 5 min. Then the solution was added into the mixture of 1-bromo-2-fluorobenzene (200 mg, 1.14 mmol, 1.0 eq), quinuclidine (222 mg, 2.00 mmol, 1.75 eq), bis[2-(2-pyridyl)phenyl] iridium(1+);4-tert-butyl-2-(4-tert-butyl- 2-pyridyl)pyridine; hexafluorophosphate (16 mg, 0.02 mmol, 0.02 eq) and (Dtpby)NiBr2 (28 mg, 0.06 mmol, 0.05 eq) in DMA (4 mL), the mixture was stirred at 900 rpm stir rateand irradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hrs. After that, the mixture was extracted with EtOAc (40 mL) and washed with brine (10 mL × 2). The combined organic layer was dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to afford the title compound (70 mg, 37% yield) as a yellow oil.

[0383] Step 2: Preparation of 3-(2-fluorophenyl)cyclobutyl (4-nitrophenyl) carbonate

[0384] Step 3: Preparation of 3-(2-fluorophenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0385] To a mixture of 3-(2-fluorophenyl)cyclobutyl (4-nitrophenyl) carbonate (138 mg, 0.42 mmol, 1.0 eq) and 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride (168 mg, 0.54 mmol, 1.3 eq) in DMF (2mL) was added Et3N (0.2 mL, 1.25 mmol, 3.0 eq), the mixture was stirred at 40 °C for 16 hrs. After that, the mixture was concentrated. The residue was purified by pre-HPLC (Welch Xtimate C18 150*30mm*5um, water(FA)-CAN, 36-66%) to afford the title compound (102.7 mg, 52% yield) as a yellow solid. LCMS (ESI): m / z 466.0 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 7.91 (t, J = 6.0 Hz, 0.5H), 7.84 (t, J = 6.4 Hz, 0.5H), 7.62 (d, J = 3.6 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.45 (t, J = 8.0 Hz, 0.5H), 7.35 (t, J = 7.2 Hz, 0.5H), 7.29 - 7.26 (m, 1H), 7.20 - 7.16 (m, 2H), 5.12 (dd, J = 13.2, 5.2 Hz, 1H), 5.06 - 5.01 (m, 0.5H), 4.92 (t, J = 7.2 Hz, 0.5H), 4.49 - 4.28 (m, 4H), 3.79 (t, J = 7.6 Hz, 0.5H), 3.27 (d, J = 7.6 Hz, 0.5H), 2.97 - 2.87 (m, 1H), 2.76 - 2.71 (m, 1H), 2.65 - 2.57 (m, 2H), 2.46 - 2.31 (m, 2H), 2.15 - 2.08 (m, 1H), 2.02 - 1.96 (m, 1H).

[0386] Example 17

[0387] Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N- (quinolin-6-yl)propenamide (Compound 33)

[0389] To a solution of spiro[2.5]octan-6-one (2.5 g, 20.13 mmol, 1.00 eq) in MeOH (30 mL) was added Br2(3.54 g, 22.15 mmol, 1.00 eq) at 0oC and the mixture was stirred at 25℃ for 12 h. The reaction was quenched with H2O (30 mL), extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (60 mL), dried with Na2SO4 and concentrated to give the title compound (2.7 g, crude) as yellow oil, which was directly used in the next step.

[0390] Step 2: Preparation of ethyl 5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'- cyclopropane]-2-carboxylate

[0391] To a solution of 5-bromospiro[2.5]octan-6-one (2.7g, 13.3mmol, 1.00 eq) in MeOH (25.0 mL) was added ethyl amino(thioxo)acetate (1.77 g, 13.3 mmol, 4.00 eq) at 20oC and the mixture was stirred at 90 ℃ for 12 h under N2. The reaction mixture was quenched with H2O (20 mL), extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried with Na2SO4and concentrated.The residue was purified by column chromatography (0-20% ethyl acetate in petroleum ether) to afford the title compound (600 mg, 19% yield). LCMS (ESI): m / z 237.9 (M+H)+.

[0392] Step 3: Preparation of (5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'- cyclopropan]-2-yl)methanol

[0393] To a solution of ethyl 5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'- cyclopropane]-2-carboxylate (500.0 mg, 1.69 mmol, 1.00 eq) in MeOH (20 mL) was added NaBH4 (255.05 mg, 6.74 mmol) in portions at 0°C. The mixture was stirred at 25oC for 12 h. The reaction mixture was quenched with H2O (50 mL), extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography (0-40% ethyl acetate in petroleum ether) to afford the title compound (90 mg, 27% yield). LCMS (ESI): m / z 195.9 (M+H)+.

[0394] Step 4: Preparation of (5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'- cyclopropan]-2-yl)methyl (4-nitrophenyl) carbonate

[0395] To a solution of (5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'-cyclopropan]- 2-yl)methanol (90.0 mg, 0.46 mmol, 1.00 eq) in DCM (10.0 mL) was added pyridine (0.11 mL, 1.38 mmol, 3.00 eq) and DMAP (5.63 mg, 0.05 mmol, 0.01eq). Then 4- nitrophenylchloroformate (139.34 mg, 0.69 mmol, 1.50 eq) was added at 0 °C. The mixture was stirred at 25oC for 16 h. After that, the reaction mixture was diluted with water (25 mL) and extracted with DCM ( 10 mL × 3). The organics were washed with brine ( 50 mL × 2), dried over sodium sulfate, filtered and concentrated to give the title compound (120 mg, 33% yield) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0396] Step 5: Preparation of (5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'- cyclopropan]-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)methyl)carbamate

[0397] To a solution of (5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'-cyclopropan]- 2-yl)methyl (4-nitrophenyl) carbonate (120.0mg, 0.15 mmol, 1.00 eq) in DMF (10.0 mL)was added Et3N (0.06 mL, 0.46 mmol, 3.00 eq) and 3-[6-(aminomethyl)-1-oxo- isoindolin-2-yl]piperidine-2,6-dione (62.79 mg, 0.23 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 25oC for 16 h under N2. After that, the reaction mixture was diluted with water (5 mL) and extracted with DCM (10 mL × 3). The organics were washed with brine ( 10 mL × 3), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by pre-HPLC ((Gilson 281(Boston Green ODS) C18 150*30mm*3um, water (0.225% FA)-ACN, 36-65%) to afford the title compound (21 mg, 28% yield) as a white solid. LCMS (ESI): m / z 495.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.10 (t, J = 6.4 Hz, 1H), 7.63 (s, 1H), 7.59 - 7.47 (m, 2H), 5.22 (s, 2H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.50 - 4.26 (m, 4H), 2.99 - 2.85 (m, 1H), 2.72 (s, 2H), 2.64 - 2.53 (m, 3H), 2.46 - 2.34 (m, 1H), 2.05 - 1.92 (m, 1H), 1.58 (t, J = 6.0 Hz, 2H), 0.42 (d, J = 8.4 Hz, 4H).

[0398] Example 18

[0399] Preparation of (4-methylbenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 34)

[0400] Step 1: Preparation of (4-methylbenzo[d]thiazol-2-yl)methanol

[0401] To a solution of 2-bromo-4-methylbenzo[d]thiazole (500.00 mg, 2.19 mmol, 1.00 eq) in 1,4-dioxane (20.00 mL) was added Pd(PPh3)4(202.6 mg, 0.18 mmol, 0.08 eq), CuI (83.5 mg, 0.44 mmol, 0.20 eq) and tributylstannylmethanol (774.20 mg, 2.41 mmol, 1.00 eq) at 25oC under N2. The reaction was stirred for 16 hrs at 100oC under N2. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. T he residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to afford the title compound (24.50 mg, 6.2% yield) as a yellow solid. LCMS (ESI): m / z 180.1 (M+H)+.

[0402] Step 2: Preparation of (4-methylbenzo[d]thiazol-2-yl)methyl (4- nitrophenyl) carbonate

[0403] To a suspension of 4-nitrophenylchloroformate (55.40 mg, 0.27 mmol, 1.20 eq) in DCM (2.00 mL) was added pyridine (0.06 mL, 0.69 mmol, 3.00 eq) and 4- dimethylamineopyridine (2.80 mg, 0.02 mmol, 0.10 eq) at 25oC under N2. Then (6,6- dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2-yl)methanol (43.30 mg, 0.23 mmol, 1.00 eq) was added at 25oC under N2. The reaction was stirred at 25 °C for 16 hrs. The solvent was concentrated by speedvac. The crude product was directly used in the next step without further purification.

[0404] Step 3: Preparation of (4-methylbenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0405] To a solution of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (62.50 mg, 0.23 mmol, 1.00 eq) in DMF (4.00 mL) were added Et3N (0.10 mL, 0.69 mmol, 3.00 eq) and (4-methylbenzo[d]thiazol-2-yl)methyl (4-nitrophenyl) carbonate (78.80 mg, 0.23 mmol, 1.00 eq) at 25oC under N2. Then mixture was stirred at 40oC for 16 hrs. The resulting residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um / water(FA)-ACN) to afford the title compound (11.00 mg, 9.3% yield) as a white solid. LCMS (ESI): m / z 479.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.32 - 8.24 (m, 1H), 7.96 - 7.89 (m, 1H), 7.69 (s, 1H), 7.59 - 7.52 (m, 2H), 7.37 - 7.33 (m, 2H), 5.48 (s, 2H), 5.17 - 5.06 (m, 1H), 4.48 - 4.27 (m, 4H), 2.98 - 2.87 (m, 1H), 2.65 (s, 3H), 2.60 - 2.57 (m, 1H), 2.46 - 2.37 (m, 1H), 2.06 - 1.96 (m, 1H).

[0406] Example 19

[0407] Preparation of (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2-yl)methyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-3-oxo-isoindolin-5-yl]methyl]carbamate (Compound 35)

[0408] Step 1: Preparation of 3-bromo-2-fluoro-6-methyl-benzaldehyde

[0409] A mixture of 3-bromo-2-fluoro-benzaldehyde (5.0 g, 24.63 mmol, 1.00 eq), 2-aminobenzenesulfonic acid (1.92 g, 11.08 mmol, 0.45 eq), potassium methyltrifluoroborate (12.0 g, 98.52 mmol, 4.00 eq), 1-fluoro-2,4,6- trimethylpyridiniumtetrafluoroborate (1.12g, 49.26 mmol, 2.00 eq) and Pd(OAc)2 (553 mg, 2.46 mmol, 0.10 eq) in mixture of TFA (6.7 mL) and HFIP (60 mL) was degassed for 3 times under Ar atmosphere and the mixture was stirred at 20oC for 20min, then heated to 90oC for 24 hrs. The mixture was filtered through diatomite, the filtrate was concentrated. The residue was purified by column chromatography (2~5% ethyl acetate in petroleum ether) to give a mixture of the title compound and the starting material (~1:1, 1.7 g) as colorless oil. LCMS (5-95AB / 1.5min) showed 43% of 3-bromo-2-fluoro-6-methyl- benzaldehyde and 49% of 3-bromo-2-fluoro-benzaldehyde. The crude product was used in next step directly.

[0410] Step 2: Preparation of 3-bromo-2-fluoro-6-methyl-benzoic acid

[0411] To a stirred solution of 3-bromo-2-fluoro-6-methyl-benzaldehyde (4.10 g, 18.89 mmol, 1.00 eq) in THF (100 mL), water (50 mL) and t-BuOH (25 mL) was added NaH2PO4 (9.07 g, 75.56 mmol, 4.00 eq) in one portion at -5oC. Then NaClO2 (6.83 g, 75.56 mmol, 4.00 eq) was added in batches. After addition, the mixture was stirred at -5oC for another one hour.2-methyl-2-butene (9.27 g, 132.23 mmol, 7.00 eq) was added dropwise to the reaction mixture and maintaining the temperature below 0oC. After addition, the mixture was stirred for 1h below 0oC. The mixture was diluted with ethyl acetate (100 mL) and 2M HCl solution (20 mL), the layers were separated. The organic phase was concentrated to give the mixture of the title compound and 3-bromo-2-fluoro-6- methyl-benzoic acid (~1:1, 5.0 g) as colorless oil. LCMS showed 40% of desired product and 42% of 3-bromo-2-fluorobenzoic acid. The mixture was difficult to be separated by column and used directly in the next step.

[0412] Step 3: Preparation of tert-butyl N-[[3-[3-[(4-methoxyphenyl) methyl]-2,4- dioxo-hexahydropyrimidin-1-yl]-6-quinolyl]methyl]carbamate

[0413] The mixture of 3-bromo-2-fluoro-6-methyl-benzoic acid and 3-bromo-2- fluorobenzoic acid (5.0 g, 21.46 mmol, 1.00 eq) in MeOH (10 mL) was added SOCl2(3.11 mL, 42.91 mmol, 2.00 eq) carefully. Then the mixture was heated to 75oC for 12h. The mixture was concentrated to residue, which was purified by column chromatography (5% ethyl acetate in petroleum ether, then 5% methanol in dichloromethane) to recover 3- bromo-2-fluoro-6-methyl-benzoic acid (2.0 g) as a white solid.3-bromo-2-fluoro-6-methyl- benzoic acid (1.2 g, 5.15 mmol, 1.00 eq) was dissolved in DMF (10 mL), followed by addition of Cs2CO3 (2.52 g, 7.72 mmol, 1.50 eq), then MeI (0.38 mL, 6.18 mmol, 1.20 eq) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at 25oC for 16h under N2 atmosphere. After that, the mixture was poured to water (10 mL), extracted with ethyl acetate (10 mL × 2), the combined organic phase was washed with brine (10 mL × 2), dried, filtered and concentrated. The residue was purified by column chromatography (5% ethyl acetate in petroleum ether) to afford the title compound (750mg, 59% yield) as a white solid. LCMS (ESI): m / z 249.0 (M+H)+.1H NMR (400MHz, MeOD-d4) δ 7.60 - 7.56 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 2.32 (s, 3H).

[0414] Step 4: Preparation of methyl 3-bromo-6-(bromomethyl)-2-fluoro-benzoate

[0415] To a mixture of methyl 3-bromo-2-fluoro-6-methyl-benzoate (750.0 mg, 3.04mmol, 1.00 eq), 1-bromo-2,5-pyrrolidinedione (594.32 mg, 3.34 mmol, 1.10 eq) in DCE (10 mL) was added 2,2'-azobis(2-methylpropionitrile) (49.85 mg, 0.30 mmol, 0.10 eq) at 25 °C. Then the reaction mixture was stirred at 90oC for 16 h under N2atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by column chromatography (2% ethyl acetate in petroleum ether) to afford the title compound (950 mg, 2.91 mmol, 96% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 6.8, 8.4 Hz, 1H), 7.12 (dd, J = 1.2, 8.4 Hz, 1H), 4.60 (s, 2H), 4.01 (s, 3H).

[0416] Step 5: Preparation of 3-(6-bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0417] To a solution of methyl 3-bromo-6-(bromomethyl)-2-fluoro-benzoate (950.0 mg, 2.91mmol, 1.00 eq) in MeCN (10 mL) was added 3-aminopiperidine-2,6-dione hydrochloride salt (576 mg, 3.5 mmol, 1.20 eq) and DIEA (2.89 mL, 17.49 mmol, 6.00 eq) at 25oC. The mixture was stirred at 80oC for 20 hours. After cooling to room temperature, the mixture was concentrated. The residue was taken up in 1M HCl solution (10 mL) and EtOAc (10 mL). The mixture was filtered and the filter cake was washed with water (10 mL × 2) to afford the title compound (690 mg, 2.02 mmol, 69% yield) as a blue solid. LCMS (ESI): m / z 341.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.01 - 7.88 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 4.8, 13.2 Hz, 1H), 4.51 - 4.30 (m, 2H), 2.95-2.84 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.09 - 1.97 (m, 1H).

[0418] Step 6: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindoline-5-carbonitrile

[0419] To a solution of 3-(6-bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6- dione (400.0 mg, 1.17 mmol, 1.00 eq) in DMF (5mL) was added Pd(PPh3)2Cl2(135.5 mg, 0.12 mmol, 0.10 eq) and Zn(CN)2 (300.0 mg, 2.56 mmol, 2.18 eq) at 25oC. The mixture was stirred at 100oC for 3 h under N2 atmosphere. The resulting solution was filtered through diatomite, cooled to room temperature, filtered and the filter cake was washed with ethyl acetate (10 mL × 2) and MeOH (10 mL × 2). The combined organic layer was concentrated to residue, which was triturated with ethyl acetate (10 mL). Solid was filtered and washed with water (5 mL × 2) to give the title compound (260 mg, 77% yield) as a grey solid. LCMS (ESI): m / z 288.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.16 (dd, J = 6.0, 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.65 - 4.43 (m, 2H), 2.95 - 2.85 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.09 - 1.97 (m, 1H).

[0420] Step 7: Preparation of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0421] A mixture of PdCl2 (200.0 mg, 1.13 mmol, 1.2 eq) and 2-(2,6-dioxo-3- piperidyl)-4-fluoro-3-oxo-isoindoline-5-carbonitrile (260.0 mg, 0.91 mmol, 1.00 eq) in MeOH (20 mL) was stirred at 20oC for 5 h under H2atmosphere (15 psi). The mixture was filtered through diatomite and the filtrate was concentrated under reduced pressure to afford the title compound (100 mg, 32% yield) as a white solid. LCMS (ESI): m / z 583.3 (2M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.53 - 8.33 (m, 2H), 7.80 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.55 - 4.33 (m, 2H), 4.15 (br s, 2H), 2.97 - 2.85 (m, 1H), 2.68 - 2.58 (m, 1H), 2.42 - 2.31 (m, 1H), 2.06 - 1.97 (m, 1H).

[0422] Step 8: Preparation of (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2- yl)methyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-3-oxo-isoindolin-5-yl]methyl]carbamate

[0423] To a solution of (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2- yl)methanol (100.0 mg, 0.51 mmol, 1.00 eq) in DCM (5 mL) was added 4- nitrophenylchloroformate (123 mg, 0.61 mmol, 1.20 eq) and DIEA (0.34 mL, 2.03 mmol, 4.00 eq). After stirring at 25oC for 2 h, the reaction mixture was concentrated. The residue was taken up in ethyl acetate (10 mL), washed with brine (5 mL × 2). The organic phase was concentrated to afford (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2- yl)methyl (4-nitrophenyl) carbonate (150 mg, crude) as yellow oil, which was taken up with DMF (5 mL). To this solution (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2- yl)methyl (4-nitrophenyl) carbonate (199 mg, 0.55 mmol, 1.20 eq) and Et3N (0.32 mL, 2.29 mmol, 5.00 eq) were added. The resulting reaction mixture was stirred at 20oC for 16 h. After that, the mixture was purified by pre-HPLC (Column: Xtimate C18 150*40mm*10um; water (FA)-ACN; ACN: 7-37%) to afford the title compound (106 mg, 0.20 mmol, 45% yield) as a white solid. LCMS (ESI): m / z 515.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.06 (t, J = 5.6 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.49 - 4.25 (m, 4H), 2.97 - 2.85 (m, 1H), 2.70 - 2.55(m, 3H), 2.53 (s, 2H), 2.44 - 2.31 (m, 1H), 2.04 - 1.95 (m, 1H), 1.57 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H).

[0424] Example 20

[0425] Preparation of (7-fluorobenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 36)

[0426] Step 1: Preparation of 7-fluorobenzo[d]thiazole-2-thiol

[0427] To a solution of 2,3-difluoroaniline (10.0 g, 77.45 mmol, 1.0 eq) in DMF (100 mL) was added potassium O-ethyl carbonodithioate (14.9 g, 92.94 mmol, 1.2 eq) at 25 °C. The mixture was stirred at 120 °C for 3 hrs. After cooling to room temperature, water (100 mL) was added to precipitate the title compound (28 g, 98% yield) as off-white power.1H NMR (400MHz, DMSO-d6) δ 7.48 - 7.42 (m, 1H), 7.23 - 7.12 (m, 2H).

[0428] Step 2: Preparation of 2-bromo-7-fluorobenzo[d]thiazole

[0429] To a solution of 7-fluoro-1,3-benzothiazole-2-thiol (10 g, 53.98 mmol, 1.0 eq) in CHCl3 (100 mL) was added bromine (32 mL, 589.14 mmol, 11 eq) was added at 0oC. The mixture was stirred at 0oC for 0.5 hr. Then it was added slowly to water (100 mL) and stirred for further 20 min. The mixture was filtered to remove a cream solid. The organic phase was separated, dried and evaporated to leave a brown solid. The brown solid was dissolved in ether and filtered. The residue was washed with ether and the filtrate and washings were combined and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to afford the title compound (4 g, 32% yield) as a yellow solid.

[0430] Step 3: Preparation of (7-fluorobenzo[d]thiazol-2-yl)methanol

[0431] To a mixture of 2-bromo-7-fluorobenzo[d]thiazole (2.0 g, 8.62 mmol, 1.0 eq), CuI (329 mg, 1.72 mmol, 0.2 eq) in 1,4-dioxane (20 mL) was added Pd(PPh3)4(797 mg, 0.69 mmol, 0.08 eq) and tributylstannylmethanol (3.1 g, 9.48 mmol, 1.1 eq), the mixture was stirred at 100 °C for 16 hrs under N2. After that, the mixture was quenched by KF solution (50 mL). The mixture was extracted with DCM (40 mL × 3), washed with water (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate =100 / 1 to 2 / 1) to afford the title compound (300 mg, 19% yield) as a white solid.1H NMR (400MHz, DMSO-d6) δ 7.82 (d, J = 8.0 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.38 - 7.28 (m, 1H), 6.45 (t, J = 6.0 Hz, 1H), 4.93 - 4.86 (m, 2H).

[0432] Step 4: Preparation of (7-fluorobenzo[d]thiazol-2-yl)methyl (4-nitrophenyl) carbonate

[0433] To a solution of (7-fluorobenzo[d]thiazol-2-yl)methanol (100 mg, 0.56 mmol, 1.0 eq) in DCM (2 mL) was added pyridine (0.14 mL, 1.67 mmol, 3.0 eq) and DMAP (14 mg, 0.11 mmol, 0.2 eq), then 4-nitrophenyl carbonochloridate (147 mg, 0.73 mmol, 1.3 eq) was added. The resulting mixture was stirred at 25 °C for 2 hrs. After that, the mixture was concentrated to afford the title compound (190 mg, crude) as a yellow solid. It was directly used in the next step without further purification.

[0434] Step 5: Preparation of (7-fluorobenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0435] To a mixture of (7-fluorobenzo[d]thiazol-2-yl)methyl (4-nitrophenyl) carbonate (190 mg, 0.55 mmol, 1.0 eq) in DMF (2 mL) was added 3-(6-(aminomethyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (169 mg, 0.55 mmol, 1.0 eq) and Et3N (0.23 mL, 1.64 mmol, 3.0 eq), the mixture was stirred at 40oC for 16 hrs. After that, the mixture was purified by pre-HPLC (Welch Xtimate C18150*30mm*5um, water (FA)- CAN, 38-68%) to afford the title compound (42.2 mg, 16% yield) as a yellow solid. LCMS (ESI): m / z 482.9 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 8.32 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.61 - 7.53 (m, 3H), 7.38 (t, J = 8.8 Hz, 1H), 5.50 (s, 2H), 5.11 (dd, J = 13.6, 5.2 Hz, 1H), 4.47 - 4.36 (m, 2H), 4.36 - 4.27 (m, 2H), 2.95 - 2.87 (m, 1H), 2.62 (s, 1H), 2.45 - 2.35 (m, 1H), 2.05 - 1.95 (m, 1H).

[0436] Example 21

[0437] Preparation of (7-methylbenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 37)

[0438] Step 1: Preparation of (7-chlorobenzo[d]thiazol-2-yl)methanol

[0439] To a mixture of 2-bromo-7-chlorobenzo[d]thiazole (2 g, 8.05 mmol, 1.0 eq), CuI (307 mg, 1.61 mmol, 0.2 eq) in 1,4-dioxane (30 mL) was added tributylstannylmethanol (2.8 g, 8.85 mmol, 1.1 eq) and Pd(PPh3)4 (744 mg, 0.64 mmol, 0.08 eq), the mixture was stirred at 100°C for 16 hrs under N2 atmosphere. After that, the mixture was quenched by addition of KF soluton (50 mL). The mixture was extracted with DCM (30 mL × 3), washed with water, dried with anhydrous Na2SO4, flitered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to afford the title compound (340 mg, 21% yield) as a white solid.1H NMR (400MHz, DMSO-d6) δ 7.95 - 7.91 (m, 1H), 7.59 - 7.53 (m, 2H), 6.42 (t, J = 6.0 Hz, 1H), 4.88 (d, J = 5.6 Hz, 2H).

[0440] Step 2: Preparation of (7-methylbenzo[d]thiazol-2-yl)methanol

[0441] To a solution of (7-chlorobenzo[d]thiazol-2-yl)methanol (100 mg, 0.50 mmol, 1.0 eq), trimethylboroxine (0.42 mL, 1.5 mmol, 3.0 eq), K3PO4(319 mg, 1.5 mmol,3.0 eq) in 1,4-dioxane (3 mL) was added Xphos (48 mg, 0.10 mmol, 0.2 eq) and Pd2(dba)3(46 mg, 0.05 mmol, 0.1 eq). The resulting reaction mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. After cooling to room temperature, the mixture was concentrated, purified by pre-TLC (10% MeOH in DCM) to afford the title compound (50 mg, 56% yield) as a white solid. LCMS (ESI): m / z 180.1 (M+H)+.

[0442] Step 3: Preparation of (7-methylbenzo[d]thiazol-2-yl)methyl (4- nitrophenyl) carbonate

[0443] To a solution of (7-methylbenzo[d]thiazol-2-yl)methanol (50 mg, 0.28 mmol, 1.0 eq) in DCM (2 mL) was added pyridine (0.07 mL, 0.84 mmol, 3.0 eq), 4- nitrophenyl carbonochloridate (74 mg, 0.36 mmol, 1.3 eq) and DMAP (7 mg, 0.06 mmol, 0.2 eq), then the mixture was stirred at 25 °C for 2 hrs. After that, the mixture was concentrated to afford the title compound (90 mg, crude) as a yellow solid. The crude product was directly used in the next step without further purification.

[0444] Step 4: Preparation of (7-methylbenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0445] To a mixture of (7-methyl-1,3-benzothiazol-2-yl)methyl (4-nitrophenyl) carbonate (90 mg, 0.26 mmol, 1.0 eq) in DMF (2 mL) was added 3-(6-(aminomethyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (81 mg, 0.26 mmol, 1.0 eq) and Et3N (0.11 mL, 0.78 mmol, 3.0 eq), the mixture was stirred at 40 °C for 16 hrs. After that, the mixture was purified by pre-HPLC (Welch Xtimate C18150*30mm*5um, water (FA)- CAN, 38-68%) to afford the title compound (42.6 mg, 34% yield) as a white solid. LCMS (ESI): m / z 478.9 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 11.00 (s, 1H), 8.30 - 8.28 (m, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.56 (s, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.29 (d, J= 7.2 Hz, 1H), 5.47 (s, 2H), 5.15 - 5.07 (m, 1H), 4.46 - 4.27 (m, 4H), 2.92 - 2.88 (m, 1H), 2.62 - 2.57 (m, 1H), 2.53 (s, 3H), 2.39 - 2.37 (m, 1H), 2.02 - 1.98 (m, 1H).

[0446] Example 22

[0447] Preparation of (7-chlorobenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 38)

[0448] Step 1: Preparation of (7-chlorobenzo[d]thiazol-2-yl)methanol

[0449] To a mixture of 2-bromo-7-chlorobenzo[d]thiazole (200 mg, 0.80 mmol, 1.0 eq), CuI (31 mg, 0.16 mmol, 0.2 eq) in 1,4-Dioxane (4 mL) was added tributylstannylmethanol (285 mg, 0.89 mmol, 1.1 eq) and Pd(PPh3)4 (75 mg, 0.06 mmol, 0.08 eq), the mixture was stirred at 100 °C for 16 hrs under N2atmosphere. After that, the mixture was quenched by KF solution (10 mL). The mixture was extracted with DCM (30 mL x3), washed with water, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to afford the title compound (340 mg, 21% yield) as a white solid. LCMS (ESI): m / z 200.1 (M+H)+.

[0450] Step 2: Preparation (7-chlorobenzo[d]thiazol-2-yl)methyl (4-nitrophenyl) carbonate

[0451] To a solution of (7-chloro-1,3-benzothiazol-2-yl)methanol (40 mg, 0.20 mmol, 1.0 eq) in DCM (2 mL) was added pyridine (0.05 mL, 0.60 mmol, 3.0 eq), 4- nitrophenyl carbonochloridate (53 mg, 0.26 mmol, 1.3 eq) and DMAP (5 mg, 0.04 mmol, 0.2 eq), then the mixture was stirred at 25 °C for 2 hrs. After that, the mixture was concentrated to afford the title compound (70 mg, crude) as a yellow solid. The crude product was directly used in the next step without further purification.

[0452] Step 3: Preparation of (7-chlorobenzo[d]thiazol-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0453] To a mixture of (7-chloro-1,3-benzothiazol-2-yl)methyl (4-nitrophenyl) carbonate (70 mg, 0.19 mmol, 1.0 eq) in DMF (1 mL) was added 3-(6-(aminomethyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (60 mg, 0.19 mmol, 1.0 eq) and Et3N (0.1 mL, 0.58 mmol, 3.0 eq), the mixture was stirred at 40 °C for 16hrs. After that, the mixture was purified by pre-HPLC (Welch Xtimate C18150*30mm*5um, water (FA)- CAN, 38-68%) to afford the title compound (13.1 mg, 13% yield) as a yellow solid. LCMS (ESI): m / z 521.0 (M+Na)+. 1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 8.32 (t, J = 6.0 Hz, 1H), 8.01 (dd, J = 6.8, 2.4 Hz, 1H), 7.67 (s, 1H), 7.62 - 7.56 (m, 4H), 5.49 (s, 2H), 5.12 (dd, J = 13.2, 4.8 Hz, 1H), 4.47 - 4.28 (m, 4H), 2.96 - 2.89 (m, 1H), 2.59 - 2.53 (m, 1H), 2.43 - 2.38 (m, 1H), 2.02 - 1.98 (m, 1H).

[0454] Example 23

[0455] Preparation of 3-(1-methyl-1H-indol-7-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 59)

[0456] Step 1: Preparation of 7-bromo-1-methyl-1H-indole

[0457] The 7-bromo-1H-indole (9.0 g, 45.91 mmol, 1.00 eq) and NaH (2.1 g, 52.5 mmol, 1.10 eq) in THF (150 mL). The mixture was stirred at 0 °C for 1 h under N2atmosphere. Then MeI (4 mL, 64.25 mmol, 1.40 eq) was added dropwise. The mixture was stirred at 25 °C for 16 h under N2 atmosphere. After that, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic layer was washed with brine (100 mL ), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0-80% ethyl acetate in petroleum ether) to afford 7-bromo-1-methyl-1H-indole (9.2 g, 95% yield) as white solid.

[0458] Step 2: Preparation of 3-(1-methyl-1H-indol-7-yl)cyclobutan-1-ol

[0459] A mixture of cyclobutane-1,3-diol (147 mg, 1.66 mmol, 1.75 eq), 5,7-ditert- butyl-3-phenyl-1,3-benzoxazol-3-ium;trifluoroborane;fluoride (752 mg, 1.9 mmol, 2 eq) in dioxane (4 mL) was stirred at 20 °C under N2 for 5 min, pyridine (0.12 mL, 1.5 mmol, 1.6 eq) in dioxane (4mL) was added. The resulting reaction mixture was stirred at 20 °C for 10 min under N2. Then the filtrate was added into a mixture of 7-bromo-1-methyl-1H-indole (200 mg, 0.95 mmol, 1 eq), quinuclidine (185.2 mg, 1.66 mmol, 1.75 eq), Ir(ppy)2(dtbbpy)PF6 (13 mg, 0.014 mmol, 0.015 eq) and (Dtpby)NiBr2 (23 mg, 0.047 mmol, 0.05 eq) in DMA (8 mL), the reaction mixture was stirred at 900 rpm stir rate andirradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 2). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by pre-TLC (50% EtOAc in petroleum ether) to afford 3-(1-methyl- 1H-indol-7-yl)cyclobutan-1-ol (80 mg, 42% yield) as yellow oil. LCMS (ESI): m / z 202.0 (M+H)+.

[0460] Step 3: Preparation of 3-(1-methyl-1H-indol-7-yl)cyclobutyl (4-nitrophenyl) carbonate

[0461] To a solution of 3-(1-methyl-1H-indol-7-yl)cyclobutan-1-ol (80 mg,0.39 mmol, 1 eq) in DCM (2 mL) were added DMAP (5 mg, 0.04 mmol, 0.1 eq) and pyridine (0.1 mL, 1.19 mmol, 3 eq). Then 4-nitrophenyl carbonochloridate (96 mg, 0.48 mmol, 1.2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction was diluted with water (5 mL) and extracted with DCM (5 mL × 2). The organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (140 mg, crude) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0462] Step 4: Preparation of 3-(1-methyl-1H-indol-7-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0463] To a mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione;hydrochloride (236 mg, 0.76 mmol, 2 eq), TEA (0.16 mL, 1.15mmol, 3 eq) in DMF (3mL) was added3-(1-methyl-1H-indol-7-yl)cyclobutyl (4-nitrophenyl) carbonate (140.0 mg, 0.38 mmol, 1 eq), and the mixture was stirred at 25 °C for 2h under N2 atmosphere.The TLC ( 50% ethyl acetate in petroleum ether, Rf = 0.3 ) indicated the reaction was completed. The crude was purified by pre-HPLC (acetonitrile 40-70% / / 0.225% FA in water) to afford [3-(1-methylindol-7-yl)cyclobutyl] N-[[2-(2,6-dioxo-3-piperidyl)-3-oxo- isoindolin-5-yl]methyl]carbamate (14.4 mg, 7.5% yield) as white solid. LCMS (ESI): m / z 501.1 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 10.98 (s, 1H), 7.95 - 7.79 (m, 1H), 7.62 (s, 1H), 7.54 (q, J = 7.8 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.15 - 7.03 (m, 1H), 7.01 - 6.92 (m, 1H), 6.37 (d, J = 2.8 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 5.07 - 4.94 (m, 1H), 4.48 - 4.21 (m, 4H), 4.04 - 3.92 (m, 3H), 3.92-3.79 (m, 1H), 2.97 - 2.85 (m, 1H), 2.78 - 2.69 (m, 1H), 2.62 - 2.57 (m, 2H), 2.44 - 2.31 (m, 2H), 2.25 - 2.18 (m, 1H), 2.04- 1.89 (m, 1H).

[0464] Example 24

[0465] Preparation of 3-(benzo[d]thiazol-7-yl)cyclobutyl ((2-(2,6-dioxopiperidin- 3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 60)

[0466] Step 1: Preparation of 3-(benzo[d]thiazol-7-yl)cyclobutan-1-ol

[0467] To a mixture of cyclobutane-1,3-diol (144 mg, 1.63 mmol, 1.75 eq), 5,7- ditert-butyl-3-phenyl-1,3-benzoxazol-3-ium, trifluoroborane, and fluoride (739 mg, 1.87 mmol, 2.0 eq) in 1,4-dioxane (4 mL) was added pyridine (0.12 mL, 1.49 mmol, 1.6 eq), the mixture was stirred at 20 °C under nitrogen for 5 min. Then the solution was added into a mixture of 7-bromobenzo[d]thiazole (200 mg, 0.93 mmol, 1.0 eq), quinuclidine (182 mg,1.63 mmol, 1.75 eq), bis[2-(2-pyridyl)phenyl] iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (13 mg, 0.01 mmol, 0.02 eq) and (Dtpby)NiBr2 (23 mg, 0.05 mmol, 0.05 eq) in DMA (4 mL), the mixture was stirred at 900 rpm stir rate and irradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hrs. After that, the mixture was extracted with EtOAc (40 mL) and washed with brine (10 mL × 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to afford the title compound (60 mg, 31% yield) as a yellow oil. LCMS (ESI): m / z 205.7 (M+H)+.

[0468] Step 2: Preparation of 3-(benzo[d]thiazol-7-yl)cyclobutyl (4-nitrophenyl) carbonate

[0469] To a solution of 3-(benzo[d]thiazol-7-yl)cyclobutan-1-ol (60 mg, 0.29 mmol, 1.0 eq), pyridine (0.1 mL, 0.88 mmol, 3.0 eq) and DMAP (8 mg, 0.06 mmol, 0.2 eq) in DCM (2 mL) was added 4-nitrophenyl carbonochloridate (77 mg, 0.38 mmol, 1.3 eq). The mixture was stirred at 25 °C for 2 hrs. After that, the mixture was concentrated to afford the title compound (108 mg, crude) as a yellow solid. The crude product was directly used in the next step without further purification.

[0470] Step 3: Preparation of 3-(benzo[d]thiazol-7-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0471] To a mixture of 3-(benzo[d]thiazol-7-yl)cyclobutyl (4-nitrophenyl) carbonate (108 mg, 0.29 mmol, 1.0 eq) and 3-(6-(aminomethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (91 mg, 0.29 mmol, 1.0 eq) in DMF (2 mL) was added Et3N (0.12 mL, 0.87 mmol, 3.0 eq), the mixture was stirred at 40 °C for 16 hrs.After that, the mixture was purified by pre-HPLC (Welch Xtimate C18150*30mm*5um, water (FA)-CAN, 38-68%) to afford the title compound (13.6 mg, 10% yield) as a yellow solid. LCMS (ESI): m / z 505.2 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 9.39 (s, 1H), 7.99 - 7.95 (m, 1H), 7.95 - 7.86 (m, 1H), 7.62 - 7.38 (m, 5H), 5.11 (dd, J = 13.2, 5.2 Hz, 1H), 5.07 - 4.93 (m, 1H), 4.46 - 4.26 (m, 4H), 3.89 - 3.81 (m, 1H), 2.94 - 2.86 (m, 2H), 2.65 - 2.59 (m, 2H), 2.58 - 2.56 (m, 1H), 2.41 - 2.38 (m, 1H), 2.22 - 2.18 (m, 1H), 2.03 - 1.97 (m, 1H).

[0472] Example 25

[0473] Preparation of (1s,3s)-3-(Benzo[d]thiazol-4-yl)cyclobutyl((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 61)

[0474] Step 1: Preparation (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol and (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol

[0475] To a mixture of cyclobutane-1,3-diol (90.0 mg, 1.02 mmol, 1.75 eq), NHC (462.0 mg, 1.17 mmol, 2.00 eq) in 1,4-dioxane (4 mL) was stirred at 20oC under N2 for 5 min. Then a pyridine (0.08 mL, 0.94 mmol, 1.60 eq) solution (in 1 mL dioxane) was added dropwise, the mixture was stirred at 20oC for 5 min. Then the solution was added into a mixture of 4-bromobenzo[d]thiazole (0.07 mL, 0.58 mmol, 1.00 eq), quinuclidine (113.0 mg, 1.02 mmol, 1.75 eq), Ir(ppy)2(dtbbpy)PF6(8.0 mg, 0.01 mmol, 0.015eq) and NiBr2.dtbbpy (14.0 mg, 0.03 mmol, 0.05 eq) in DMF (4 mL), the mixture was stirred at 20oC at 900 rpm stir rate and irradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 30 mL), the organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (0 - 50% EtOAc in petroleum ether) to afford (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol (70.0 mg, 37% yield) and (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol (70.0 mg, 37% yield) as colorless oil.

[0476] (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol:1H NMR (400MHz, CDCl3): δ 9.01 (s, 1H), 7.84 (dd, J = 1.6, 7.6 Hz, 1H), 7.43 - 7.37 (m, 2H), 4.45 - 4.38 (m, 1H), 3.79 - 3.71 (m, 1H), 3.05 - 2.93 (m, 2H), 2.35 - 2.29 (m, 2H).

[0477] (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol:1H NMR (400MHz, CDCl3): δ 8.99 (s, 1H), 7.84 (dd, J = 2.0, 6.8 Hz, 1H), 7.48 - 7.39 (m, 2H), 4.71 - 4.57 (m, 1H), 4.48 - 4.40 (m, 1H), 2.73 - 2.64 (m, 2H), 2.63 - 2.54 (m, 2H).

[0478] Step 2: Preparation of (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutyl (4- nitrophenyl) carbonate

[0479] To a mixture of (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol (70.0 mg, 0.34 mmol, 1.00 eq) in DCM (5 mL) was added DMAP (4.0 mg, 0.03 mmol, 0.10 eq) and pyridine (0.08 mL, 1.02 mmol, 3.00 eq). Then 4-nitrophenyl carbonochloridate (82.0 mg, 0.41 mmol, 1.20 eq) was added at 25oC. The mixture was stirred at 25oC for 16 h. The reaction was concentrated to afford the title product (120.0 mg, crude) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0480] Step 3: Preparation of (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0481] To a mixture of (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobutyl(4-nitrophenyl) carbonate (126.0 mg, 0.34 mmol, 1.00 eq), Et3N (0.14 mL, 1.02 mmol, 3.00 eq) in DMF (2 mL) was added 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (210.0 mg, 0.68 mmol, 2.00 eq), the mixture was stirred at 25oC for 16h. The mixture was purified by pre-HPLC (C18150 × 30mm, water (FA)-ACN; 35 / 65) to afford the title product (94.0 mg, 54% yield) as a yellow solid. LCMS (ESI): m / z 505.1 (M+H)+.1H NMR (400MHz, DMSO-d6)δ10.99 (s, 1H), 9.37 (s, 1H), 8.02 (dd, J = 1.6, 6.8 Hz, 1H), 7.86 (t, J = 6.0 Hz, 1H), 7.62 (s, 1H), 7.57 - 7.51 (m, 2H), 7.49 - 7.42 (m, 2H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.48 - 4.24 (m, 4H), 3.89 - 3.76 (m, 1H), 2.97 - 2.86 (m, 1H), 2.85 - 2.76 (m, 2H), 2.61 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H), 2.35 - 2.24 (m, 2H), 2.04 - 1.95 (m, 1H).

[0482] Example 26

[0483] Preparation of (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 62)

[0484] Step 1: Preparation of (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutyl (4- nitrophenyl) carbonate

[0485] To a mixture of (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutan-1-ol (50.0 mg, 0.24 mmol, 1.00 eq) in DCM (5 mL) was added DMAP (3.0 mg, 0.02 mmol, 0.10 eq) and pyridine (0.06 mL, 0.73 mmol, 3.00 eq). Then 4-nitrophenyl carbonochloridate (59.0 mg, 0.29 mmol, 1.05 eq) was added at 25oC. The mixture was stirred at 25oC for 16 h. The reaction was concentrated to afford the title product (90.0 mg, 99%, yield) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0486] Step 2: Preparation of (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0487] To a mixture of (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobutyl (4-nitrophenyl) carbonate (90.0 mg, 0.24 mmol, 1.00 eq), Et3N (0.10 mL, 0.73 mmol, 3.00 eq) in DMF (1 mL) was added 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (150.0 mg, 0.49 mmol, 2.00 eq), the mixture was stirred at 25oC for 16h. The mixture was purified by pre-HPLC (C18150×30mm, water (FA)-ACN; 35 / 65) to afford the title product (22.0 mg, 18%, yield) as a yellow solid. LCMS (ESI): m / z 505.1 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 9.36 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.63 (s, 1H), 7.59 - 7.50 (m, 3H), 7.48 - 7.45 (m, 1H), 5.14 - 5.09 (m, 2H), 4.48 - 4.41 (m, 1H), 4.38 - 4.29 (m, 1H), 4.34 - 4.28 (m, 3H), 2.97 - 2.86 (m, 1H), 2.60 - 2.58 (m, 5H), 2.44 - 2.36 (m, 1H), 2.05 - 1.94 (m, 1H).

[0488] Example 27

[0489] Preparation of 3-(2,6-difluorophenyl)cyclobutyl ((2-(2,6-dioxopiperidin-3- yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 63)

[0490] Step 1: Preparation of 3-(2,6-difluorophenyl)cyclobutan-1-ol

[0491] A solution of 5,7-ditert-butyl-3-phenyl-1,3-benzoxazol-3- ium;trifluoroborane;fluoride (819.19 mg, 2.07 mmol, 2 eq) and cyclobutane-1,3-diol (159.79 mg, 1.81 mmol, 1.75 eq) in 1,4-dioxane (4 mL) was stirred at 25oC for 5 min in glove box. Then pyridine (0.13 mL, 1.66 mmol, 1.6 eq) in 1,4-dioxane (4 mL) was added to the above solution, the resulting mixture was stirred at 25oC for 10 min. After filtration, the filtrate was added into the mixture of 2-bromo-1,3-difluoro-benzene (200.0 mg, 1.04 mmol, 1 eq), quinuclidine (201.63 mg, 1.81 mmol, 1.75 eq), bis[2-(2- pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (14.21 mg, 0.02 mmol, 0.015 eq) and (Dtpby)NiBr2(25.23 mg, 0.05 mmol, 0.05 eq) in DMA (8 mL) in glove box. Then the mixture was stirred at 900 rpm stir rate and irradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hrs. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The organics were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (30% ethyl acetate in petroleum ether, Rf = 0.5) to afford the title compound (20 mg, 9.4% yield) as a yellow oil.1H NMR (400MHz, CDCl3) δ 7.16 - 7.09 (m, 1H), 6.86 - 6.79 (m, 2H), 4.70 - 4.67 (m, 0.4H), 4.28 - 4.22 (m, 0.6H), 4.08 - 4.04 (m, 0.4H), 3.16 - 3.14 (m, 0.6H), 2.83 - 2.73 (m, 2H), 2.47 - 2.31 (m, 2H).

[0492] Step 2: Preparation of 3-(2,6-difluorophenyl)cyclobutyl (4-nitrophenyl) carbonate

[0493] To a solution of 3-(2,6-difluorophenyl)cyclobutanol (20.0 mg, 0.11 mmol, 1.00 eq) in DCM (2 mL) was added 4-dimethylaminopyridine (1.33 mg, 0.01 mmol, 0.1 eq) and pyridine (0.03 mL, 0.33 mmol, 3.00 eq). Then 4-nitrophenyl carbonochloridate (26.26 mg, 0.13 mmol, 1.20 eq) was added at 0 ℃. The mixture was stirred at 25oC for 4 h. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL × 3). The organics were washed with brine (10 mL × 3), dried over sodium sulfate, filtered and the filtrate was concentrated to afford the crude title compound (30 mg, crude) as a yellow oil. The crude product would be directly used in the next step without further purification.

[0494] Step 3: Preparation of 3-(2,6-difluorophenyl)cyclobutyl ((2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0495] To a solution of 4-nitrophenyl [3-(2,6-difluorophenyl)cyclobutyl] (4- nitrophenyl) carbonate (30.0 mg, 0.09 mmol, 1.00 eq) in DMF (2 mL) was added Et3N (0.04 mL, 0.26 mmol, 3.00 eq) and 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione;hydrochloride (53.2 mg, 0.17 mmol, 2.00 eq) at 25oC. Then the solution was stirred at 25oC for 16 hrs. The reaction mixture was purified by prep-HPLC (Welch Xtimate C18150*30mm*5um / water(FA)-CAN, 36-66%) to afford the title compound (11.8 mg, 28%)as a white solid. LCMS (ESI): m / z 484.1 (M+H)+.1H NMR (400MHz, CDCl3) δ 10.98 (s, 1H), 7.92 - 7.85 (m, 1H), 7.62 - 7.60 (m, 1H), 7.56 - 7.50 (m, 2H), 7.32 - 7.29 (m, 1H), 7.07 - 7.02 (m, 2H), 5.13 - 5.09 (m, 1H), 4.90 - 4.87 (m, 1H), 4.45 - 4.41 (m, 1H), 4.32 - 4.26 (m, 3H), 3.96 - 3.94 (m, 1H), 2.94 - 2.86 (m, 1H), 2.76 - 2.58 (m, 4H), 2.42 - 2.33 (m, 2H), 2.01 - 1.99 (m, 1H).

[0496] Example 28

[0497] Preparation of 3-(1H-indol-7-yl)cyclobutyl ((2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)methyl)carbamate (Compound 64)

[0498] Step 1: Preparation of 7-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H- indole

[0499] To a mixture of 3-[tert-butyl(dimethyl)silyl]oxycyclobutanol (774.22 mg, 3.83 mmol, 1.50 eq), 5,7-ditert-butyl-3-phenyl-1,3-benzoxazol-3- ium;trifluoroborane;fluoride (2016.12 mg, 5.1 mmol, 2 eq) in 1,4-dioxane (10 mL) was added pyridine (0.33 mL, 4.08 mmol, 1.60 eq), the mixture was stirred at 20oC under N2for 5 min. Then the solution was added into a mixture of 7-bromo-1H-indole (500.0 mg, 2.55 mmol, 1.00 eq), quinuclidine (496.24 mg, 4.46 mmol, 1.75 eq), bis[2-(2- pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (34.97 mg, 0.04 mmol, 0.015 eq) and (Dtpby)NiBr2(62.09 mg, 0.13 mmol, 0.05 eq) in DMA (10 mL), the resulting mixture was stirred at 900 rpm stir rate and irradiated under 450 nm blue LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 h. After that, the reaction mixture was poured into ice-water (25 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (100 mL × 5), dried with Na2SO4, concentrated to give crude product, which was purified by column chromatography (0-2% EtOAc in petroleum ether) to afford the title compound (760 mg, crude) as an off-yellow oil. The crude product would be directly used in the next step without further purification.

[0500] Step 2: Preparation of 3-(1H-indol-7-yl)cyclobutan-1-ol

[0501] To a solution of tert-butyl-[3-(1H-indol-4-yl)cyclobutoxy]-dimethyl-silane (760 mg, 2.52 mmol, 1 eq) in THF (2 mL) was added TBAF (2.77 mL, 2.77 mmol, 1.10 eq). The resulting solution was stirred at 20oC for 0.5 h. After that, the reaction mixture was concentrated. The residue was purified by column chromatography (0-2% MeOH in DCM ) to afford the title compound (120 mg, 25%) as an off-yellow oil.

[0502] Step 3: Preparation of 3-(1H-indol-7-yl)cyclobutyl (4-nitrophenyl) carbonate

[0503] To a solution of 4-nitrophenylchloroformate (129.18 mg, 0.64 mmol, 1.20 eq) in DCM (4 mL) was added pyridine (0.13 mL, 1.6 mmol, 3.00 eq), 3-(1H-indol-7- yl)cyclobutanol (100.0 mg, 0.53 mmol, 1.00 eq) and DMAP (6.52 mg, 0.05 mmol, 0.10 eq). The mixture was stirred at 25oC for 16h. After that, the reaction mixture was concentrated to give crude product, which was purified by column chromatography on silica gel (0-5% EtOAc in petroleum ether) to afford the title compound (25.5 mg, 11%) as an off-yellow solid. LCMS (ESI): m / z 352.9 (M+H)+.

[0504] Step 4: Preparation of 3-(1H-indol-7-yl)cyclobutyl ((2-(2,6-dioxopiperidin- 3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0505] To a mixture of [3-(1H-indol-7-yl)cyclobutyl] (4-nitrophenyl) carbonate (60.0 mg, 0.17 mmol, 1 eq) and Et3N (0.07 mL, 0.51 mmol, 3 eq) in DMF (3 mL) was added 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (55.85 mg, 0.2 mmol, 1.2 eq). The mixture was stirred at 25oC for 16 h under nitrogen atmosphere. After that, the reaction mixture was purified by pre-HPLC ((Gilson 281(Boston Green ODS) C18150*30mm*3um, water (0.225% FA)-ACN, 40-70%) to afford the title compound (25.5 mg, 30% yield) as a white solid. LCMS (ESI): m / z 487.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.90 (s, 1H), 7.86 (t, J = 6.4 Hz, 1H), 7.62 (s, 1H), 7.58 - 7.50 (m, 2H), 7.39 (dd, J = 3.2, 5.6 Hz, 1H), 7.29 (t, J = 2.8 Hz, 1H), 7.01 - 6.93 (m, 2H), 6.42 (dd, J = 1.6, 2.8 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.96 (t, J = 7.2 Hz, 1H), 4.48 - 4.24 (m, 4H), 3.49 - 3.40 (m, 1H), 2.97 - 2.84 (m, 3H), 2.62 - 2.57 (m, 1H), 2.46 - 2.36 (m, 1H), 2.17 - 2.04 (m, 2H), 2.03 - 1.96 (m, 1H).

[0506] Example 29

[0507] Preparation of 3-(6-(aminomethyl)-4-chloro-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (INT2)

[0508] Step 1: Preparation of 3-chloro-5-iodo-2-methylbenzoic acid

[0509] To a solution of methyl 3-chloro-2-methylbenzoate (2.0 g, 10.83 mmol, 1 eq) in H2SO4(15 mL) was added NIS (2.44 g, 10.83 mmol, 1 eq). The reaction was stirred at 25 °C for 16 h. The reaction was added ice water (30 mL) and extracted with ethyl acetate (30 mL × 3) and the organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to afford the title compound (2.8 g, 87.2% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 2.65 (s, 3H).

[0510] Step 2: Preparation of methyl 3-chloro-5-iodo-2-methylbenzoate

[0511] To the mixture of 3-chloro-5-iodo-2-methylbenzoic acid (2.8 g, 9.44 mmol, 1 eq) in MeOH (20 mL) was added SOCl2 (1.37 mL, 18.89 mmol, 2 eq). The mixture was stirred at 80oC for 16 hrs. The mixture was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to afford the title compound (2 g, 6.44 mmol, 68.2% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 3.83 (s, 3H), 2.47 (s, 3H).

[0512] Step 3: Preparation of methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate

[0513] Step 4: Preparation of 3-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0514] To a solution of methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (4.0 g, 10.27 mmol, 1 eq), 3-aminopiperidine-2,6-dione; hydrochloride (2.2 g, 13.35 mmol, 1.3 eq) in ACN (50 mL) at 25oC was added DIEA (5.37 mL, 30.82 mmol, 3 eq). The reaction mixture was stirred at 90oC for 16 hrs. The reaction was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (20 mL) and triturated with water (20 mL) to afford the title compound (3.7 g, 9.15 mmol, 89% yield) as purple solid. LCMS (ESI): m / z 405.0 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 11.03 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 5.19 - 5.10 (m, 1H), 4.47 - 4.45 (m, 1H), 4.33 - 4.25 (m, 1H), 2.92 (s, 1H), 2.63 -2.60 (m, 1H), 2.48-2.43 (m, 1H), 2.06 - 1.97 (m, 1H).

[0515] Step 5: Preparation of tert-butyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)methyl)carbamate

[0516] Under N2, a mixture of 3-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (2.0 g, 4.94 mmol, 1 eq), Catacxium A Pd G3 (330 mg, 0.49 mmol, 0.1 eq), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.41 g, 5.93 mmol, 1.2 eq) and Cs2CO3 (4.83 g, 14.83 mmol, 3 eq) in 1,4-Dioxane (24 mL) and Water (2.4 mL) was heated at 100oC for 1 h under microwave. The organic layer was concentrated under vacuum. The mixture was puiping by ethyl acetate (5 mL) and water (5 mL), and then after filtration, to afford the title compound (1.5 g, 3.68 mmol, 74.4% yield) as a gray solid. LCMS (ESI): m / z 460.2 (M+H)+.

[0517] Step 6: Preparation of 3-(6-(aminomethyl)-4-chloro-1-oxoisoindolin-2- yl)piperidine-2,6-dione;hydrochloride

[0518] To a mixture of tert-butyl N-[[7-chloro-2-(2,6-dioxo-3-piperidyl)-3-oxo- isoindolin-5-yl]methyl]carbamate (1.5 g, 3.68 mmol, 1 eq) in DCM (5 mL) was added 4 M HCl in 1,4-Dioxane (5 mL). The reaction mixture was stirred 25 oC for 4 h. The mixture was concentrated under vacuum to afford the title compound (1 g, 2.91 mmol, 79% yield) as yellow solid. LCMS (ESI): m / z 444.2 (M+H)+.

[0519] Example 30

[0520] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-3-oxoisoindolin-5-yl)methyl)carbamate (INT3)

[0521] Step 1: Preparation of 3-bromo-2-hydroxy-6-methylbenzaldehyde

[0522] To a solution of 2-bromo-5-methylphenol (20.0 g, 106.84 mmol, 1 eq) and TEA (59.62 mL, 427.74 mmol, 4 eq) in acetonitrile (400mL) was added MgCl2 (7.64 g, 80.2 mmol) and the mixture was stirred at 20 °C for 15 min. Methanol (30.32 mL, 748.54 mmol, 7 eq) was added and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cool to 25 °C and slowly pour to 600 mL 3M HCl solution and the mixture was stirred at for 15 min. The mixture was extracted with ethyl acetate (3 × 200 mL), dried over Na2SO4and concentrated. The residue was purified by flash column (0-2% ethyl acetate in petroleum ether) to obtain the title compound (7.2 g, 62.6% yield) as a yellow oil.

[0523] Step 2: Preparation of 3-bromo-2-methoxy-6-methylbenzaldehyde

[0524] To a solution of 3-bromo-2-hydroxy-6-methylbenzaldehyde (14.4 g, 66.96 mmol, 1 eq) in DMF (150 mL) was added K2CO3 (18.51 g, 133.93 mmol, 2 eq) and iodomethane (4.38 mL, 70.31 mmol, 1 eq) at 0 °C. The reaction was stirred at 25oC for 1 h. The mixture was filter and the cake was washed with ethyl acetate (100 mL) and the mixture was concentrated. The residue was diluted with ethyl acetate (100 mL) andwashed with brine (2 × 60 mL), dried over Na2SO4and concentrated. The residue was purified by flash column (100% petroleum ether) to afford the title compound (14 g, 91.3% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 2.55 (s, 3H).

[0525] Step 3: Preparation of 3-bromo-2-methoxy-6-methylbenzoic acid

[0526] To a solution of 3-bromo-2-methoxy-6-methylbenzaldehyde (14 g, 61.12 mmol, 1 eq) in THF (110 mL), water (55 mL) and butan-1-ol (27.5 mL) was added NaH2PO4 (14.67 g, 122.23 mmol) and NaClO2 (22.1 g, 244.46 mmol, 4 eq) at 0 °C. The mixture was stirred at 25oC for 1h. 2-methylbut-2-ene (30 g, 427.82 mmol, 7 eq) was added and the mixture was stirred at 25oC for 30 min. The reaction mixture was poured into water (200 mL) and adjust pH = 9-10 with 1M NaOH solution. The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The aqueous phase was adjust pH = 5-6 with 1M HCl solution. The aqueous phase was extracted with ethyl acetate (3 x 150 mL). The combined organic lay was dried over Na2SO4 and concentrated. The residue was purified by flash column (10-25% ethyl acetate in petroleum ether) to afford the title compound (10.2 g, 68.1% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 7.57 (d, J =8.0 Hz, 1H), 7.00 (d, J =8.4 Hz, 1H), 3.78 (s, 3H), 2.23 (s, 3H).

[0527] Step 4: Preparation of methyl 3-bromo-2-methoxy-6-methylbenzoate

[0528] To a solution of 3-bromo-2-methoxy-6-methylbenzoic acid (6.2 g, 25.3 mmol, 1 eq) and K2CO3 (6.99 g, 50.6 mmol, 2 eq) in DMF (62 mL) was added iodomethane (1.57 mL, 25.3 mmol, 1 eq) at 0 °C. The reaction was stirred at 25oC for 1 h. The mixture was filtered and the cake was washed with ethyl acetate (200 mL). The filter was concentrated and the residue was diluted with water (50 mL) and extracted with ethyl acetate (3 × 70 mL). The combined organic layer was washed with brine (4 × 70 mL), dried over Na2SO4and concentrated. The residue was purified by flash column (0-1% ethylacetate in petroleum ether) to afford the title compound (5.85 g, 89% yield) as a light- yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 2.19 (s, 3H).

[0529] Step 5: Preparation of methyl 3-bromo-6-(bromomethyl)-2- methoxybenzoate

[0530] To a solution of methyl 3-bromo-2-methoxy-6-methylbenzoate (5.85 g, 22.58 mmol, 1 eq) in 1,2-dichloroethane (60 mL) was added AIBN (1.09 g, 4.52 mmol, 0.2 eq) and NBS (4.42 g, 24.84 mmol, 1.1 eq) at 25 °C. The mixture was stirred at 90oC under N2(15 psi) for 2 h. The mixture was concentrated and the residue was purified by flash column (100% petroleum ether) to afford the title compound (7 g, 91.7% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.48 (s, 2H), 4.00 (s, 3H), 3.92 (s, 3H).

[0531] Step 6: Preparation of 3-(6-bromo-7-methoxy-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0532] To a solution of methyl 3-bromo-6-(bromomethyl)-2-methoxybenzoate (7.0 g, 20.71 mmol, 1 eq) in acetonitrile (80 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (4.09 g, 24.85 mmol, 1.2 eq) and DIEA (10.82 mL, 62.13 mmol, 3 eq). The reaction mixture was stirred at 90oC under N2(15 psi) for 16h. The reaction mixture was concentrated and the residue was purified by flash column (0-100% (ethanol : ethyl acetate = 1: 3) in petroelum ether, then 10-20% dichloromethane in methanol) to give a crude. The crude was diluted with water (30 mL) and ethyl acetate (60 mL) and stirred for 20 min. After filtered, the cake was washed with ethyl acetate (50 mL) and the cake was concentrated to afford the title compound (3.2 g, 43.7% yield) as a light brown solid. LCMS (ESI): m / z 353.0, 355.0 [M + H]+.

[0533] Step 7: tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxoisoindolin- 5-yl)methyl)carbamate

[0534] A mixture of 3-(6-bromo-7-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6- dione (500.0 mg, 1.42 mmol, 1 eq), Cs2CO3 (922.56 mg, 2.83 mmol, 2 eq) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (671.26 mg, 2.83 mmol, 2 eq) in 1,4- Dioxane (8 mL) and Water (0.8 mL) was added cataCXium A Pd G3(95 mg, 0.14 mmol, 0.1 eq). Then the resulting mixture was microwaved at 100oC for 1 h under nitrogen atmosphere. The solution was diluted with water (5 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuo, the residue was purified by column chromatography (10 - 50%(ethyl acetate: ethanol = 3:1) in petroleum ether) to give the title compound (530 mg, 92% yield) as yellow solid. LCMS (ESI): m / z 426.0 [M + H]+.

[0535] Step 8: 3-(6-(aminomethyl)-7-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6- dione

[0536] To a solution of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3- oxoisoindolin-5-yl)methyl)carbamate (100.0 mg, 0.25 mmol) in DCM (4.5 mL) was added BBr3(0.12mL, 1.24mmol) added at 0oC and the mixture was stirred at 0oC for 0.5 h. The mixture was diluted with dichloromethane (15 mL) and the mixture was slowly added to water (10 mL). After separated, the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The aqueous phase was freeze-dried to afford the crude title compound (65 mg, 90% yield) as a white solid. LCMS (ESI): m / z 290.1 [M + H]+.

[0537] Example 31

[0538] Preparation of tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclobutoxy)silane (Int4)

[0539] Step 1: Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclobutan-1-ol

[0540] To a solution of LDA(2M in THF) in THF (200 mL) was added bis(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methane (21.13g, 78.84 mmol) in THF (100 mL) at 0oC. The mixture was stirred at 0oC for 1 h. Then 2-(chloromethyl)oxirane (5.62 mL, 65.7 mmol) in THF (100 mL)was added at 0℃, and the resulting mixture was stirred at 25oC for 1h. Then the CuCl (1.30 g, 13.14 mmol) was added, the mixture was stirred at 60℃ for 16 hours under nitrogen atmosphere. The mixture was quenched with NH4Cl solution, then extracted with ethyl acetate (300 ml × 2), washed with brine (200 mL), dried with Na2SO4, filtrated and concentrated under vacuum. The crude was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 20%) to afford the title compound (19 g, 95.93 mmol) as yellow oil.1H NMR (400 MHz, DMSO- d6) δ 5.00 - 4.94 (m, 1H), 4.07 - 3.96 (m, 1H), 2.19 - 2.08 (m, 2H), 1.96 - 1.86 (m, 1H), 1.79 - 1.64 (m, 2H), 1.17 (s, 12H).

[0541] Step 2: Preparation of tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclobutoxy)silane(INT5)

[0542] To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclobutan- 1-ol (10.0 g, 50.49 mmol) in Dichloromethane (120 mL) was added imidazole (6.87 g, 100.97 mmol), DMAP (1.23 g, 10.10 mmol) and tert-butylchlorodimethylsilane (9.13 g, 60.58 mmol) at 0oC, then the mixture was stirred at 25oC for 16 hours. The reaction crude was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 10%) to afford the title compound (9.50 g, 60 % yield). as colorless oil.1H NMR (400 MHz, CDCl3) δ 4.33 - 4.12 (m, 1H), 2.36 - 2.22 (m, 2H), 2.27 - 2.14 (m, 1H), 2.12 - 1.82 (m, 2H), 1.27 (s, 12H), 0.91 (s, 9H), 0.00 - 0.07 (s, 6H).

[0543] Example 32

[0544] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (Int5)

[0545] Step 1: Preparation of 2-bromo-4,4-dimethylcyclohexanone

[0546] A solution of 4,4-dimethylcyclohexanone (20.00 g, 158.48 mmol, 1.00 eq) in Dichloromethane (500 mL) was added 4-methylbenzenesulfonic acid (2.73 g, 15.85 mmol, 0.10 eq) and 1-bromopyrrolidine-2,5-dione (33.85 g, 190.17 mmol, 1.20 eq) at 0 ℃. The mixture was stirred at 40oC for 4 h. The reaction mixture was quenched by addition of water (300 mL), extracted with dichloromthane (200 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (36.4 g, crude) as yellow solid.1H NMR (400 MHz, CDCl3) δ 4.80 - 4.72 (m, 1H), 2.61 - 2.54 (m, 2H), 2.37 - 2.29 (m, 1H), 2.13 - 2.05 (m, 1H), 1.78 - 1.68 (m, 2H), 1.23 (s, 3H), 1.08 (s, 3H)

[0547] Step 2: Preparation of ethyl 6,6-dimethyl-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate

[0548] A solution of 2-bromo-4,4-dimethylcyclohexanone (36.30 g, 177.00 mmol, 1.00 eq) and ethyl 2-amino-2-thioxoacetate (23.57 g, 177.00 mmol, 1.00 eq) in Ethanol (500 mL) was stirred at 90oC for 6 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (ethyl acetate: petroleum ether = 2 / 1 to 3 / 2) to afford the title compound (7.80 g, 18% yield) as a yellow oil. LCMS (ESI): m / z 240.0 (M+H)+

[0549] Step 3: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0550] To a solution of thyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate (7.80 g, 32.59 mmol, 1.00 eq) in THF (80 mL) and Methyl alcohol (80 mL) was added sodium tetrahydroborate (11.53 g, 304.78 mmol, 9.35 eq) slowly at 0℃. The mixture was stirred atoC for 0.5 h. The mixture was stirred at 25oC for 2 h. The reaction was quenched by addition of 200 mL of water. The reaction mixture was extracted with EtOAc (300 mL × 3) and the organic layer was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (ethyl acetate : petroleum ether = 2 / 1 to 3 / 2) to afford the title compound (3.8 g, 59% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 5.87 (t, J = 6.0 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 2.66 - 2.59 (m, 2H), 2.50 - 2.48 (m, 2H), 1.56 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H).

[0551] Example 33

[0552] Preparation of (5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 65)

[0553] Step 1: Preparation of 2-bromo-5-methylcyclohexan-1-one

[0554] To a solution of 3-methylcyclohexanone (5.00 g, 44.58 mmol) in water (20 mL) was added Br2 (2.51 mL, 49.03 mmol) and AcOH (0.48 mL, 8.33 mmol) at 5 °C. During the addition, the color of the solution changed from colorless to orange and later to red. After full addition, the reaction was stirred at 25 °C for 16 h. The reaction mixture was extracted with DCM (20 mL × 3) and washed by brine (10 mL × 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (10% ethyl acetate in petroleum ether) to afford title compound (1.8 g, 21.1% yield) as a yellow oil. LCMS (ESI): m / z 191.0 (M+H)+.

[0555] Step 2: Preparation of ethyl 5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate

[0556] To a solution of 2-bromo-5-methyl-cyclohexanone (1.8 g, 9.42 mmol, 1 eq) in EtOH (20 mL) was added ethyl amino(thioxo)acetate (1.25 g, 9.42 mmol, 1 eq) at 20 °C, the resulting mixture was stirred at 90oC for 3 h under nitrogen atmosphere. The reaction mixture was concentrated. The residue was diluted with water (20 mL), extracted with ethyl acetate (50 mL) and the organic layers was washed with brine (20 mL). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (8% ethyl acetate in petroleum ether) to afford the title compound (300 mg, 14% yield) as a yellow oil.

[0557] Step 3: Preparation of (5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0558] To a solution of ethyl 5-methyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2- carboxylate (400 mg, 1.78 mmol) in MeOH (4 mL) was added NaBH4(402 mg, 10.65 mmol) slowly at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h, then was stirred at 25oC for 16 h. The reaction mixture was diluted with water (3 mL), extracted with EtOAc (10 mL × 3) and washed with brine (5 mL). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% ethyl acetate in petroleum ether) to afford the title compound (167 mg, 51.3% yield) as a yellow oil. LCMS (ESI): m / z 184.2 (M+H)+.

[0559] Step 4: Preparation of (5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0560] To a solution of (5-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2- yl)methanol (50 mg, 0.27 mmol) in THF (1 mL) was added CDI (57 mg, 0.35mmol). The reaction was stirred at 25oC for 2 h, then the resulting solution was added to the mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (89 mg, 0.33 mmol), DBU (0.04 mL, 0.27 mmol) and TEA (0.04 mL, 0.27 mmol) in DMF (1 mL), the reaction was stirred at 25oC for 16 h. The resulting residue was purified by reverse phase chromatography (acetonitrile 35-65% / 0.1% HCl in water) to afford title compound (7.4 mg, 0.01 mmol, 5.3% yield) as a white solid.1H NMR (400 MHz, MeOD) δ 7.76 - 7.68 (m, 1H), 7.61 - 7.52 (m, 2H), 5.58 - 5.45 (m, 2H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 4.57 - 4.44 (m, 2H), 4.43 (s, 2H), 3.03 - 2.73 (m, 5H), 2.57 - 2.36 (m, 2H), 2.21 - 2.12 (m, 1H), 2.03-2.01 (m, 2H), 1.62 - 1.48 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H).

[0561] Example 34

[0562] Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate hydrochloride (Compound 66)

[0563] Step 1: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0564] To a solution of ethyl ethyl 6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazole- 2-carboxylate (420 mg, 1.70 mmol, 1.00 eq) in THF (4 mL) and methyl alcohol (4 mL) was added NaBH4(300 mg, 7.93 mmol, 4.66 eq) slowly at 0oC. The mixture was stirred at 0oC for 0.5 hour, then stirred at 25oC for 3 hours. The reaction mixture was quenched with NH4Cl solution (3 mL), the solution was concentrated under vacuo, the residue was purified by flash chromatography on silica gel (0 -50 % ethyl acetate in petroleum ether) to afford the title compound (140 mg, 40% yield) as a yellow oil. LCMS (ESI): m / z 205.8 (M+H)+

[0565] Step 2: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate hydrochloride

[0566] To a solution of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (40 mg, 0.19 mmol, 1.00 eq) in THF (2 mL), was added CDI (32 mg, 0.19 mmol, 1.00 eq), the solution was stirred at 25 ℃ for 2 hours, the resulting solution was added to a mixture of DBU (30 mg, 0.19 mmol, 1.00 eq), 3-(6-(aminomethyl)-7-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (64 mg, 0.19 mmol, 1.00 eq), andTEA (39 mg, 0.39 mmol, 2.00 eq) in DMF (2 mL), the mixture was stirred at 25 ℃ for 12 hours. The solution was purified by pre-HPLC (Welch Xtimate C18150*25mm*5um, water (HCl)-ACN, 30 - 60%) to afford the title compound (11 mg, 9% yield) as a white solid. LCMS (ESI): m / z 523.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.10 (t, J = 6.0 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.34 - 4.30 (m, 3H), 3.39 (t, J = 14.0 Hz, 2H), 2.95 - 2.86 (m, 3H), 2.59 (d, J = 17.2 Hz, 1H), 2.40 - 2.28 (m, 3H), 2.01 - 1.99 (m, 1H).

[0567] Example 35

[0568] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl (R)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 67) and (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl (S)-((2- (2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 68)

[0569] Step 1: (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl (R)- ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate and (6,6- dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl (S)-((2-(2,6-dioxopiperidin-3-yl)- 4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0570] The product was further purified by chiral SFC (Column =DAICEL CHIRALCEL OJ; Column dimensions = 250 mm × 30 mm × 10 µm; Detection wavelength = 220 nm; Flow rate = 70 mL / min; Mobile phase: A: CO2B: ethanol (0.05% DEA); Isocratic: 50% B) ) to afford two peaks tentatively assigned:

[0571] peak1: (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl (R)- ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (5 mg,26.7% yield) as white solid LCMS (ESI): m / z 515.1 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.10 (t, J = 6.0 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 5.06 (dd, J= 5.2, 18.8 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.38 - 4.30 (m, 3H), 2.66 (m, 3H), 2.95 - 2.86 (m, 3H), 2.60 (m, 1H), 2.40 - 2.28 (m, 3H), 1.20 (m, 1H, 0.92 (s, 6H).

[0572] peak 2: (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl (S)- ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate(5 mg, 25.7% yield). LCMS (ESI): m / z 515.1 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.10 (t, J 6.0 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 5.06 (dd, J= 5.2, 18.8 Hz, 1H), 4.47 - 4.45 (m, 1H), 4.38 - 4.30 (m, 3H), 2.66 (m, 3H), 2.95 - 2.86 (m, 3H), 2.60 (m, 1H), 2.40 - 2.28 (m, 3H), 1.20 (m, 1H, 0.92 (s, 6H).

[0573] Example 36

[0574] Preparation of (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 69)

[0575] Step 1: Preparation of 2-bromocyclohex-2-en-1-one

[0576] A solution of dibromine (2.73 mL, 53.23mmol,1.2 eq) in dichloromethane (50mL) was added dropwise over a period of 3h to a stirred solution of cyclohex-2-en-1- one (5.05 mL, 52 mmol,1.0 eq) in dichloromethane (120 mL) at 0℃. The solution was stirred 3h at 0℃. Then triethylamine (10.61mL, 76.09mmol,1.5 eq) was dropwise, and the mixture was stirred at 25 ℃ for 3h. The rection mixture was washed with 3%HCl and brine, and dried with Na2SO4. The mixture was purified by flash chromatography (0-10 % ethyl acetate in petroleum ether) to afford title compound (7.50g, 82 % yield).1H NMR(400 MHz, CDCl3) δ 7.42 (t, J = 4.8 Hz, 1H), 2.69 - 2.58 (m, 2H), 2.51 - 2.36 (m, 2H), 2.15 - 2.04 (m, 2H).

[0577] Step 2: Preparation of 2-bromo-3-methylcyclohexan-1-one

[0578] To a solution of triphenylphosphane (750 mg, 2.86mmol,0.1 eq) in Toluene (50mL) was added trimethylaluminum (30 mL, 60 mmol,1.5 eq) under N2. The solution was stirred at 25℃ for 0.5h, and then cooled to -60℃, the solution was stirred for 5 min and 2-bromocyclohex-2-en-1-one (7.5g, 42.85mmol,1.0 eq) and copper (I) (250 mg, 1.75mmol,1.0 eq) in 50mL of toluene was added dropwise. The mixture was stirred blow - 60℃ for 2h and then allowed to warm to 25℃ for 16h. The solution was diluted with tert- butyl methyl ether, the reaction was quenched with methyl alcohol (20mL), and the mixture washed with 2M HCl and was dried by Na2SO4, the organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with (0-20% ethyl acetate in petroleum ether) to afford the title compound (3.5g, 43% yield).

[0579] Step 3: Preparation of ethyl 7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate and ethyl 4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0580] To the mixture of 2-bromo-3-methyl-cyclohexanone (3.50g, 18.32mmol,1.0 eq) in Ethanol (50mL) was added ethyl amino(thioxo)acetate (2.44g, 18.32mmol,1.0 eq) at 20 °C. Then the resulting mixture was stirred at 90oC for 3 h under nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol. The residue was diluted with water (20 mL), extracted with ethyl acetate (50 mL) and the organic layers was washed with brine (20 mL). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10%ethyl acetate in petroleum ether) to afford 650 mg mixture as a yellow oil. The above product was further purified by chiral SFC(Column =AICEL CHIRALCEL OJ; Column dimensions = 250 mm × 30 mm × 10 µm; Detection wavelength = 220 nm; Flow rate = 70 mL / min; Mobile phase: A: CO2B: ethanol (0.05% DEA); Isocratic: 50% B)) to afford:

[0581] Peak1: ethyl 7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate (200 mg,0.89mmol, 4.8% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 4.47 - 4.41 (m, 2H), 3.13 - 3.01 (m, 1H), 2.99 - 2.88 (m, 1H), 2.86 - 2.73 (m, 1H), 2.09 - 1.96 (m, 2H), 1.88 - 1.73 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.33 (d, J = 7.2 Hz, 3H).

[0582] Peak2: ethyl 4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate (180 mg,0.80mmol, 4.4% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 4.47 - 4.42 (m, 2H), 3.03 (dd, J = 5.0, 16.8 Hz, 1H), 2.97 - 2.89 (m, 1H), 2.86 - 2.73 (m, 1H), 2.52 - 2.35 (m, 1H), 2.06 - 1.90 (m, 2H), 1.55 - 1.46 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H).

[0583] Step 4: Preparation of (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0584] To a solution of ethyl 7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate (200mg, 0.89mmol,1.0 eq) in Methyl alcohol (4mL) and was added NaBH4 (269mg, 7.10mmol,8.0 eq) slowly at 0℃. The mixture was stirred at 25oC for 16h. The reaction mixture was diluted with water (3 mL), extracted with dichloromethane (10 mL × 3) and washed by brine (5ml). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by TLC (0-30 % ethyl acetate in petroleum ether) to afford the title compound (100mg,0.55mmol, 62% yield). LCMS (ESI): m / z 184.1 [M + H]+.

[0585] Step5: Preparation of (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0586] To a solution of (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (40 mg, 0.22mmol,1.0 eq) in THF (1mL), was added CDI (42mg, 0.26mmol1.2 eq). The solution was stirred at 25oC for 2 hours. The resulting solution was added to a mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (72 mg, 0.26mmol,1.2 eq)and DBU (0.03mL, 0.22mmol,1.0eq) and triethylamine (0.03mL, 0.22mmol,1.0eq) in DMF (1mL). The mixture was stirred at 25oC for 16 hours. After that, the reaction mixture was purified by pre-HPLC (C18150*30mm, water (HCl)-ACN, 25-55%) to afford the title compound (10 mg, 0.02mmol, 10 % yield).1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.54 (d, J = 4.4 Hz, 2H), 5.20 (s, 2H), 5.15 - 5.06 (m, 1H), 4.41 (s, 1H), 4.36 - 4.24 (m, 3H), 3.00 - 2.84 (m, 2H), 2.69 - 2.57 (m, 3H), 2.43 - 2.33 (m, 1H), 2.03 - 1.87 (m, 3H), 1.72 - 1.60 (m, 1H), 1.38 - 1.33 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H).

[0587] Example 37

[0588] Preparation of (4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 70)

[0589] Step 1: Preparation of 2-bromocyclohex-2-en-1-one

[0590] To a solution of stirred solution of cyclohex-2-en-1-one (5.05 mL, 52.01 mmol) in DCM (120 mL) was added Br2(2.73 mL, 53.23 mmol) in DCM (50 mL) at 0 ℃. The reaction was stirred at 0 ℃ for 3 h, then TEA (10.61 mL, 76.09 mmol) was added, the mixture was stirred at 25℃ for 3 h. The mixture was washed with 3% HCl and brine, dried with Na2SO4. The mixture was purified by flash chromatography on silica gel (10 % ethylacetate in petroleum ether) to afford title compound (7.5 g, 42.85 mmol, 82.4% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 4.8 Hz, 1H), 2.69 - 2.58 (m, 2H), 2.51 - 2.36 (m, 2H), 2.15 - 2.04 (m, 2H).

[0591] Step 2: Preparation of 2-bromo-3-methylcyclohexan-1-one

[0592] The solution of PPh3(750 mg, 2.86 mmol) and CuBr (250 mg, 1.74 mmol) in toluene (50 mL) under N2was stirred at 25 ℃ for 0.5 h. Then the mixture was cooled to -60 ℃, and Me3Al (30 mL, 60 mmol) was added dropwise. The resulting mixture was stirred for 5 min, then 2-bromocyclohex-2-en-1-one (7.5g, 42.85mmol) in toluene (50 mL) was added dropwise, the mixture was stirred at -60 ℃ for 2 h, then allowed to 25℃ for 16 h. The solution was diluted with tert-butyl methyl ether, the reaction was quenched with methyl alcohol (20 mL), the mixture was washed with 2M HCl, dried by Na2SO4, the organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with (20% ethyl acetate in petroleum ether) to afford title compound (3.5 g, 18.31 mmol, 42.7% yield) as a white solid. LCMS (ESI): m / z 191.0 (M+H)+.

[0593] Step 3: Preparation of ethyl 4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate

[0594] To a solution of 2-bromo-3-methyl-cyclohexanone (3.5 g, 18.32 mmol) in EtOH (50 mL) was added ethyl amino(thioxo)acetate (2.44 g, 18.32 mmol) at 20 °C. Then the resulting mixture was stirred at 90oC for 3 h under nitrogen atmosphere. The reaction mixture was concentrated. The residue was diluted with water (20 mL), extracted with ethyl acetate (50 mL) and the organic layers was washed with brine (20 mL), dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10% ethyl acetate in petroleum ether) to afford650 mg crude product as a yellow oil. The mixture was purified by SFC to afford title compound (200 mg, 0.88 mmol, 4.8% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.45 (q, J = 7.2Hz, 2H), 3.03 (dd, J = 5.2, 16.8 Hz, 1H), 2.97 - 2.89 (m, 1H), 2.86 - 2.73 (m, 1H), 2.52 - 2.35 (m, 1H), 2.06 - 1.90 (m, 2H), 1.55 - 1.46 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H). LCMS (ESI): m / z 247.9 (M+H)+.

[0595] Step 4: Preparation of (4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0596] To a solution of ethyl 7-methyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2- carboxylate (180 mg, 0.80 mmol) in MeOH (4 mL) was added NaBH4(241 mg, 6.39 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h, then the mixture was stirred at 2oC for 16 h. The reaction mixture was diluted with water (3 mL), extracted with dichloromethane (10 mL × 3) and washed by brine (5 mL). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by TLC (30 % ethyl acetate in petroleum ether) to afford the title compound (100 mg, 68.3% yield) as a yellow oil. LCMS (ESI): m / z 183.2 (M+H)+.

[0597] Step 5: Preparation of (4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0598] To a solution of (4-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2- yl)methanol (40 mg, 0.22 mmol) in THF (1 mL) was added CDI (53 mg, 0.33 mmol), the solution was stirred at 25oC for 2 h. The resulting solution was added to the mixture of DBU (0.03mL, 0.22mmol), 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (71 mg, 0.26 mmol) and TEA (0.03 mL, 0.22 mmol) in DMF (1 mL). The reaction mixture was stirred at 25oC for 16 h. The resulting residue was purified by reverse phase chromatography (acetonitrile 35-65% / 0.1% HCl in water) to afford title compound (17.3mg, 16.3% yield) as a white solid (HCl salt).1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.10 (s, 1H), 7.69 - 7.45 (m, 3H), 5.21 (s, 2H), 5.14 - 4.97 (m, 1H), 4.49 - 4.38 (m, 1H), 4.35 - 4.15 (m, 3H), 2.98 - 2.75 (m, 3H), 2.73 - 2.57 (m, 2H), 2.44 - 2.32 (m, 1H), 2.27- 2.21 (m, 1H), 2.03 - 1.80 (m, 3H), 1.48 - 1.27 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). LCMS (ESI): m / z 482.5 (M+H)+.

[0599] Example 38

[0600] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 71)

[0601] Step 1: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl 1H-imidazole-1-carboxylate

[0602] To the mixture of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (45.0 mg, 0.23 mmol) in THF (1.5mL) was added CDI (36.98 mg, 0.23 mmol) at 0oC. Then the resulting mixture was stirred at 0oC for 1 h. The crude title compound was used for next step directly.

[0603] Step 2: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-3-oxoisoindolin-5-yl)methyl)carbamate

[0604] To the mixture of 3-[6-(aminomethyl)-7-hydroxy-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (64.54 mg, 0.22 mmol, 1 eq) in DMF (1 mL) was added TEA (0.06 mL, 0.45 mmol, 2 eq) and DBU (0.03 mL, 0.22mmol, 1 eq) at 25oC. A mixture of (6,6- dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl 1H-imidazole-1-carboxylate(64.54mg, 0.22mmol) in THF (1 mL) was added into the reaction solution at 25oC. Then the resulting mixture was stirred at 25oC for 16 h. The reaction mixture was concentrated to dryness. The residue was purified by prep-HPLC (31-62% HCl in water, acetonitrile) to afford the title compound (16.1 mg, 13% yield) as a white solid. LCMS (ESI): m / z 513.1 [M + H]+.1H NMR (400 MHz,DMSO-d6) δ 11.00 (s, 1H), 7.89 (t, J = 6.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H), 5.04 (dd, J = 5.2 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.31 - 4.25 (m, 1H), 4.23 (d, J = 5.2 Hz, 2H), 2.96-2.84 (m, 1H), 2.69 - 2.64 (m, 2H), 2.63 - 2.56 (m, 1H), 2.54 (s, 2H), 2.43 - 2.33 (m, 1H), 2.06 - 1.96 (m, 1H), 1.57 (t, J = 6.8 Hz, 2H), 0.98 (s, 6H).

[0605] Example 39

[0606] Preparation of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2- (2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 72)

[0607] (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol (18 mg, 0.12 mmol, 1.5 equiv.) and 1,1'-carbonyldiimidazole (19 mg, 0.12 mmol, 1.5 equiv.) were added to a 2 dram vial and dissolved in THF (0.20 mL). Triethylamine (0.24 mmol, 0.033 mL, 3 equiv.) was then added, and the reaction was allowed to stir at rt for 30 minutes.

[0608] To a separate vial containing 3-[6-(aminomethyl)-7-fluoro-1-oxo- isoindolin-2-yl]piperidine-2,6-dione;hydrochloride (26 mg, 0.080 mmol, 1.0 equiv.) was added THF (0.10 mL), DMF (0.10 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mmol, 0.02 mL, 1.7 equiv.). The activated alcohol solution was then added to this reaction in one portion, and excess THF (0.10 mL) was used to rinse the vial with activated alcohol and ensure full transfer. The reaction was stirred at rt until full consumption of the starting material was observed as monitored by LCMS.

[0609] The reaction was quenched by the addition of as saturated aqueous solution of NH4Cl and extracted with DCM (3x). The organics layers were combined, dried with anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by preparative HPLC (XSelect CSH Prep C18, column dimensions 50 x 30mm, 5µm, NeatWater / ACN) to afford the title compound (19.98 mg, 53% yield) as a white solid. LCMS (ESI): m / z 470.18 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.76 (t, J = 6.1 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 5.94 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.88 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.37 – 4.22 (m, 3H), 3.99 (t, J = 6.1 Hz, 2H), 2.90 (ddd, J = 18.5, 13.9, 5.5 Hz, 1H), 2.70 (t, J = 6.4 Hz, 2H), 2.64 – 2.55 (m, 1H), 2.45 – 2.33 (m, 1H), 2.04 – 1.97 (m, 1H), 1.97 – 1.86 (m, 2H), 1.80 – 1.69 (m, 2H).

[0610] Example 40

[0611] Preparation of (5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 73)

[0612] Step 1: Preparation of 2-bromo-5,5-dimethylcyclohexanone

[0613] To a solution of 3,3-dimethylcyclohexanone (5.00 g, 39.62 mmol, 1.0 eq) in Dichloromethane (50 mL) was added NBS (7.26 g, 40.81 mmol, 1.0 eq). The reaction mixture was stirred at 25°C for 16 h. The resulting solution was extracted with Dichloromethane (100 mL × 3). After filtration, the solid was collected and washed by NaHCO3 (100 mL × 3). And the organic layers were combined to afford the title compound (8.00 g,39.0 mmol, 98.5% yield) as a yellow oil.

[0614] Step 2: Preparation of ethyl 5,5-dimethyl-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate

[0615] To the mixture of 2-bromo-5,5-dimethyl-cyclohexanone (8.00 g, 39.01 mmol, 1.0 eq) in Ethanol (20 mL) was added ethyl 2-amino-2-thioxo-acetate (6.75 g, 50.71 mmol, 1.3 eq) at 20 °C. Then the resulting mixture was stirred at 90 °C for 12 hrs. The reaction mixture was concentrated to dryness. The resulting residue was purified by reverse phase chromatography (0-10% ethyl acetate in petroleum ether) to afford the title compound (750 mg, 8% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 4.48 - 4.42(m, 2H), 2.90 - 2.77 (m, 2H), 2.67 (s, 2H), 1.66 - 1.61 (m, 2H), 1.42 (t, J = 6.8 Hz, 3H), 1.03 (s, 6H).

[0616] Step 3: Preparation of (5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0617] To a solution of ethyl 5,5-dimethyl-6,7-dihydro-4H-1,3-benzothiazole-2- carboxylate (200 mg, 0.84 mmol, 1.0 eq) in Methyl alcohol (4 mL) and was added NaBH4(252 mg, 6.69 mmol, 8.0 eq) slowly at 0℃. The mixture was stirred at 0 °C for 0.5 h. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (3 mL), extracted with dichloromethane (20 mL × 3) and washed by brine (5 mL). The organic layers was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by TLC (30 % ethyl acetate in petroleum ether) to afford the title compound (120 mg, 73% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 4.86 (s, 2H), 2.98 (s, 1H), 2.84 - 2.70 (m, 2H), 2.55 (s, 2H), 1.63 - 1.58 (m, 2H), 1.03 (s, 6H).

[0618] Step 4: Preparation of (5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0619] CDI (73 mg, 0.46 mmol, 1.0 eq) was added into (5,5-dimethyl-6,7-dihydro- 4H-1,3-benzothiazol-2-yl)methanol (60 mg, 0.30 mmol, 1.5 eq) in THF (1 mL). The solution was stirred at 25 °C for 2 hrs. The mixture was added in to the solution of 3-(6- (aminomethyl)-4-chloro-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (148 mg, 0.25 mmol, 1.5 eq), DBU (50 µL, 0.36 mmol, 1.2 eq), and TEA (80 µL, 0.60 mmol, 2.0 eq) in DMF (1 mL), the mixture was stirred at 25 C for 16 hrs. The reaction mixture was concentrated under vacuum and purified by pre-HPLC (Xtimate C18150*40mm*10um, water (0.05% HCl)-ACN, 40-70%), after lyophilization to give the tittle compound (30.5mg, 19.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.19 - 7.98 (m, 1H), 7.69 - 7.49 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 5.10 - 5.01 (m, 1H), 4.50 - 4.41 (m, 1H), 4.36 - 4.27 (m, 3H), 2.97 - 2.83 (m, 1H), 2.73 (s, 2H), 2.63- 2.58 (m, 1H), 2.46 (s, 2H), 2.41 - 2.31 (m, 1H), 2.07 - 1.92 (m, 1H), 1.55 (t, J = 5.6 Hz, 2H), 0.96 (s, 6H). LCMS (ESI): m / z 515.1 (M+H)+.

[0620] Example 41

[0621] Preparation of ((S)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 74)

[0622] Step 1: Preparation of (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl 1H-imidazole-1-carboxylate

[0623] To a solution of (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (49.8mg, 0.27mmol) in THF (1mL) was added CDI (66.09mg, 0.41mmol), the solution was stirred at 25oC for 2 hours. The product no purification and used in next step directly.

[0624] Step 2: Preparation of ((S)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0625] (S)-(7-Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl 1H- imidazole-1-carboxylate (60.95mg, 0.2500mmol) was added to a mixture of 3-(6- (aminomethyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68.0mg, 0.2500mmol), DBU (0.05mL, 0.33mmol) and triethylamine (0.08mL, 0.55mmol) in DMF (1mL) , the mixture was stirred at 25oC for 16 hours. The organic layer was concentrated under vacuum and purified by pre-HPLC (acetonitrile 25-55 / 0.225% HCl in water) to afford [(7R)-7-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]methyl N-[[2-(2,6-dioxo-3- piperidyl)-4-fluoro-3-oxo-isoindolin-5-yl]methyl]carbamate (30.2mg,0.0591mmol, 21.6% yield). LCMS (ESI): m / z 501.0 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.08 (t, J = 6.0 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 5.06 (dd, J = 12.8, 4.8 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.39 - 4.23 (m, 3H), 3.06 - 2.83 (m, 2H), 2.72 - 2.54 (m, 3H), 2.39 - 2.35 (m, 1H), 2.06 - 1.84 (m, 3H), 1.74 - 1.61 (m, 1H), 1.42 - 1.31 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H).

[0626] Example 42

[0627] Preparation ((R)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 75)

[0628] Step 1: Preparation of (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol and (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methanol

[0629] (7-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)methanol (300.0mg, 1.64mmol) was further purified by chiral SFC (Column =DAICEL CHIRALCEL OJ; Column dimensions = 250 mm × 30 mm × 10 µm; Detection wavelength = 220 nm; Flow rate = 70 mL / min; Mobile phase: A: CO2B: ethanol (0.01% NH3.H2O); Isocratic: 15% B) ) to afford two peaks tentatively assigned:

[0630] Peak1： (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methanol (145mg, 48.3% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 4.85 (s, 2H), 3.31 - 3.05 (m, 1H), 3.03 - 2.95 (m, 1H), 2.83 - 2.61 (m, 2H), 2.06 - 1.94 (m, 2H), 1.84 - 1.72 (m, 1H), 1.48 - 1.37 (m, 1H), 1.32 - 1.25 (m, 3H).

[0631] Peak2： (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methanol (140mg,0.76mmol, 47 % yield) as white solid.1H NMR (400 MHz, CDCl3) δ 4.86 (s, 2H), 3.00 - 2.81(m, 1H), 2.77 - 2.76 (m, 1H), 2.75 - 2.68 (m, 2H), 2.04 - 1.95 (m, 2H), 1.84 - 1.70 (m, 1H), 1.47 - 1.38 (m, 1H), 1.30 - 1.28 (m, 3H).

[0632] Step 2: Preparation of (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl 1H-imidazole-1-carboxylate

[0633] To a solution of (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (50 mg, 0.27 mmol, 1 eq) in THF (1mL) was added CDI (66 mg, 0.41 mmol, 1.5 eq) the solution was stirred at 25oC for 2 hrs. The product was used in next step directly.

[0634] Step 3: Preparation of ((R)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0635] To a solution of 3-phenylcyclobutyl) imidazole-1-carboxylate (76g, 0.27 mmol, 1 eq) was added to a mixture of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (135 mg, 0.411 mmol, 1.5 eq), DBU (0.049 mL, 0.33 mmol, 1.2 eq)and TEA (0.076 mL, 0.55 mmol, 2 eq) in DMF (1 mL) , the mixture was stirred at 25oC for 16 hours. The organic layer was concentrated under vacuum and purified by pre-HPLC (acetonitrile 25-55 / 0.225% HCl in water) to afford the title compound (19 mg, 14%yield) as a white solid. LCMS (ESI): m / z 501.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.08 (t, J = 6.0 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 5.06 (dd, J = 12.8, 4.8 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.39 - 4.23 (m, 3H), 3.06 - 2.83 (m, 2H), 2.72 - 2.54 (m, 3H), 2.39 - 2.35 (m, 1H), 2.06 - 1.84 (m, 3H), 1.74 - 1.61 (m, 1H), 1.42 - 1.31 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H).

[0636] Example 43

[0637] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 76)yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0639] To a solution of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (40 mg, 0.21 mmol, 1 eq) in THF (1 mL) was added CDI (36 mg, 0.22 mmol, 1.1 eq), the solution was stirred at 25oC for 2 hrs. The resulting solution was added to a mixture of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride (30 mg, 0.01 mmol, 1 eq), DBU (0.02 mL, 0.17 mmol, 2 eq) and TEA (0.02 mL, 0.17 mmol, 2eq) in DMF (2 mL), the mixture was stirred at 25oC for 16 hrs. The residue was purified by Pre-HPLC (Xtimate C18150*30mm, water (0.225% HCl)-ACN, 40-70%) to afford the title compound(5.2 mg, 0.01 mmol, 11% yield) as a white solid. LCMS (ESI): m / z 549.1 (M+H)+.1H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 8.11 (t, J = 5.6 Hz, 1H), 7.62 (d, J = 4.8 Hz, 1H), 5.21 (s, 2H), 5.12 - 5.05 (m, 1H), 4.50 - 4.43 (m, 1H), 4.34 - 4.27 (m, 3H), 2.97 - 2.86 (m, 1H), 2.69 - 2.63 (m, 2H), 2.61 - 2.52 (m, 3H), 2.46 - 2.39 (m, 1H), 2.05 - 1.95 (m, 1H), 1.57 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H).

[0640] Example 44

[0641] Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 77)

[0642] For this example, the same sequence of steps was followed as for Compound 88 except that 4-methylpiperidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0643] Step 1: Preparation of 4-methyl-1-nitrosopiperidine-2-carboxylic acidReaction was run on a 1.35 mmol scale with 4-methylpiperidine-2-carboxylic acid hydrochloride to give 98.9 mgs (43 % Yield) of 4-methyl-1-nitrosopiperidine-2-carboxylic acid as a white solid which was used without further purification. LCMS (ESI): m / z 173.050 (M+H)+.

[0644] Step 2: Preparation of 5-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4- a]pyridin-8-ium-3-olate

[0645] Reaction was run on a 0.57 mmol scale with 4-methyl-1-nitrosopiperidine- 2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-80% iPrOAc in Heptanes) to give 69.2 mgs (78% Yield) of 5-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 155.1 (M+H)+.

[0646] Step 3: Preparation of ethyl 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0647] Reaction was run on a 0.45 mmol scale with 5-methyl-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-40 % iPrOAc in Heptanes) to give 26.7 mgs (29% Yield) of ethyl 5- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a yellow solid. LCMS (ESI): m / z 209.050 (M+H)+.

[0648] Step 4: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 2-yl)methanol

[0649] Reaction was run on a 0.125 mmol scale with ethyl 5-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 19.1 mgs (92% Yield) of (5- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 167.100 (M+H)+.

[0650] Step 5: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0651] Reaction was run on a 0.080 mmol scale with 3-[6-(aminomethyl)-7- fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.10.32 mgs of (5-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (27 % Yield)following preparative HPLC (Triart C18, column dimensions 100 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 484.20 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.76 (t, J = 6.0 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 5.93 (s, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.88 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.36 – 4.23 (m, 3H), 4.15 – 4.05 (m, 1H), 3.93 (td, J = 11.9, 4.9 Hz, 1H), 2.97 – 2.78 (m, 2H), 2.60 (ddd, J = 17.2, 4.5, 2.3 Hz, 1H), 2.45 – 2.33 (m, 1H), 2.33 – 2.22 (m, 1H), 2.09 – 1.83 (m, 3H), 1.71 – 1.56 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H).

[0652] Example 45

[0653] Preparation of (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 78)

[0654] For this example, the same sequence of steps was followed as for Compound 88 except that 5-methylpiperidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0655] Step 1: Preparation of 5-methyl-1-nitrosopiperidine-2-carboxylic acid

[0656] Reaction was run on a 1.39 mmol scale with 5-methylpiperidine-2- carboxylic acid hydrochloride to give 130 mgs (54% Yield) of 5-methyl-1- nitrosopiperidine-2-carboxylic acid as an off-white semi-solid which was used without further purification. LCMS (ESI): m / z 173.050 (M+H)+.

[0657] Step 2: Preparation of 6-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4- a]pyridin-8-ium-3-olate

[0658] Reaction was run on a 0.76 mmol scale with 5-methyl-1-nitrosopiperidine- 2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-80% iPrOAc in Heptanes) to give 102.6 mgs (88% Yield) of 6-methyl-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 155.050 (M+H)+.

[0659] Step 3: Preparation of ethyl 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0660] Reaction was run on a 0.67 mmol scale with 6-methyl-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-40% iPrOAc in Heptanes) to give 58.9 mgs (43% Yield) of 6-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a yellow solid. LCMS (ESI): m / z 209.050 (M+H)+.

[0661] Step 4: Preparation of (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 2-yl)methanol

[0662] Reaction was run on a 0.16 mmol scale with 6-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 24.5 mgs (92% Yield) of (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 167.100 (M+H)+.

[0663] Step 5: Preparation of (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0664] Reaction was run on a 0.080 mmol scale with 3-[6-(aminomethyl)-7- fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.12.53 mgs of (6-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (32 % Yield) following preparative HPLC (Triart C18, column dimensions 100 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 484.20 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.76 (t, J = 5.9 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 5.95 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.88 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.36 – 4.24 (m, 3H), 4.11 (dd, J = 12.4, 5.2 Hz, 1H), 3.56 – 3.46 (m, 1H), 2.90 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.84 – 2.75 (m, 1H), 2.70 – 2.54 (m, 2H), 2.45 – 2.33 (m, 1H), 2.12 – 1.95 (m, 2H), 1.92 – 1.80 (m, 1H), 1.47 – 1.32 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H).

[0665] Example 46

[0666] Preparation of (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 79)

[0667] For this example, the same sequence of steps was followed as for Compound 88 except that 3-methyl-piperidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0668] Step 1: Preparation of 3-methyl-1-nitrosopiperidine-2-carboxylic acid

[0669] Reaction was run on a 1.06 mmol scale with 3-methyl-piperidine-2- carboxylic acid hydrochloride to give 90.2 mgs (50 % Yield) of 3-methyl-1- nitrosopiperidine-2-carboxylic acid as an off-white solid which was used without further purification. LCMS (ESI): m / z 173.100 (M+H)+.

[0670] Step 2: Preparation of 4-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4- a]pyridin-8-ium-3-olate

[0671] Reaction was run on a 0.524 mmol scale with 3-methyl-1- nitrosopiperidine-2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-75% iPrOAc in Heptanes) to give 78.4 mgs (97% Yield) of 4-methyl- 4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 155.100 (M+H)+.

[0672] Step 3: Preparation of ethyl 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0673] Reaction was run on a 0.51 mmol scale with 4-methyl-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-30% iPrOAc in Heptanes) to give 33.7 mgs (32% Yield) of ethyl 4- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a yellow oil. LCMS (ESI): m / z 209.050 (M+H)+.

[0674] Step 4: Preparation of (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 2-yl)methanol

[0675] Reaction was run on a 0.153 mmol scale with ethyl 4-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 25.2 mgs (99 % Yield) of (4- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 167.100 (M+H)+.

[0676] Step 5: Preparation of (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0677] Reaction was run on a 0.080 mmol scale with 3-[6-(aminomethyl)-7-fluoro- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.12.11 mgs of (4-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (31% Yield) following preparative HPLC (Triart C18, column dimensions 100 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 484.20 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.77 (t, J = 6.1 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 6.03 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.89 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.36 – 4.26 (m, 3H), 4.06 (dt, J =12.9, 4.6 Hz, 1H), 3.89 (td, J = 11.8, 5.0 Hz, 1H), 2.96 – 2.77 (m, 2H), 2.65 – 2.54 (m, 1H), 2.45 – 2.33 (m, 1H), 2.09 – 1.96 (m, 2H), 1.95 – 1.82 (m, 2H), 1.34 (q, J = 11.3 Hz, 1H), 1.20 (d, J = 6.8 Hz, 3H).

[0678] Example 47

[0679] Preparation of (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 80)

[0680] For this example, the same sequence of steps was followed as for Compound 88 except that 4,4-difluoropiperidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0681] Step 1: Preparation of 4,4-difluoro-1-nitrosopiperidine-2-carboxylic acid

[0682] Reaction was run on a 0.94 mmol scale with 4,4-difluoropiperidine-2- carboxylic acid hydrochloride to give 180.5 mgs (99 % Yield) of 4,4-difluoro-1- nitrosopiperidine-2-carboxylic acid as an off-white solid which was used without further purification. LCMS (ESI): m / z 195.000 (M+H)+.

[0683] Step 2: Preparation of 5,5-difluoro-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate

[0684] Reaction was run on a 0.93 mmol scale with 4,4-difluoro-1- nitrosopiperidine-2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-70% iPrOAc in Heptanes) to give 159.2 mgs (97% Yield) of 5,5- difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 177.050 (M+H)+.

[0685] Step 3: Preparation of ethyl 5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0686] Reaction was run on a 0.90 mmol scale with 5,5-difluoro-4,5,6,7- tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-55% iPrOAc in Heptanes) to give 118.2 mgs (57% Yield) of ethyl 5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a white solid. LCMS (ESI): m / z 231.000 (M+H)+.

[0687] Step 4: Preparation of (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methanol

[0688] Reaction was run on a 0.16 mmol scale with ethyl 5,5-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 29.4 mgs (98 % Yield) of (5,5- difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 189.050 (M+H)+.

[0689] Step 5: Preparation of (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0690] Reaction was run on a 0.080 mmol scale with 3-[6-(aminomethyl)-7- fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.11.12 mgs of (5,5- difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3- yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (28% Yield) following preparative HPLC (Triart C18, column dimensions 100 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 506.16 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.80 (t, J = 6.0 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 6.09 (s, 1H), 5.11 – 4.99 (m, 1H), 4.91 (s, 2H), 4.45 (d, J = 17.5 Hz, 1H), 4.35 – 4.25 (m, 3H), 4.21 (t, J = 6.5 Hz, 2H), 3.45 – 3.37 (m, 1H), 2.90 (ddd, J = 18.3, 13.7, 5.4 Hz, 1H), 2.64 – 2.51 (m, 3H), 2.45 – 2.33 (m, 1H), 2.04 – 1.96 (m, 1H), 1.65 – 1.38 (m, 1H).

[0691] Example 48

[0692] Preparation of (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 81)

[0693] For this example, the same sequence of steps was followed as for Compound 88 except that 5,5-difluoropiperidine-2-carboxylic acid was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0694] Step 1: Preparation of 5,5-difluoro-1-nitrosopiperidine-2-carboxylic acid

[0695] Reaction was run on a 1.51 mmol scale with 5,5-difluoropiperidine-2- carboxylic acid to give 265 mgs (90 % Yield) of 5,5-difluoro-1-nitrosopiperidine-2- carboxylic acid as a yellow solid which was used without further purification. LCMS (ESI): m / z 195.050 (M+H)+.

[0696] Step 2: Preparation of 6,6-difluoro-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate

[0697] Reaction was run on a 1.37 mmol scale with 5,5-difluoro-1- nitrosopiperidine-2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-70 % iPrOAc in Heptanes) to give 216 mgs (90 % Yield) of 6,6- difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 177 (M+H)+.

[0698] Step 3: Preparation of ethyl 6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0699] Reaction was run on a 1.23 mmol scale with 6,6-difluoro-4,5,6,7- tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-30% iPrOAc in Heptanes) to give 139.7 mgs (50 % Yield) ofethyl 6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a yellow oil. LCMS (ESI): m / z 231.100 (M+H)+.

[0700] Step 4: Preparation of (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methanol

[0701] Reaction was run on a 0.16 mmol scale with ethyl 6,6-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 31.7 mgs (110 % Yield) of (6,6- difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 189.000 (M+H)+.

[0702] Step 5: Preparation of (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0703] Reaction was run on a 0.080 mmol scale with 3-[6-(aminomethyl)-7- fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.7.43 mgs of (6,6- difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3- yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (18 % Yield) following preparative HPLC (Triart C18, column dimensions 100 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 506.16 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.81 (t, J = 6.1 Hz, 1H), 7.58 (t, J = 7.0 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.17 – 6.08 (m, 1H), 5.12 – 5.00 (m, 1H), 4.92 (s, 2H), 4.62 – 4.41 (m, 3H), 4.37 – 4.26 (m, 3H), 2.92 (t, J = 6.8 Hz, 2H), 2.65 – 2.56 (m, 1H), 2.46 – 2.31 (m, 3H), 2.05 – 1.97 (m, 1H), 1.68 – 1.41 (m, 1H).

[0704] Example 49

[0705] Preparation of (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 82)

[0706] For this example, the same sequence of steps was followed as for Compound 88 except that 3,3-dimethylpiperidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.eparation of 3,3-dimethyl-1-nitrosopiperidine-2-carboxylic acid

[0708] Reaction was run on a 0.95 mmol scale with 3,3-dimethylpiperidine-2- carboxylic acid hydrochloride to give 124.1 mgs (70 % Yield) of 3,3-dimethyl-1- nitrosopiperidine-2-carboxylic acid as a white solid which was used without further purification. LCMS (ESI): m / z 187.050 (M+H)+.

[0709] Step 2: Preparation of 4,4-dimethyl-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate

[0710] Reaction was run on a 0.67 mmol scale with 3,3-dimethyl-1- nitrosopiperidine-2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-70% iPrOAc in Heptanes) to give 96.6 mgs (86 % Yield) of 4,4-dimethyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 169.050 (M+H)+.

[0711] Step 3: Preparation of ethyl 4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0712] Reaction was run on a 0.57 mmol scale with 4,4-dimethyl-4,5,6,7- tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-45% iPrOAc in Heptanes) to give 65.7 mgs (52 % Yield) of ethyl 4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a brown oil. LCMS (ESI): m / z 223.050 (M+H)+.

[0713] Step 4: Preparation of (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methanol

[0714] Reaction was run on a 0.16 mmol scale with ethyl 4,4-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 28.6 mgs (99 % Yield) of (4,4- dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 181.100 (M+H)+.

[0715] Step 5: Preparation of (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0716] Reaction was run on a 0.08 mmol scale with 3-[6-(aminomethyl)-7-fluoro- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.11.02 mgs of 4,4-dimethyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (28 % Yield) following preparative HPLC (Gemini-NX C18, column dimensions 50 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 498.22 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.79 (t, J = 5.9 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 6.05 (s, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.87 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.36 – 4.26 (m, 3H), 3.96 (t, J = 6.1 Hz, 2H), 2.97 – 2.83 (m, 1H), 2.64 – 2.52 (m, 1H), 2.39 (td, J = 13.1, 4.4 Hz, 1H), 1.96 (dd, J = 11.9, 6.2 Hz, 3H), 1.66 – 1.59 (m, 2H), 1.22 (s, 6H).

[0717] Example 50

[0718] Preparation of (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 83)

[0719] For this example, the same sequence of steps was followed as for Compound 88 except that 3-tert-butylpiperidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0720] Step 1: Preparation of 3-(tert-butyl)-1-nitrosopiperidine-2-carboxylic acid

[0721] Reaction was run on a 0.95 mmol scale with 3-tert-butylpiperidine-2- carboxylic acid hydrochloride to give 203 mgs (100 % Yield) of 3-(tert-butyl)-1- nitrosopiperidine-2-carboxylic acid as a yellow oil which was used without further purification. LCMS (ESI): m / z 215.050 (M+H)+.

[0722] Step 2: Preparation of 4-(tert-butyl)-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate

[0723] Reaction was run on a 0.95 mmol scale with 3-(tert-butyl)-1- nitrosopiperidine-2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-70 % iPrOAc in Heptanes) to give 174.6 mgs (94 % Yield) of 4-(tert- butyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 197.050 (M+H)+.

[0724] Step 3: Preparation of ethyl 4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine-2-carboxylate

[0725] Reaction was run on a 0.89 mmol scale with 4-(tert-butyl)-4,5,6,7- tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-45% iPrOAc in Heptanes) to give 41.1 mgs (19 % Yield) of ethyl 4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a brown oil. LCMS (ESI): m / z 251.050 (M+H)+.

[0726] Step 4: Preparation of (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methanol

[0727] Reaction was run on a 0.164 mmol scale with ethyl 4-(tert-butyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 31.5 mgs (92 % Yield) of (4-(tert- butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 209.100 (M+H)+.

[0728] Step 5: Preparation of (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0729] Reaction was run on a 0.08 mmol scale with 3-[6-(aminomethyl)-7-fluoro- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.13.18 mgs of (4-(tert-butyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (31 % Yield) following preparative HPLC (Gemini-NX C18, column dimensions 50 x 30mm, 5µm, Neat Water / ACN). LCMS (ESI): m / z 526.24 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.80 (t, J = 6.0 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.13 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.90 (s, 2H), 4.45 (d, J = 17.7 Hz, 1H), 4.36 – 4.25 (m, 3H), 4.07 (d, J = 12.5 Hz, 1H), 3.86 (td, J = 11.7, 4.2 Hz, 1H), 2.91 (ddd, J = 18.0, 13.5, 5.4 Hz, 1H), 2.71 – 2.55 (m, 2H), 2.38 (qd, J = 13.1, 4.3 Hz, 1H), 2.09 – 1.90 (m, 3H), 1.69 (d, J = 12.8 Hz, 1H), 1.59 – 1.45 (m, 1H), 0.94 (s, 9H).

[0730] Example 51

[0731] Preparation of Preparation of (4-(trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate (Compound 84)

[0732] For this example, the same sequence of steps was followed as for Compound 88 except that 3-(trifluoromethyl)piperidine-2-carboxylic acid was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0733] Step 1: Preparation of 1-nitroso-3-(trifluoromethyl)piperidine-2-carboxylic acid

[0734] Reaction was run on a 0.95 mmol scale with 3-(trifluoromethyl)piperidine- 2-carboxylic acid to give 114.2 mgs (53 % Yield) of 1-nitroso-3- (trifluoromethyl)piperidine-2-carboxylic acid as a yellow oil which was used without further purification. LCMS (ESI): m / z 227.00 (M+H)+.

[0735] Step 2: Preparation of 4-(trifluoromethyl)-4,5,6,7-tetrahydro- [1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate

[0736] Reaction was run on a 0.50 mmol scale with 1-nitroso-3- (trifluoromethyl)piperidine-2-carboxylic acid. Reaction purified by silica gel column chromatography (0-80 % iPrOAc in Heptanes) to give 89.3 mgs (85 % Yield) of 4- (trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate as a white solid. LCMS (ESI): m / z 209.000 (M+H)+.

[0737] Step 3: Preparation of ethyl 4-(trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[0738] Reaction was run on a 0.43 mmol scale with 4-(trifluoromethyl)-4,5,6,7- tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate. Reaction purified by silica gel column chromatography (0-40 % iPrOAc in Heptanes) to give 103.9 mgs (92 % Yield) of ethyl 4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate as a brown oil. LCMS (ESI): m / z 263.00 (M+H)+.1H NMR (400 MHz, CDCl3) δ 6.85 (s, 1H),4.46 – 4.36 (m, 2H), 4.32 (dt, J = 13.5, 4.6 Hz, 1H), 4.21 (ddd, J = 13.3, 8.6, 4.5 Hz, 1H), 3.75 – 3.60 (m, 1H), 2.35 – 2.19 (m, 2H), 2.09 – 1.94 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0739] Step 4: Preparation of (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methanol

[0740] Reaction was run on a 0.16 mmol scale with ethyl 4-(trifluoromethyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate. Gave 33.8 mgs (96 % Yield) of (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 221.100 (M+H)+.

[0741] Step 5: Preparation of (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0742] Reaction was run on a 0.08 mmol scale with 3-[6-(aminomethyl)-7-fluoro- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.8.22 mgs of (4- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((2-(2,6- dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (19% Yield) following preparative HPLC (Gemini-NX C18, column dimensions 50 x 30mm, 5µm, 0.1% Formic Acid in Water / ACN). LCMS (ESI): m / z 538.17 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.83 (t, J = 6.1 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.20 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.94 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.36 – 4.26 (m, 3H), 4.16 – 3.97 (m, 3H), 2.90 (ddd, J = 18.0, 13.4, 5.4 Hz, 1H), 2.64 – 2.52 (m, 1H), 2.38 (qd, J = 13.1, 4.3 Hz, 1H), 2.20 – 2.05 (m, 2H), 1.97 (td, J = 13.2, 6.1 Hz, 2H), 1.88 – 1.76 (m, 1H).

[0743] Example 52

[0744] Preparation of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate hydrochloride (Compound 85)

[0745] Step 1: Preparation of ((3,3-dimethylcyclohex-1-en-1- yl)oxy)trimethylsilane

[0746] To a solution of copper (I) iodide (0.08 mL, 2.27 mmol) in THF (30 mL) was added 3-methylcyclohex-2-en-1-one (5.15 mL, 45.39 mmol) in THF (20 mL) and TMSCl (5.42 g, 49.93 mmol) in THF (15 mL) at -60oC under N2 (15 psi) and the mixture was stirred at -60oC for 15 min. methylmagnesium bromide (22.7 mL, 68.09 mmol) was added at -60oC and the mixture was stirred at -60oC for 1h. The mixture was warmed to 25 °C and stirred for 1 h and the mixture was quenched slowly with saturated NH4Cl solution (60 mL). The mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layer was dried over Na2SO4and concentrated. The residue was purified by flash column (100% petroleum ether) to afford the title compound (3.45 g, 38% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.66 (s, 1H), 1.94 (td, J = 6.4, 1.2 Hz, 2H), 1.73-1.62 (m, 2H), 1.37-1.31 (m, 2H), 0.98 (s, 6H), 0.18 (s, 9H).

[0747] Step 2: Preparation of 2-bromo-3,3-dimethylcyclohexan-1-one

[0748] To a solution of ((3,3-dimethylcyclohex-1-en-1-yl)oxy)trimethylsilane (2.0 g, 10.08 mmol) in THF (30 mL) was added methyllithium (9.45 mL, 15.12 mmol) at 0oC under N2(15 psi) and the mixture was stirred at 0oC for 10 min. The mixture was cooledto -60 °C and Br2(0.52 mL, 10.08 mmol) in THF (10 mL) was added slowly. The mixture was stirred at -60 °C for 1 min, then rapidly mixture was quenched with saturated NaHCO3 solution (20 mL) at -60 °C under N2 (15 psi). The mixture was extracted with ethyl acetate (3 × 70 mL) and the combined organic layer was dried over Na2SO4and concentrated. The residue was purified by flash column (0-100% ethyl acetate in petroleum ether) to afford the title compound (1.8 g, 87% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.17 (s, 1H), 3.00-2.90 (m, 1H), 2.34-2.25 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.83 (m, 2H), 1.60-1.52 (m, 1H), 1.14 (s, 3H), 1.08 (s, 3H).

[0749] Step 3: Preparation of ethyl 7,7-dimethyl-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate

[0750] To the mixture of 2-bromo-3,3-dimethylcyclohexan-1-one (1400.0 mg, 6.83 mmol) in EtOH (36 mL) was added ethyl 2-amino-2-thioxoacetate (909.05 mg, 6.83 mmol) at 0 C. Then the resulting mixture was stirred at 90oC for 16 h under nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol. The residue was purified by pre- TLC (50% ethyl acetate in petroleum ether) and pre-HPLC (water(FA)- ACN, 55-85%) again to afford the title compound(35mg, 2% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.46 (q, J = 7.2 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.68 (s, 2H), 1.65 (t, J = 6.4 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.04 (s, 6H). LCMS (ESI): m / z 240.1 [M + H]+.

[0751] Step 4: Preparation of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol

[0752] To a solution of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylate (38.0 mg, 0.16 mmol) in MeOH (1.5 mL) was added NaBH4(48.05 mg, 1.27 mmol) slowly at 0℃. The mixture was stirred at 0℃ for 0.5 h. The mixture was stirred at 25oC for 2 h. The reaction mixture was diluted with water (0.5 mL), and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over with Na2SO4,filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (50-100% ethyl acetate in petroleum ether) to afford (7,7- dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methanol (20mg, 63.8% yield)as a white solid.1H NMR (400 MHz, CDCl3) δ 4.94 (s, 2H), 2.78 (t, J = 7.2Hz, 2H), 2.62 (s, 2H), 1.65-1.63 (m, 2H), 1.05 (s, 6H). LCMS (ESI): m / z 198.1 [M + H]+.

[0753] Step 5: Preparation of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl 1H-imidazole-1-carboxylate

[0754] To a solution of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (20.0 mg, 0.1 mmol) in THF (1.5 mL) was added CDI (24.66 mg, 0.15 mmol) at 25oC, and the solution was stirred at 25oC for 0.5 h. The crude product was directly used to the next step. LCMS (ESI): m / z 292.0 [M + H]+.

[0755] Step 6: Preparation of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate hydrochloride

[0756] To a solution of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl 1H-imidazole-1-carboxylate (29.0 mg, 0.1 mmol) in DMF (1.5 mL) was added DBU (0.03 mL, 0.2 mmol).and TEA (0.03 mL, 0.2 mmol) and 3-[6-(aminomethyl)-7- fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride (52.19 mg, 0.16 mmol). The mixture was stirred at 25oC for 16 hours. Then the residue was purified by pre-HPLC (water(HCl)-ACN, 38-68%) to give the title compound (2 mg, 3.8% yield) as a white solid.1H NMR (400 MHz,DMSO-d6) δ 11.00(s, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 5.19 (s, 2H), 5.07 (dd, J = 12.8, 5.6 Hz, 1H), 4.50-4.41 (m, 1H), 4.37-4.28 (m, 3H), 2.98-2.84 (m, 1H), 2.73 (t, J = 6.4 Hz, 2H), 2.68-2.56 (m, 1H),2.46 (s, 2H), 2.41-2.32 (m, 1H), 2.03-1.95 (m, 1H), 1.55 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H). LCMS (ESI): m / z 515.1 [M + H]+.

[0757] Example 53

[0758] Preparation of (7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 86)

[0759] Step 1: Preparation of 2-chloro-3-(trifluoromethyl)cyclohexan-1-one

[0760] To an oven-dried borosilicate vial equipped with a magnetic stirrer, cyclohex-2-en-1-one (2.00 g, 20.80 mmol, 1.00 eq), Cu(dap)2Cl (92 mg, 0.10 mmol, 0.005 eq) and K2HPO4(725 mg, 4.16 mmol, 0.20 eq) were added. After covering with nitrogen, 1,2-dichloroethane (100 mL) and CF3SO2Cl (7.01 g, 41.61 mmol, 2.00 eq) were added in subsequence. The reaction mixture was stirred overnight at room temperature while being irradiated by a fluorescent light bulb (Daylight GE Energy Smart, 26 W, 1600 lumens) mounted directly above the flask, and then the solution was removed by rotary evaporation. The residue was purified by column chromatography on silica gel (0 - 5% ethyl acetate in petroleum ether) to afford the title compound (2.60 g, 62% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) 4.41 - 4.40 (m, 1H), 3.09 - 2.67 (m, 2H), 2.44 - 1.63 (m, 6H).

[0761] Step 2: Preparation of ethyl 7-(trifluoromethyl)-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate

[0762] To the mixture of 2-chloro-3-(trifluoromethyl)cyclohexan-1-one (2.00 g, 9.97 mmol, 1.00 eq) in ethanol (40 mL) was added ethyl 2-amino-2-thioxoacetate (2.66 g, 19.94 mmol, 2.00 eq) at 25 °C. Then the resulting mixture was stirred at 90oC for 16 hours under nitrogen atmosphere. The reaction mixture was concentrated under vacuo to remove the ethanol. The residue was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3) and the organic layers was washed with brine (20 mL). The organic layers was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0% - 5%) to afford the title compound (100 mg, 4% yield) as a yellow solid. LCMS (ESI): m / z 280.0 (M+H)+.

[0763] Step 3: Preparation of (7-(trifluoromethyl)-4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl)methanol

[0764] To a solution of ethyl 7-(trifluoromethyl)-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxylate (100 mg, 0.36 mmol, 1.00 eq) in methyl alcohol (5 mL) was added NaBH4 (68 mg, 1.79 mmol, 5.00 eq) slowly at 0℃. The mixture was stirred at 0℃ for 5 minutes. Then continue to stir at 25oC for 3 hours. The solution was quenched with NH4Cl solution (5 mL) and concentrated under vacuo, the residue was purified by pre-TLC (25% ethyl acetate in petroleum ether, Rf = 0.3) to afford the title compound (30 mg, 35% yield) as a white solid. LCMS (ESI): m / z 238.0 (M+H)+.

[0765] Step 4: Preparation of (7-(trifluoromethyl)-4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate

[0766] To a solution of (7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2- yl)methanol (30 mg, 0.13mmol, 1.00 eq) in THF (2 mL), was added CDI (41 mg, 0.25 mmol, 2.00 eq), the solution was stirred at 25oC for 2 hours, the resulting solution was added to a mixture of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (83 mg, 0.25 mmol, 2.00 eq), TEA (26 mg, 0.25 mmol, 2.00 eq) and DBU (29 mg, 0.19 mmol, 1.50 eq) in DMF (2 mL), the mixture was stirred at 25oC for 12 hours. The solution was purified by pre-HPLC (C18150*30mm, water (HCl)-ACN, 50- 80%) to afford the title compound (2 mg, 3% yield) as a white solid. LCMS (ESI): m / z 554.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.12 (t, J = 6.0 Hz, 1H), 7.59 (t, J = 6.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 5.07 (dd, J = 5.2 Hz, 13.2 Hz, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.34 - 4.30 (m, 3H), 4.13 - 4.07 (m, 1H), 2.95 - 2.86 (m, 1H), 2.73 (t, J = 4.8 Hz, 2H), 2.62 - 2.57 (m, 1H), 2.42 - 2.33 (m, 1H), 2.11 - 2.07 (m,1H), 2.01 - 1.94 (m, 2H), 1.91 - 1.85 (m, 1H), 1.82 - 1.75 (m, 1H).

[0767] Example 54

[0768] Preparation of (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 87)

[0769] For this example, the same sequence of steps was followed as for Compound 88 except that 3,3-dimethylpyrrolidine-2-carboxylic acid hydrochloride was used in the first step instead of 3-methylpyrrolidine-2-carboxylic acid hydrochloride.

[0770] Step 1: Preparation of 3,3-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid

[0771] Reaction was run on a 1.00 mmol scale with 3,3-dimethylpyrrolidine-2- carboxylic acid hydrochloride to give 130.8 mgs (76% Yield) of (3,3-dimethyl-1- nitrosopyrrolidine-2-carboxylic acid as a white solid which was used without further purification. LCMS (ESI): m / z 173.050 (M+H)+.

[0772] Step 2: Preparation of 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2- c][1,2,3]oxadiazol-7-ium-3-olate

[0773] Reaction was run on a 0.76 mmol scale with (3,3-dimethyl-1- nitrosopyrrolidine-2-carboxylic acid. Reaction purified by silica gel column chromatography. (0-80% iPrOAc in Heptanes) to give 115.1 mgs (98% Yield) of 4,4- dimethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3-olate as a white solid. LCMS (ESI): m / z 155.100 (M+H)+.

[0774] Step 3: Preparation of ethyl 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylate

[0775] Reaction was run on a 0.75 mmol scale with 4,4-dimethyl-5,6-dihydro-4H- pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3-olate. Reaction purified by silica gel column chromatography (0-50% iPrOAc in Heptanes) to give 43.2 mgs (28% Yield) of ethyl 4,4- dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate as a brown oil. LCMS (ESI): m / z 209.000 (M+H)+.

[0776] Step 4: Preparation of (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 2-yl)methanol

[0777] Reaction was run on a 0.207 mmol scale with ethyl 4,4-dimethyl-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. Gave 35.6 mgs (103% Yield) of (4,4- dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol as a clear oil which was used without further purification. LCMS (ESI): m / z 167.100 (M+H)+.

[0778] Step 5: Preparation of (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0779] Reaction was run on a 0.104 mmol scale with 3-[6-(aminomethyl)-7-fluoro- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochloride.13.59 mgs of (4,4-dimethyl-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate was obtained as a white solid (27% Yield) following first preparative HPLC (Gemini-NX C18, column dimensions 50 x 30mm, 5µm, 0.1% Formic Acid in Water / ACN) followed by achiral SFC (2-Ethyl Pyridine column, column dimensions 150 x 21.2mm, 5µm, Carbon Dioxide / Neat MeOH). LCMS (ESI): m / z 484.20 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.78 (t, J = 6.0 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 5.92 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.88 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.36 – 4.26 (m, 3H), 4.06 (t, J = 7.0 Hz, 2H), 2.90 (ddd, J = 17.5, 13.6, 5.5 Hz, 1H), 2.65 – 2.54 (m, 1H), 2.45 – 2.28 (m, 3H), 2.09 – 1.96 (m, 1H), 1.26 (s, 6H).

[0780] Example 55

[0781] Preparation of (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 88)

[0782] Step 1: Preparation of 3-methyl-1-nitrosopyrrolidine-2-carboxylic acid

[0783] To a solution of 3-methylpyrrolidine-2-carboxylic acid hydrochloride (174 mg, 1.00 mmol, 1.0 equiv.) in H2O (1.25 mL) at 0°C was added sodium nitrite (3.00 mmol, 207 mg, 3.0 equiv.) followed by HCl (12.18 mol / L) in H2O (1.20 mmol, 0.0985 mL, 1.2 equiv.). The mixture was then gradually allowed to warm to room temperature while stirring overnight. Once the reaction was complete, the reaction was diluted additional H2O and extracted with iPrOAc. The aqueous layer was extracted an additional 2x with iPrOAc. The organic layers were then combined and washed with brine (1x), dried over anhydrous Na2SO4, filtered, and concentrated to give 3-methyl-1-nitroso-pyrrolidine-2- carboxylic acid (134.0 mg, 84.7% yield) as an off-white semi-solid. The crude material was then used directly without further purification. LCMS (ESI): m / z 159.050 (M+H)+.

[0784] Step 2: Preparation of 4-methyl-5,6-dihydro-4H-pyrrolo[1,2- c][1,2,3]oxadiazol-7-ium-3-olate

[0785] To a solution of crude 3-methyl-1-nitroso-pyrrolidine-2-carboxylic acid (0.85 mmol, 134.0 mg, 1.0 equiv.) in toluene (1.7 mL) at 0 °C was added trifluoroacetic anhydride (1.27 mmol, 0.18 mL, 1.5 equiv.) dropwise. The resulting solution was gradually allowed to warm to rt. Once reaction was complete as judged by full consumption of starting material by LCMS, the reaction was directly concentrated under reduced pressure and purified by silica gel column chromatography (0-80% iPrOAc in Heptanes) to afford the desired product 4-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3-olate (104.9 mg, 88% yield) as a red oil. LCMS (ESI): m / z 141.100 (M+H)+.

[0786] Step 3: Preparation of ethyl 4-methyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylate

[0787] To a 20 mL microwave vial containing 4-methyl-5,6-dihydro-4H- pyrrolo[1,2-c]oxadiazol-7-ium-3-olate (104.9 mg, 1.0 equiv.) was added ethyl propiolate (1.50 mmol, 146.9 mg, 0.15 mL, 2.0 equiv.) followed by Xylenes (2.5 mL). Reaction wascapped and stirred at 120 °C overnight. Reaction was then quenched by cooling to room temperature and diluting with water. The aqueous layer was then extracted with DCM (3x), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography. (0-50% iPrOAc in Heptanes). Note that both desired product and regioisomer formed from the cyclization but could be separated during purification. After purification 4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (46.3 mg, 32% yield) was obtained as a brown oil. LCMS (ESI): m / z 195.000 (M+H)+.

[0788] Step 4: Preparation of (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2- yl)methanol

[0789] To 2 dram vial containing 4-methyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylate (46.3 mg, 0.24 mmol, 1.0 equiv.) in anhydrous THF (1.5 mL) was added lithium aluminum hydride (2.3 mol / L) in 2-methyltetrahydrofuran (0.72 mmol, 0.30 mL, 3.0 equiv.) dropwise at 0°C. Reaction was allowed to gradually warm to rt after 30 minutes. Once complete, the reaction was quenched by the portion wise addition of Sodium Sulfate Dodecahydrate until no further gas evolution observed. Suspension was then filtered through Celite, washed with additional DCM, and concentrated to afford (4- methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (38 mg, 105% yield) as a clear oil which was used directly without further purification. LCMS (ESI): m / z 153.100 (M+H)+.

[0790] Step 5: Preparation of (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2- yl)methyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0791] The crude alcohol (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2- yl)methanol (36.2 mg, 0.238 mmol, 2.0 equiv.) and 1,1'-carbonyldiimidazole (33.6 mg, 0.207 mmol, 1.75 equiv.) were added to a 2 dram vial and dissolved in THF (0.30 mL). Triethylamine (0.47 mmol, 0.07 mL, 4 equiv.) was then added, and the reaction was allowed to stir at rt for 30 minutes.

[0792] To a separate vial containing 3-[6-(aminomethyl)-7-fluoro-1-oxo- isoindolin-2-yl]piperidine-2,6-dione;hydrochloride (39 mg, 0.12 mmol, 1.0 equiv.) was added THF (0.22 mL), DMF (0.22 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mmol, 0.044 mL, 2.5 equiv.). The activated alcohol solution was then added to this reaction in one portion, and excess THF ( 0.22 mL) was used to rinse the vial with activated alcohol and ensure full transfer. The reaction was stirred at rt until reaction was complete. Then the reaction was quenched by adding saturated aqueous solution of NH4Cl and extracted with DCM (3x). The organics layers were combined, dried with anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified first by preparative HPLC (Gemini- NX C18, column dimensions 50 x 30mm, 5µm, 0.1% Formic Acid in Water / ACN) followed by achiral SFC (2-Ethyl Pyridine column, column dimensions 150 x 21.2mm, 5µm, Carbon Dioxide / Neat MeOH) to afford the title compound (10.29 mg, 18.6% yield) as a white solid. LCMS (ESI): m / z 470.18 (M+H)+.1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.77 (t, J = 6.0 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 5.96 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.89 (s, 2H), 4.45 (d, J = 17.6 Hz, 1H), 4.35 – 4.23 (m, 3H), 4.08 (ddd, J = 12.9, 8.9, 4.1 Hz, 1H), 3.96 (dt, J = 10.6, 7.7 Hz, 1H), 3.20 (h, J = 7.0 Hz, 1H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.70 (dtd, J = 12.3, 8.0, 4.1 Hz, 1H), 2.60 (ddd, J = 17.2, 4.5, 2.3 Hz, 1H), 2.45 – 2.29 (m, 1H), 2.10 – 1.94 (m, 2H), 1.21 (d, J = 6.9 Hz, 3H).

[0793] Example 56

[0794] Preparation of (8-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 89)

[0795] Step 1: Preparation of methyl 2-(3-methyl-2-oxocyclohexyl)acetate

[0796] To a solution of 2-methylcyclohexan-1-one (5.00 g, 44.58 mmol, 1.00 eq) in THF (100 mL), was added 2M LDA in THF (22 mL, 44.58 mmol, 1.00 eq) at -78 ℃ under N2. The mixture was stirred for 20 minutes at -78 ℃, then methyl 2-bromoacetate (10.23 g, 66.86 mmol, 1.50 eq) and HMPA (9.59 g, 53.49 mmol, 1.20 eq) was added at - 78 ℃, and the stirring was continued at -78 ℃ for 3 hours, the solution was quenched with NH4Cl solution and extracted with ethyl acetate (30 mL × 3), the organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuo, the residue was purified by column chromatography (0 - 5% ethyl acetate in petroleum ether) to afford the title compound (8.00 g, 98% yield, cis:trans mixture,1.6：1) as a white solid.1H NMR (400 MHz, CDCl3) 3.70 (s, 3H), 3.67 (s, 3H), 2.85-2.93 (m, 2H), 2.81 (m, 2H), 2.74-3.70 (s, 3H), 2.43-2.53 (m, 2H), 2.09-2.18 (m, 6H), 1.74-1.90 (m, 4H), 1.30-1.46 (m, 4H), 1.21 (d, J = 7.6 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H).

[0797] Step 2: Preparation of 8-methyl-4,4a,5,6,7,8-hexahydrocinnolin-3(2H)-one

[0798] To a solution of methyl 2-(3-methyl-2-oxocyclohexyl)acetate (8.00 g, 43.42 mmol, 1.00 eq) in ethanol (100 mL), was added 85% N2H4.H2O (5.11 g, 86.85 mmol, 2.00 eq), the solution was stirred at 80 ℃ for 2 hours, the solution was concentrated under vacuo to afford the title compound (7.00 g, 97% yield) as a yellow solid. LCMS (ESI): m / z 167.1 (M+H)+.

[0799] Step 3: Preparation of 8-methyl-5,6,7,8-tetrahydrocinnolin-3(2H)-one

[0800] To a solution of 8-methyl-4,4a,5,6,7,8-hexahydrocinnolin-3(2H)-one (7.00 g, 42.11 mmol, 1.00 eq) in acetonitrile (100 mL), was added CuCl2 (11.32 g, 84.23 mmol, 2.00 eq). The solution was stirred at 84 ℃ for 1 hour. The solution was filtered and washed with water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic layer was concentrated under vacuo and purified by column chromatography (0 - 50% ethyl acetate in petroleum ether ) to afford the title compound (2.40 g, 35% yield) as a yellow solid. LCMS (ESI): m / z 165.1 (M+H)+.

[0801] Step 4: Preparation of 3-chloro-8-methyl-5,6,7,8-tetrahydrocinnoline

[0802] POCl3 (8.96 g, 263.09 mmol, 8.00 eq) in flask and purged with N2, till temperature cooled to 0 ℃, 8-methyl-5,6,7,8-tetrahydrocinnolin-3(2H)-one (1.20 g, 7.31 mmol, 1.00 eq) was added, the solution was stirred at 100 ℃ for 30 minutes under N2, the solution was poured in to water (30 mL) slowly, and extracted with ethyl acetate (20 mL × 3), the organic layer was concentrated under vacuo, purified by column chromatography (0 - 10% ethyl acetate in petroleum ether ) to afford the title compound (700 mg, 52% yield) as a yellow solid. LCMS (ESI): m / z 182.8 (M+H)+.

[0803] Step 5: Preparation of methyl 8-methyl-5,6,7,8-tetrahydrocinnoline-3- carboxylate

[0804] To a solution of 3-chloro-3-chloro-8-methyl-5,6,7,8-tetrahydrocinnoline (600 mg, 3.28 mmol, 1.00 eq) in DMSO(10 mL), was added K2CO3 (690 mg, 4.93 mmol, 1.50 eq), and Pd2(dba)3(36 mg, 0.16 mmol, 0.10 eq) at 25 ℃ under N2. The suspension was degassed under vacuo and purged with CO, the mixture was stirred at 100 ℃ for 1.5 hours, the solution was diluted with water (5 mL) and extracted with ethyl acetate(10 mL × 3), the organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuo, the residue was purified by column chromatography (0 - 10% ethyl acetate in petroleum ether) to give the title compound (330 mg, 49% yield) as a white solid. LCMS (ESI): m / z 207.1 (M+H)+.

[0805] Step 6: Preparation of (8-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methanol

[0806] To a solution of methyl 8-methyl-5,6,7,8-tetrahydrocinnoline-3-carboxylate (200 mg, 0.97 mmol, 1.00 eq) in methyl alcohol (4 mL) and THF (2 mL), was added CaCl2 (430 mg, 3.88 mmol, 4.00 eq) at 0℃, followed by the addition of NaBH4 (73 mg, 1.94 mmol, 2.00 eq) slowly. The mixture was stirred at 0 ℃ for 5 minutes. The mixture was stirred at 25 ℃ for 2 hours. the solution was quenched with NH4Cl solution (3 mL) and concentrated under vacuo, the residue was purified by column chromatography (0 - 80% EE(ethanol / ethyl acetate 1 / 3) in petroleum ether) to afford the title compound (130 mg, 75% yield) as a colorless oil. LCMS (ESI): m / z 179.1 (M+H)+.

[0807] Step 7: Preparation of (8-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0808] To a solution of (8-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methanol (30 mg, 0.17 mmol, 1.00 eq) in THF (2 mL) was added CDI (55 mg, 0.34 mmol, 2.00 eq). The solution was stirred at 25 ℃ for 2 hours, the resulting solution was added to a mixture of 3- (6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (91 mg, 0.25 mmol, 1.50 eq), triethylamine (34 mg, 0.34 mmol, 2.00 eq) and DBU (26 mg, 0.17 mmol, 1.00 eq) in DMF (2 mL), the mixture was stirred at 25 ℃ for 12 hours. The solution was purified by pre-HPLC (C18150*40mm, water (HCl)-ACN, 25 - 55%) to afford the title compound (12 mg, 12.5% yield) as a white solid. LCMS (ESI): m / z 530.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) 11.02 (s, 1H), 8.11 (t, J = 6.0 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.58 (s, 1H), 5.27 (s, 2H), 5.09 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 4.49-4.45 (m, 1H), 4.33 - 4.28 (m, 3H), 3.27 - 3.19 (m, 1H), 2.94 - 2.82 (m, 3H), 2.61 - 2.56 (m, 1H), 2.45 - 2.42 (m, 1H), 2.03 - 1.99 (m, 2H), 1.85 - 1.80 (m, 1H), 1.77 - 1.69 (m, 1H), 1.67 - 1.58 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H).

[0809] Example 57

[0810] Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate (Compound 90)

[0811] Step 1: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl)methanol

[0812] To a solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (100 mg, 0.65 mmol， 1.00 eq) in Methyl alcohol (2 mL) and acetic acid (0.2 mL)was added formaldehyde (0.02 mL, 0.65 mmol, 1.00 eq) at 0 °C and the mixture was stirred at25oC for 0.5h. Sodium cyanotrihydroborate (82 mg, 1.31 mmol, 2.00 eq) was added and stirred at 50 °C for 1h. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 × 4 mL) and the combined organic layers was washed with brine(2 x 6 mL). The organic layers was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane / methyl alcohol =20 / 1 to 10 / 1) to afford the title compound (50 mg, 45% yield) as a colourless oil.1H NMR (400 MHz, CHLOROFORM-d) δ 5.94 (s, 1H), 4.57 (s, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.59 (s, 2H), 2.85 (t, J = 5.2 Hz, 2H), 2.45 (s, 3H)

[0813] Step 2: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl)methyl 1H-imidazole-1-carboxylate

[0814] A mixture of CDI (48 mg, 0.3 mmol, 1.00 eq) in THF (1 mL) was added (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (50 mg, 0.3 mmol, 1.00 eq) at 25oC. Then the resulting mixture was stirred at 25oC for 0.5 h. The reaction mixture title compound (78 mg, 99% yield) as a colourless oil was used directly in the next step without purification. LCMS (ESI): m / z 284.1 (M+Na)+.

[0815] Step 3: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 2-yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0816] A solution of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl)methyl 1H-imidazole-1-carboxylate (78 mg, 0.3 mmol, 1.00 eq), 3-(6-(aminomethyl)-4- chloro-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (108 mg, 0.3 mmol, 1.00 eq), triethylamine (0.12 mL, 0.9 mmol, 3.00 eq) and DBU (0.04 mL, 0.3 mmol, 1.00 eq) in DMF (2 mL) was stirred at 25oC for 12 hours. The reaction mixture was concentrated to dryness. The residue was purified by Pre-HPLC (Xtimate C18150 * 40 mm * 10 um, water( FA)-ACN, 10-40%) to afford the title compound (11.99 mg, 7% yield)as a white soild. LCMS (ESI): m / z 519.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.82 (t, J = 5.2 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 5.98 (s, 1H), 5.13 - 5.04 (m, 1H), 4.92 (s, 2H), 4.50 - 4.43 (m, 1H), 4.35 - 4.30 (m, 1H), 4.30 - 4.23 (m, 2H), 4.03 (t, J = 5.6 Hz, 2H), 3.53 (s, 2H), 2.96 - 2.85 (m, 1H), 2.80 (t, J = 5.6 Hz, 2H), 2.63 - 2.56 (m, 1H), 2.47 - 2.40 (m, 1H), 2.36 (s, 3H), 2.07 - 1.96 (m, 1H).

[0817] Example 58

[0818] Preparation of (5-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 91)

[0819] Step 1: Preparation of trimethyl((3-methylcyclohex-1-en-1-yl)oxy)silane trimethyl((3-methylcyclohex-1-en-1-yl)oxy)silane

[0820] Copper (I) iodide (1.39 g, 7.28 mmol, 0.1eq) was added in to 3M methylmagnesium bromide (26.7 mL, 80.1 mmol, 1.1 eq) at 20 °C. The resulting solution was cooled to -30 °C, a solution of cyclohex-2-en-1-one (7.05 mL, 72.82 mmol, 1eq) in THF (100 mL) was added dropwise, the reaction mixture was cooled to −50 °C and then was stirred at this temperature for 30 min. The mixture was cooled to −60 °C, triethylamine (20.3 mL, 145.64 mmol, 2 eq.) and chlorotrimethylsilane (13.85 mL, 109.23 mmol, 1.5eq) were added in sequence to the cooled solution. The resulting mixture wasfurther cooled to −78 °C, and was stirred at this temperature for 1 h. The product mixture was warmed over 10 min to 20 °C, and the warmed solution was stirred for 10 min at 20 °C. The reaction mixture was then quenched with ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, the residue was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 1%) to afford the title compound (4.8g, 35% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.75 (d, J = 1.2 Hz, 1H), 2.32 - 2.16 (m, 1H), 2.03 - 1.91 (m, 2H), 1.79 - 1.66 (m, 2H), 1.10 - 1.02 (m, 1H), 0.95 (d, J = 7.2 Hz, 3H), 0.90 - 0.86 (m, 1H), 0.19 (s, 9H).

[0821] Step 2: Preparation of methyl 2-(2-methyl-6-oxocyclohexyl)acetate

[0822] TBAF (26.0 mL, 26.04 mmol, 1 eq) was added to methyl 2-bromoacetate (2.46 mL, 26.04 mmol, 1eq) and trimethyl((3-methylcyclohex-1-en-1-yl)oxy)silane (4.8 g, 26.04 mmol, 1eq) in THF (30 mL), the reaction mixture was stirred under nitrogen at 20 °C for 2 h. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to afford the title compound (900 mg, 18% yield) as yellow oil.

[0823] Step 3: Preparation of 5-methyl-4,4a,5,6,7,8-hexahydrocinnolin-3(2H)-one

[0824] A mixture of methyl 2-(2-methyl-6-oxocyclohexyl)acetate (900 mg, 4.89 mmol, 1 eq) in ethanol (10 mL) was added hydrazine hydrate (0.5 mL, 10.19 mmol, 2 eq) . The reaction mixture was stirred under nitrogen at 80 °C for 1 h, the mixture was concentrated under vacuum to afford the title compound (812 mg, 100% yield) as yellow solid. LCMS (ESI): m / z 166.8 (M+H)+.

[0825] Step 4: Preparation of 5-methyl-5,6,7,8-tetrahydrocinnolin-3(2H)-one

[0826] To a solution of 5-methyl-4,4a,5,6,7,8-hexahydrocinnolin-3(2H)-one (810 mg, 4.87mmol, 1 eq) in acetonitrile (20 mL) was added copper(II) chloride (1.22 g, 9.04 mmol, 1.8 eq), the solution was stirred at 84 °C for 1 hours. The reaction mixture was quenched with 30 mL of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate (30 mL × 3), the organic layers were combined, the organic phase was dried to afford the title compound (800 mg, 99% yield) as a yellow solid. LCMS (ESI): m / z 164.8 (M+H)+.

[0827] Step 5: Preparation of 3-chloro-5-methyl-5,6,7,8-tetrahydrocinnoline

[0828] 5-Methyl-5,6,7,8-tetrahydrocinnolin-3(2H)-one (800.0 mg, 4.87 mmol, 1 eq) was added into phosphoryl trichloride (3.0 mL, 32.61 mmol, 6.7 eq) at 0 °C, the solution was stirred at 100 °C for 1 h. The reaction mixture was quenched with 20 mL of water. the residue was basified by aq.NaHCO3 to pH = 8. The resulting solution was extracted with ethyl acetate (30 mL × 3), the organic phase was dried and filtered to afford crude and the crude was purified by column (0-15% ethyl acetate in petroleum ether) to afford the title compound (550 mg, 61% yield) as a colorless oil. LCMS (ESI): m / z 182.8 (M+H)+

[0829] Step 6: Preparation of methyl 5-methyl-5,6,7,8-tetrahydrocinnoline-3- carboxylate

[0830] To a solution of 3-chloro-5-methyl-5,6,7,8-tetrahydrocinnoline (550.0 mg, 3.01 mmol, 1 eq) in dimethyl sulfoxide (8 mL) was added methanol (1.83 mL, 45.17mmol, 15 eq), K2CO3(633.35 mg, 4.52 mmol, 1.5 eq), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (184.37 mg, 0.3 mmol, 0.1 eq) and palladium(ii)acetate (33.8 mg,0.15 mmol, 0.05 eq) at 25 °C under N2. The suspension was degassed under vacuo and purged with CO (15 psi), the mixture was stirred at 100 °C for 1.5 hours. The reaction mixture was quenched with 20 mL of water, the residue was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (50 mL × 3), the organic phase was dried and filtered to afford crude and the crude was purified by column (0-40% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 56% yield) as a colorless oil. LCMS (ESI): m / z 207.1 (M+H)+.

[0831] Step 7: Preparation of (5-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methanol

[0832] To a solution of methyl methyl 5-methyl-5,6,7,8-tetrahydrocinnoline-3- carboxylate (350.0 mg, 1.7 mmol, 1 eq) in methyl alcohol (4 mL) and THF (2 mL) was added calcium chloride (753.3 mg, 6.79 mmol, 4 eq) and NaBH4 (130.0 mg, 3.44 mmol, 2 eq) slowly at 0°C. The mixture was stirred at 0°C for 5 min. The mixture was stirred at 25 °C for 2 hours. The solution was quenched with NH4Cl solution (3 mL) and concentrated under vacuo, the residue was purified by column chromatography (0-30% [(3:1) ethyl acetate / ethanol] in petroleum ether) to give the title compound (250 mg, 82% yield) as colorless oil. LCMS (ESI): m / z 178.9 (M+H)+.

[0833] Step 8: Preparation of (5-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methyl 1H-imidazole-1-carboxylate

[0834] To a solution of (5-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methanol (60.0 mg, 0.27 mmol, 1 eq) in THF (2 mL) was added CDI (48.04 mg, 0.3 mmol, 1.1 eq). The solution was stirred at 25 °C for 2 hours. The reaction was used in the next step directly.

[0835] Step 9: Preparation of (5-methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0836] To a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (101.82 mg, 0.28 mmol, 1.1 eq), DBU ( 38.44 uL, 0.26 mmol, 1eq), triethylamine (71.66 uL, 0.51 mmol, 2 eq) in DMF (2 mL) was added (5- methyl-5,6,7,8-tetrahydrocinnolin-3-yl)methyl 1H-imidazole-1-carboxylate (70.0 mg, 0.26 mmol, 1 eq) in THF (2 mL). The mixture was stirred at 25 °C for 12 hours. The residue was purified by Pre-HPLC (water (FA)-ACN, 23-53%) to give the title compound (30.7 mg, 22% yield) as white solid. LCMS (ESI): m / z 530.1 (M+H)+,1H NMR (400 MHz, DMSO-d6) δ 11.10 - 10.93 (m, 1H), 8.06 (t, J = 5.6 Hz, 1H), 7.64 (d, J = 5.2 Hz, 1H), 7.44 (s, 1H), 5.24 (s, 2H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.37 - 4.25 (m, 3H), 3.00 (t, J = 6.0 Hz, 2H), 2.96 - 2.85 (m, 2H), 2.62-2.59 (m, 1H), 2.47 - 2.38 (m, 1H), 2.05 - 1.97 (m, 1H), 1.95 - 1.87 (m, 2H), 1.83 - 1.73 (m, 1H), 1.50 - 1.40 (m, 1H), 1.22 (d, J = 7.2 Hz, 3H).

[0837] Example 59

[0838] Preparation of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 93)

[0839] Step 1: Preparation of 1-nitrosopiperidine-2-carboxylic acid

[0840] To a solution of piperidine-2-carboxylic acid (200 mg, 1.55 mmol，1.00 eq) and hydron chloride (0.14 mL, 1.63 mmol, 1.05 eq) in Water (10 mL) was added a solution of sodiumnitrite (117 mg, 1.70 mmol, 1.1 eq) in water (5 mL) at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 25 ℃ for 4 hours. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were concentrated to dryness under reduced pressure to give the title compound (2440 mg, 99% yield) as colorless oil. The crude was used in next step without purification.

[0841] Step 2: Preparation of 4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8- ium-3-olate

[0842] To a solution of 1-nitrosopiperidine-2-carboxylic acid (2440 mg, 15.43 mmol, 1.00 eq) in THF (50 mL) was added trifluoroacetic anhydride (2.4 mL, 16.97 mmol, 1.10 eq) at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 25 ℃ for 16 hours. The mixture was concentrated to dryness under reduced pressure to give the title compound (2100 mg, 97% yield) as colorless oil. The crude was used in next step directly without purification.

[0843] Step 3: Preparation of ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2- carboxylate

[0844] To a solution of 4,5,6,7-tetrahydrooxadiazolo[3,4-a]pyridin-8-ium-3-olate (2100 mg, 14.99 mmol, 1.00 eq) in m-Xylene (100 mL) was added ethyl propiolate (1.82 mL, 17.98 mmol, 1.20 eq). The mixture was stirred at 140 ℃ for 4 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: ethyl acetate in petroleum ether, gradient 0% to 50%) to afford the title compound (450 mg, 2.3168 mmol, 15.5% yield) as a colorless oil.1H NMR(400 MHz, CDCl3) δ 6.54 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.08 - 2.03 (m, 2H), 1.91 - 1.86 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[0845] Step 4: Preparation of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methanol

[0846] To a stirred solution of 3-hydroxy-3-[6-(trifluoromethyl)-3- pyridyl]propanenitrile (3.34g, 6.49 mmol, 1.00 eq) was added LAH (5.19 mL, 12.98 mmol, 1.20 eq) in THF (30 mL) dropwise at 0 ℃, and then warmed to room temperature and stirred for 6 hours under N2 protection. The mixture was quenched with Sodium sulfate decahydrate. Then the mixture was filtrated and concentrated to dryness under reduced pressure to give the title compound (260 mg, 8% yield) as colorless oil.1H NMR (400 MHz, MeOD) δ 6.01 (s, 1H), 4.50 (s, 2H), 4.04 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.06 - 2.01 (m, 2H), 1.88 - 1.82 (m, 2H).

[0847] Step 5: Preparation of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0848] The solution of DIPEA (0.12 mL, 0.71 mmol, 5.00 eq), (4-nitrophenyl) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylmethyl carbonate (45 mg, 0.14 mmol, 1.00 eq) and 3-[6-(aminomethyl)-4-chloro-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6- dione;hydrChloride (62 mg, 0.17 mmol, 1.20 eq) in DMF (1 mL) was stirred at 20 ℃ for 12 hours. The mixture was purified by pre-HPLC (with the following conditions: Column, C18150×30mm; mobile phase: water (FA) - ACN; Detector, UV 254 nm.) to give the title compound (17 mg, 24% yield) as a white solid. LCMS (ESI): m / s 504.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.82 (t, J = 6.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 5.95 (s, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.90 (s, 2H), 4.51 - 4.43 (m, 1H), 4.35 - 4.26 (m, 3H), 4.00 (t, J = 6.0 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.70 (t, J = 6.4 Hz, 2H), 2.63 -2.56 (m, 1H), 2.46 - 2.43 (m, 1H), 2.05 - 1.98 (m, 1H), 1.97 - 1.89 (m, 2H), 1.80 - 1.70 (m, 2H).

[0849] Example 60

[0850] Preparation of (5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate (Compound 94)

[0851] Step 1: Preparation of (5-(2,2,2-trifluoroethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol

[0852] A solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (100 mg, 0.65 mmol， 1.00 eq), N,N-Diisopropylethylamine (0.23 mL, 1.31 mmol, 2.00 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (227 mg, 0.98 mmol, 1.5 eq) in DMF (3 mL) was stirred at 60oC for 12 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3 × 15 mL) and the combined organic layers was washed with brine (2 × 20 mL). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane / methyl alcohol =20 / 1 to 10 / 1) to afford the title compound (110 mg, 71% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 5.96 (s, 1H), 4.93 (t, J = 6.0 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H), 4.02 (t, J = 5.6 Hz, 2H), 3.86 (s, 2H), 3.48 - 3.37 (m, 2H), 3.12 (t, J = 5.6 Hz, 2H)

[0853] Step 2: Preparation of (5-(2,2,2-trifluoroethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl 1H-imidazole-1-carboxylate

[0854] CDI (35 mg, 0.21 mmol, 1.00 eq) was added into the solution of (5-(2,2,2- trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (50 mg, 0.21 mmol, 1.00 eq) in THF (1 mL) at 25oC. Then the resulting mixture was stirred at 25oC for 0.5 h. The crude title compound in the reaction mixture was used directly in the next step without purification. LCMS (ESI): m / z 330.0 (M+H)+.

[0855] Step 3: Preparation of (5-(2,2,2-trifluoroethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0856] The above solution of (5-(2,2,2-trifluoroethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl 1H-imidazole-1-carboxylate (114 mg, 0.31 mmol, 1 eq) was added into triethylamine (0.09 mL, 0.63 mmol, 3 eq) and DBU (0.03 mL, 0.21 mmol, 1 eq) in DMF (2 mL). The resulting mixture was stirred at 25oC for 12 hours. The reaction mixture was concentrated to dryness. The residue was purified by Pre-HPLC (Xtimate C18150 * 40 mm * 10 um, water (FA)-ACN, 10-40%) to afford the title compound (12 mg, 7% yield) as a white solid. LCMS (ESI): m / z 587.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.84 (t, J = 5.6 Hz, 1H), 7.66 - 7.50 (m, 1H), 6.02 (s, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.92 (s, 2H), 4.52 - 4.41 (m, 1H), 4.35 - 4.30 (m, 1H), 4.29 (s, 2H), 4.05 (t, J = 4.8 Hz, 2H), 3.87 (s, 2H), 3.44 - 3.40 (m, 2H), 3.13 (t, J = 5.2 Hz, 2H), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.47 - 2.36 (m, 1H), 2.06 - 1.95 (m, 1H).

[0857] Example 61

[0858] Preparation of (1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 95)

[0859] Step 1: Preparation of (1-methyl-5-(trifluoromethyl)-1H-pyrazol-3- yl)methyl 1H-imidazole-1-carboxylate

[0860] To a solution of(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanol (30.0 mg, 0.17 mmol) in THF (1 mL) was added CDI (27.01 mg, 0.17 mmol) at 25oC and the solution was stirred at 25oC for 0.5h. The crude product was directly used to the next step. LCMS (ESI): m / z 295.0 [M + H]+.

[0861] Step 2: Preparation of (1-methyl-5-(trifluoromethyl)-1H-pyrazol-3- yl)methyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamate

[0862] To a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (59.44 mg, 0.16 mmol) in DMF (1 mL) was added DBU (0.05 mL, 0.33 mmol) and TEA (0.05 mL, 0.33 mmol) at 0 °C and stirred for 5 min. (1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl 1H-imidazole-1-carboxylate (45.0 mg, 0.16 mmol) was added at 0 °C and the reaction mixture was warmed to 25oC and stirred another 16 h. The reaction mixture was purified by pre-HPLC (water (FA)-ACN, 37-67%) to afford the title compound (24.4 mg, 27.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.93 (t, J = 5.6 Hz, 1H), 7.61 (d, J = 4.8 Hz, 1H), 6.84 (s, 1H), 5.09 (dd, J =13.2, 4.8 Hz, 1H), 4.99 (s, 2H), 4.50-4.42 (m, 1H), 4.35-4.26 (m,3H), 3.94 (s, 3H), 2.99-2.84 (m, 1H), 2.64-2.55 (m, 1H), 2.47-2.37 (m, 1H), 2.05-1.95 (m, 1H). LCMS (ESI): m / z 532.0 [M + H]+.

[0863] Example 62

[0864] Preparation of (1-(2, 2, 2-trifluoroethyl)-1H-pyrazol-3-yl) methyl ((7- chloro-2-(2, 6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl) methyl) carbamate (Compound 96)

[0865] Step 1: Preparation of 4-nitrophenyl ((1-(2, 2, 2-trifluoroethyl)-1H- pyrazol-3-yl) methyl) carbonate

[0866] To a solution of [1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methanol (40 mg, 0.22 mmol, 1.00 eq) in Dichloromethane (2 mL) was added pyridine (0.05 mL, 0.67 mmol, 3.00 eq) and DMAP (3 mg, 0.02 mmol, 0.10 eq). Then 4-nitrophenylchloroformate (90 mg, 0.44 mmol, 2.00 eq) was added at 0 ℃. The mixture was stirred at 25 °C for 12 h. The reaction was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3).The organic layers was dried over with Na2SO4, filtered and concentrated under reduced pressure to afford crude (4-nitrophenyl) [1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methyl carbonate (76 mg,0.22 mmol, 99.1% yield).The crude was used directly in next step. LCMS (ESI): m / z 346 (M+H)+

[0867] Step 2: Preparation of (1-(2, 2, 2-trifluoroethyl)-1H-pyrazol-3-yl) methyl ((7-chloro-2-(2, 6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl) methyl) carbamate

[0868] A mixture of (4-nitrophenyl) [1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methyl carbonate (76 mg, 0.22 mmol, 1.00 eq), triethylamine (153.42 ul, 1.1mmol, 5.00 eq) and 3- [6-(aminomethyl)-4-chloro-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6- dione;hydrochloride (159 mg, 0.44 mmol, 2.00 eq) in DMF (2 mL) was degassed and purged with N2for 3 times. Then the mixture was stirred at 25oC for 16 h. The residue was purified by pre-HPLC (35-65% HCl in water, acetonitrile) to afford the title compound (9 mg, 7.7% yield) as a white solid. LCMS (ESI): m / z 532.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 - 10.99 (m, 1H), 7.92 (t, J = 6.0 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.67 - 7.56 (m, 1H), 6.35 (d, J = 1.6 Hz, 1H), 5.16 - 5.05 (m, 3H), 4.98 (s, 2H), 4.51 - 4.42 (m, 1H), 4.35 - 4.25 (m, 3H), 2.96 - 2.86 (m, 1H), 2.68 - 2.61 (m, 1H), 2.43 - 2.37 (m, 1H), 2.05 - 1.97 (m, 1H).

[0869] Example 63

[0870] Preparation of (1-cyclobutyl-5-methyl-1H-pyrazol-3-yl)methyl ((7-chloro- 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 97)

[0871] Step 1: Preparation of Ethyl 1-cyclobutyl-5-methyl-1H-pyrazole-3- carboxylate

[0872] To the solution of cyclobutylhydrazine;hydrochloride (100 mg, 0.82 mmol, 1.00 eq) in Toluene (1 mL) and Ethanol (1 mL) was added ethyl acetopyruvate (0.11 mL, 0.82 mmol, 1.00 eq) at 0 ℃，then the mixture was stirred at 100 ℃ for 1h. The resulting residue was quenched by aq. Na2SO3(10 mL). The resulting solution was extracted with dichloromethane (20 mL × 3) and the organic layers were combined and concentrated. Then the mixture was purified by reverse phase chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (80 mg, 47% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ 6.60 (s, 1H), 5.61 (m, 1H), 4.31 (m, 2H), 2.73 - 2.60 (m, 2H), 2.45 - 2.36 (m, 2H), 2.30 (s, 3H), 1.89 - 1.77 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0873] Step 2: Preparation of (1-cyclobutyl-5-methyl-1H-pyrazol-3-yl)methanol

[0874] To a stirred solution of 3-hydroxy-3-[6-(trifluoromethyl)-3- pyridyl]propanenitrile (3.34g, 6.49 mmol, 1.20 eq) in THF (30 mL) was added LAH (5.19 mL, 12.98 mmol, 1.00 eq) dropwise at 0 ℃, and then warmed to room temperature and stirred for 6 hours under N2 protection. The mixture was quenched by Sodium sulfate decahydrate, the mixture was filtrated and concentrated in vacuum to give the title compound (50 mg, 78% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ 5.99 (s, 1H), 4.65 (s, 2H), 4.65 - 4.58 (m, 1H), 2.74 - 2.62 (m, 2H), 2.41 - 2.33 (m, 2H), 2.23 (s, 3H), 1.90 - 1.80 (m, 2H).

[0875] Step 3: Preparation of (1-cyclobutyl-5-methyl-1H-pyrazol-3-yl)methyl 1H- imidazole-1-carboxylate

[0876] To a solution of (1-cyclobutyl-5-methyl-pyrazol-3-yl)methanol (50 mg, 0.3 mmol, 1.00 eq) in THF (2 mL), was added CDI (51 mg, 0.32 mmol, 1.05 eq), the solution was stirred at 25 ℃ for 2 hours. The mixture was directly used to next step without work up

[0877] Step 4: Preparation of (1-cyclobutyl-5-methyl-1H-pyrazol-3-yl)methyl ((7- chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate

[0878] To a solution of 3-[6-(aminomethyl)-4-chloro-7-fluoro-1-oxo-isoindolin-2- yl]piperidine-2,6-dione;hydrochloride (114 mg, 0.31 mmol, 2.00 eq), triethylamine (0.08 mL, 0.6 mmol, 1.05 eq) and DBU (0.09 mL, 0.6 mmol, 2.00 eq) in THF (1 mL), was added (1-cyclobutyl-5-methyl-pyrazol-3-yl)methyl imidazole-1-carboxylate (78 mg, 0.3 mmol, 1.00 eq) and the solution was stirred at 25 ℃ for 16 hours. The mixture was purified by pre-HPLC (acetonitrile 27-57 % / 0.225% formic acid in water) to get a crude. The crude was purified by Chiral-Prep-HPLC (0.1% NaHCO3 in ethyl alcohol 60-60% / CO2) to give the title compound (8 mg, 5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.84 (s, 1H), 7.61 (d, J = 4.2 Hz, 1H), 5.98 (s, 1H), 5.09 (dd, J = 4.8, 13.2 Hz, 1H), 4.91 (s, 2H), 4.73 (t, J = 8.4 Hz, 1H), 4.53 - 4.41 (m, 1H), 4.37 - 4.22 (m, 3H), 2.96 - 2.83 (m, 1H), 2.61 (s, 1H), 2.31 - 2.98 (m, 2H), 2.18 (s, 3H), 2.05 - 1.94 (m, 1H), 1.81 - 1.70 (m, 2H). LCMS (ESI): m / z 518.0 (M+H)+.

[0879] Example 64

[0880] Preparation of (1-cyclohexyl-1H-pyrazol-3-yl)methyl ((7-chloro-2-(2,6- dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (Compound 99)

[0881] Step 1: Preparation of ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate

[0882] Ethyl pyruvate (4.78mL, 43.06mmol) was solubilized in Dichloromethane (100mL) and to the previous solution was added dropwise DMF dimethyl acetal (5.72mL, 43.06mmol). Reaction mixture was stirred at 25oC for 4 h. After the volatiles were evaporated under reduced pressure to obtain a dark brown oil that was purified by flash column chromatography using 1% MeO...

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I), wherein: (1) each R1is independently selected from halogen, cyano, C1-6alkyl, hydroxy, and C1-6 haloalkyl, C1-6 alkoxy, O-C1-6 haloalkyl, and -N(Ra)(Rb); (2) p is an integer selected from 0, 1, 2, and 3; (3) each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6 alkyl, C1-6 alkoxy; hydroxy, C1-6 haloalkyl, O-C1-6 haloalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, and optionally substituted O-C3-6cycloalkyl; (4) q is an integer selected from 0, 1, 2, and 3; (5) R3is hydrogen or C1-4alkyl; (6) each R4is independently selected from hydrogen, optionally substituted C1-6alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted 3-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl; (7) m is 1 or 2; (8) A is selected from (i) 5-membered monocyclic heteroaryl, and (ii) 6-10-membered fused bicyclic heteroaryl; and (9) each Raand Rbis independently selected from H and optionally substituted C1-6alkyl, or Raand Rbtogether with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A is selected from:

3. The compound of claim 1 or claim 2, wherein p is 1.

4. The compound of claim 1 or claim 2, wherein p is 2.

5. The compound of any one of claims 1 to 4, wherein each R1is independently selected from: -CH3, -F, -Cl, and -OH.

6. The compound of any one of claims 1 to 4, wherein each R1is halogen.

7. The compound of claim 6, wherein each R1is selected from -F and -Cl.

8. The compound of any one of claims 1 to 4, wherein each R1is C1-6alkyl.

9. The compound of any one of claims 1 to 8, wherein each R2is independently selected from halogen, haloalkyl, optionally substituted C1-4 alkyl, C3-6 cycloalkyl, and C5-6 aryl.

10. The compound of any one of claims 1 to 8, wherein each R2is independently selected from fluoro, chloro, methyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, cyclohexyl, and phenyl.

11. The compound of any one of claims 1 to 10, wherein R3is hydrogen 12. The compound of any one of claims 1 to 10, wherein R3is methyl.

13. The compound of any one of claims 1 to 12, wherein m is 1.

14. The compound of any one of claims 1 to 12, wherein m is 2.

15. The compound of any one of claims 1 to 12 and 14, wherein m is 2 and at least one of R4is hydrogen.

16. The compound of any one of claims 1 to 15, wherein each R4is hydrogen.

17. The compound of any one of claims 1 to 14, wherein each R4is optionally substituted C6-10aryl.

18. The compound of any one of claims 1 to 14, wherein each R4is optionally substituted phenyl.

19. The compound of claim 1, selected from:Compound 25 Compound 4Compound 17 Compound 10Compound 12 Compound 28Compound 30 Compound 18Compound 7 Compound 16Compound 1 Compound 20Compound 32 Compound 34Compound 37 Compound 38Compound 33 Compound 3or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1 to 19, characterized by a CDK2 Dmax of at least 50%, at least 60%, or at least 70% when measured by HiBiT assay.

21. The compound of any one of claims 1 to 20, characterized by a CDK2 DC50of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

22. The compound of claim 20 or claim 21, wherein the HiBiT assay is conducted in HEK293 cells.

23. A compound of formula (II), wherein: (1) Y is optionally substituted monocyclic C3-6 cycloalkyl or optionally substituted monocyclic 3-5 membered heterocycloalkyl; (2) each R1is independently selected from halogen, cyano, C1-6 alkyl, hydroxy, and C1-6 haloalkyl;(3) p is an integer selected from 0, 1, 2, and 3; (4) each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6 alkyl, C1-6 alkoxy, hydroxy, C1-6 haloalkyl, O-C1-6 haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, O-C3-6cycloalkyl, and -NR2aR2b; (5) q is an integer selected from 0, 1, 2, and 3; (6) each R2aand R2bare independently selected from H and optionally substituted C1-6 alkyl, or R2aand R2btogether with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocycloalkyl; (7) R3is hydrogen or C1-4alkyl; (8) L3is a bond or a linker selected from optionally substituted -C1-4 alkylene-, optionally substituted -O-C1-4 alkylene-, optionally substituted -C(O)O-C1-4 alkylene-, and - C(O)-; and (9) B is selected from (i) C6-10 aryl, (ii) 5-10 membered heteroaryl, and (iii) 5-10 membered fused bicyclic heterocycloalkyl, or a pharmaceutically acceptable salt thereof, with the proviso that when (i) L3is a bond and (ii) B is phenyl, q is 1, 2, or 3.

24. The compound of claim 23, wherein Y is monocyclic C3-6cycloalkyl.

25. The compound of claim 24, wherein Y is cyclobutyl.

26. The compound of claim 24, wherein Y is cyclopentyl.

27. The compound of claim 23, wherein Y is monocyclic 3-5 membered heterocycloalkyl.

28. The compound of claim 27, wherein Y is azetidinyl.

29. The compound of any one of claims 23 to 28, wherein Y is substituted with hydroxy or halo.

30. The compound of any one of claims 23 to 29, wherein B is selected from:

31. The compound of any one of claims 23 to 30, wherein each R1is independently selected from: -CH3, -F, -Cl, and –OH.

32. The compound of any one of claims 23 to 30, wherein each R1is halogen.

33. The compound of claim 32, wherein each R1is selected from -F and -Cl.

34. The compound of any one of claims 23 to 30, wherein each R1is C1-6alkyl.

35. The compound of any one of claims 23 to 34, wherein each R2is independently selected from halogen, haloalkyl, O-C1-6 haloalkyl, optionally substituted C1-4 alkyl, C3-6 cycloalkyl, oxo, C1-4 alkoxy, and N(C1-6 alkyl)2.

36. The compound of claim 35, wherein each R2is independently selected from fluoro, chloro, trifluoromethyl, cyclopropyl, and methoxy.

37. The compound of any one of claims 23 to 36, wherein L3is a bond.

38. The compound of any one of claims 23 to 36, wherein L3is C1-4alkylene.

39. The compound of claim 38, wherein L3is methylene.

40. The compound of any one of claims 23 to 36, wherein L3is -O-C1-4 alkylene-.

41. The compound of claim 40, wherein L3is -OCH2-.

42. The compound of any one of claims 23 to 36, wherein L3is -C(O)O-C1-4alkylene-.

43. The compound of 42, wherein L3is -C(O)OCH2-.

44. The compound of any one of claims 23 to 36, wherein L3is -C(O)-.Compound 43 Compound 45Compound 57 Compound 41Compound 62 Compound 61Compound 53 Compound 48Compound 49 Compound 39Compound 138 Compound 139Compound 142 Compound 143Compound 144 Compound 145Compound 150 Compound 151Compound 154 Compound 155Compound 158 Compound 159Compound 162 Compound 163Compound 164 Compound 165Compound 168 Compound 169Compound 174 Compound 175Compound 180 Compound 181Compound 184 Compound 185Compound 194 Compound 195Compound 198 Compound 199Compound 202 Compound 203Compound 212 Compound 213Compound 216 Compound 217Compound 222Compound 225 Compound 226Compound 229Compound 230Compound 235Compound 236Compound 237 or a pharmaceutically acceptable salt thereof.

46. The compound of any one of claims 23 to 45, characterized by a CDK2 Dmaxof at least 50%, at least 60%, or at least 70% when measured by HiBiT assay.

47. The compound of any one of claims 23 to 46, characterized by a CDK2 DCso of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

48. The compound of claim 46 or claim 47, wherein the HiBiT assay is conducted in HEK293 cells.

49. A pharmaceutical composition comprising the compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

50. The pharmaceutical composition of claim 49, further comprising an additional therapeutic agent.

51. A method of degrading CDK2 in a subject, the method comprising administering to the subject: (i) the compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 49 or claim 50.

52. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 49 or claim 50.

53. The method of claim 52, wherein the cancer is selected from bladder cancer; bone cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; prostate cancer; esophagus cancer; eye cancer; head cancer; kidney cancer; liver cancer; lymph node cancer; lung cancer; upper aerodigestive tract cancer; oral cancer; oropharynx cancer; larynx cancer; hypopharynx cancer; salivary gland cancer; neck cancer; thyroid cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; uterine cancer; neuroblastoma; meningioma; hemangiopericytoma; leiomyoma; leukemia; lymphoma; and myeloma.

54. The method of claim 52, wherein the cancer is selected from: leukemia; bladder cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; kidney cancer; liver cancer; lung cancer; neuroblastoma; ovarian cancer; prostate cancer; skin cancer; thyroid cancer; and uterine cancer.

55. A method of treating a solid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 49 or claim 50.

56. A method of treating a liquid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 49 or claim 50.

57. A compound of formula (III)wherein:(1) Y is optionally substituted monocyclic C3-6 cycloalkyl or optionally substituted monocyclic 3-5 membered heterocycloalkyl;(2) each R1is independently selected from halogen, cyano, C1-6 alkyl, hydroxy, and C1-6 haloalkyl;(3) p is an integer selected from 0, 1, 2, and 3;(4) each R2is independently selected from halogen, cyano, oxo, optionally substituted C1-6 alkyl, C1-6 alkoxy, hydroxy, C1-6 haloalkyl, O-C1-6 haloalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, O-C3-6 cycloalkyl;(5) q is an integer selected from 0, 1, 2, and 3;(6) R3is hydrogen or C1-4 alkyl;(7) L3is a bond or a linker selected from optionally substituted -C1-4 alkylene-, optionally substituted -O-C1-4 alkylene-, optionally substituted -C(O)O-Ci-4 alkylene-, and - C(O)-; and(8) C is a 3 to 6 membered heterocycloalkyl having a nitrogen heteroatom attached to L3, or a pharmaceutically acceptable salt thereof.

58. The compound of claim 57, wherein Y is monocyclic C3-6 cycloalkyl.

59. The compound of claim 58, wherein Y is cyclobutyl.

60. The compound of any one of claims 57 to 59, wherein L3is selected from a bond and -C(O)-.

61. The compound of any one of claims 57 to 60, wherein C is selected from:

62. The compound of any one of claims 57 to 61, wherein each R2is independently selected from halogen, oxo, and C1-6 haloalkyl.

63. The compound of claim 57, selected from:Compound 206 Compound 20764. The compound of any one of claims 57 to 63, characterized by a CDK2 Dmaxof at least 50%, at least 60%, or at least 70% when measured by HiBiT assay.

65. The compound of any one of claims 57 to 64, characterized by a CDK2 DC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

66. The compound of claim 64 or claim 65, wherein the HiBiT assay is conducted in HEK293 cells.

67. A pharmaceutical composition comprising the compound of any one of claims 59 to 66, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

68. The pharmaceutical composition of claim 67, further comprising an additional therapeutic agent.

69. A method of degrading CDK2 in a subject, the method comprising administering to the subject: (i) the compound of any one of claims 57 to 66, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 67 or claim 68.

70. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of the compound of any one of claims 57 to 66, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 67 or claim 68.

71. The method of claim 70, wherein the cancer is selected from bladder cancer; bone cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; prostate cancer; esophagus cancer; eye cancer; head cancer; kidney cancer; liver cancer; lymph node cancer; lung cancer; upper aerodigestive tract cancer; oral cancer; oropharynx cancer; larynx cancer; hypopharynx cancer; salivary gland cancer; neck cancer; thyroid cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; uterine cancer; neuroblastoma; meningioma; hemangiopericytoma; leiomyoma; leukemia; lymphoma; and myeloma.

72. The method of claim 70, wherein the cancer is selected from: leukemia; bladder cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; kidney cancer; liver cancer; lung cancer; neuroblastoma; ovarian cancer; prostate cancer; skin cancer; thyroid cancer; and uterine cancer.

73. A method of treating a solid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound of any one of claims 57 to 66, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 67 or claim 68.

74. A method of treating a liquid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound of any one of claims 57 to 66, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 67 or claim 68.

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