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, as degraders of cyclin-dependent kinase 2 (CDK2), and pharmaceutical compositions thereof, and methods of using the same to treat cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 578,549, filed August 24, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] The field of this disclosure generally relates to cyclin-dependent kinase 2 degrader compounds.

[0004] The ubiquitin-proteasome pathway (UPP) is a key pathway that controls protein metabolism in cells by degrading / eliminating misfolded and abnormal proteins. UPP is central to many cellular processes, and if it is defective or imbalanced, it can lead to the pathogenesis of a variety of diseases, such as cancer.

[0005] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases that are activated when heterodimerized with cyclin regulatory subunits and regulate key cellular processes, including cell cycle progression and cell division. Dysregulation of CDK activity is associated with aberrant cell cycle regulation and is detected in almost all forms of human cancer characterized by uncontrolled cell proliferation. Therefore, therapeutic agents that utilize UPP-mediated protein degradation to target cancer-associated proteins such as cyclin-dependent kinase 2 (“CDK2”) are considered potential chemotherapeutic agents. Consequently, the search for compounds that can serve as CDK2 degraders for therapeutic purposes remains crucial.

[0006] Brief description

[0007] On the one hand, this paper provides compounds of formula (I):

[0008] ,

[0009] in

[0010] Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Haloalkyl, C 1-6 Alkoxy, OC 1-6 Halogenated alkyl groups and -N(R) a (R) b );

[0011] p is an integer selected from 0, 1, 2, and 3;

[0012] Each R a and Rb Independently selected from H and optionally substituted C 1-6 Alkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted 3- to 8-membered heterocyclic alkyl groups;

[0013] Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted OC 3-6 cycloalkyl;

[0014] q is an integer selected from 0, 1, 2, and 3;

[0015] R 3 It is hydrogen or C 1-4 alkyl;

[0016] Each R 4 C independently selected from hydrogen, optionally substituted 1-6 Alkyl groups, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 3- to 6-membered heterocyclic alkyl and optionally substituted 5- to 6-membered heteroaryl;

[0017] m is 1 or 2; and

[0018] A is selected from: (i) 5-membered monocyclic heteroaryl; and (ii) 6- to 10-membered fused bicyclic heteroaryl;

[0019] Or its pharmaceutically acceptable salt.

[0020] On the other hand, this paper also provides compounds of formula (II):

[0021] ,

[0022] in

[0023] Y is an optionally substituted monocyclic C 3-6 Cycloalkyl or optionally substituted monocyclic 3- to 5-membered heterocyclic alkyl groups;

[0024] Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Halogenated alkyl groups;

[0025] p is an integer selected from 0, 1, 2, and 3;

[0026] Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, OC 3-6 cycloalkyl and NR 2a R 2b ;

[0027] q is an integer selected from 0, 1, 2, and 3;

[0028] Each R 2a and R 2b Independently selected from H and optionally substituted C 1-6 Alkyl, or R 2a and R 2b Together with the nitrogen atoms to which they are attached, they form optionally substituted 3- to 8-membered heterocyclic alkyl groups;

[0029] R 3 It is hydrogen or C 1-4 alkyl;

[0030] L 3 For a key or connector, the connector is selected from optionally substituted -C 1-4 Alkylene-, optionally substituted -OC 1-4 Alkylene-, optionally substituted -C(O)OC 1-4 alkylene- and -C(O)-; and

[0031] B is selected from: (i) C 6-10 (ii) 5- to 10-membered heteroaryl; and (iii) 5- to 10-membered fused bicyclic heterocyclic alkyl;

[0032] Or its pharmaceutically acceptable salt.

[0033] The condition is when (i) L 3 When (ii) B is a phenyl group, q is 1, 2, or 3.

[0034] On the other hand, this paper also provides compounds of formula (III):

[0035] ,

[0036] in

[0037] Y is an optionally substituted monocyclic C 3-6 Cycloalkyl or optionally substituted monocyclic 3- to 5-membered heterocyclic alkyl groups;

[0038] Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Halogenated alkyl groups;

[0039] p is an integer selected from 0, 1, 2, and 3;

[0040] Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, OC 3-6 cycloalkyl;

[0041] q is an integer selected from 0, 1, 2, and 3;

[0042] R 3 It is hydrogen or C 1-4 alkyl;

[0043] L 3 For a key or connector, the connector is selected from optionally substituted -C 1-4 Alkylene-, optionally substituted -OC 1-4 Alkylene-, optionally substituted -C(O)OC 1-4 Alkylene- and -C(O)-;

[0044] C is connected to L 3 The nitrogen-containing heterocyclic alkyl group consisting of 3 to 6 members.

[0045] Or its pharmaceutically acceptable salt. Detailed Implementation

[0046] This document provides degrading agents for CDK2, such as degrading agents of formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof. Further, pharmaceutical compositions thereof and methods of use thereof are provided, for example, for treating CDK2-mediated diseases such as cancer. Methods for preparing the CDK2 degrading agents (such as degrading agents of formulas (I), (II), and (III)) described herein are also provided.

[0047] The cell cycle plays a crucial and central role in controlling cell growth and proliferation. Each cell cycle step is a well-regulated process controlled by CDKs, defined by serine / threonine protein kinases and their associated cyclin chaperones. CDK2 is known to control cell division and is central to oncogenic signaling. (See, for example, Chi et al., “A novel landscape of nuclear human CDK2 substrates revealed by in situphosphorylation”, Sci. Adv. 2020, Vol. 6, No. 16.) Cyclins are activated by cyclin E and cyclin A, with the E-CDK2 complex regulating cell cycle reentry, G1 progression, and S phase entry, and the cyclin A-CDK2 complex coordinating S phase progression and function in G2 and M phases. (Ibid.) Therefore, CDK2 inhibition may be an effective therapy to halt or inhibit cancer cell proliferation.

[0048] Unbound by any particular theory, the compounds disclosed herein are believed to act as CDK2 degrading compounds, inducing protein-protein interactions (aggregation) and promoting the ubiquitination and degradation of CDK2 in the context of ubiquitin ligases. The compounds presented herein achieve degradation selectivity against GSPT1 (G1 to S phase transition 1), a protein reportedly degraded by compounds of a similar class. GSPT1 is a generally essential translation termination factor. Depletion of GSPT1 can lead to downstream effects on a wide range of proteins and cellular functions; therefore, achieving degradation selectivity against GSPT1 is crucial to avoiding widespread toxicity. The compounds presented herein are able to efficiently degrade CDK2 with a selectivity superior to that of GSPT1.

[0049] definition

[0050] Unless otherwise specifically stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Additionally, any methods or materials similar to or equivalent to those described or used herein may be used. The following terms are defined for the purposes described herein.

[0051] As used herein, “a,” “an,” or “the” includes not only aspects having one member but also aspects having more than one member. For example, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include a plural of indicators. Thus, for example, reference to “a cell” includes multiple such cells, and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so on.

[0052] The term "alkyl" is used in its conventional sense, either alone or as part of another substituent, and refers to a straight-chain or branched hydrocarbon group. The number of carbon atoms may suitably be 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Non-limiting examples of such unsaturated alkyl groups include straight-chain and branched groups, including vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, as well as higher homologues and isomers.

[0053] The terms "alkoxy," "alkylamino," and "alkathio" are used in their conventional sense and refer to those alkyl groups attached to the remainder of a molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group, and further include their monohalogenated and polyhalogenated variants. Additionally, for dialkylamino groups, the alkyl moiety may be the same or different.

[0054] The term "halogenated" or "halogen" is used in its conventional meaning, either alone or as part of another substituent, and refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl," for example, C... 1-6 Halogenated alkyl groups and C 1-4 Haloalkyl, intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, etc.

[0055] The terms "cycloalkyl" and "cycloalkylene" are used in their conventional sense and refer to a saturated or partially saturated carbocyclic moiety having a monocyclic or bicyclic structure and containing 3 to 10 carbon atoms. The cycloalkyl moiety may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl moiety contains 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other specific embodiments, the cycloalkyl moiety contains 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Non-limiting examples of the cycloalkyl moiety include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially saturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl). In some aspects, the bicyclic cycloalkyl ring is limited to a fused ring sharing two carbon atoms. In some aspects, the bicyclic cycloalkyl ring does not include bridging bicyclic and spirobicyclic structures.

[0056] The terms “heterocyclic,” “heterocyclic alkyl,” and “heterocyclic alkylene” are used in their conventional sense and refer to a saturated or partially saturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 6-, 7-, 8-, 9-, and 10-membered bicyclic heterocyclic portion having one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur, with the remaining ring atoms being carbon. In some embodiments, a bicyclic heterocycle is limited to a fused ring sharing two carbon atoms. In some embodiments, a bicyclic heterocycle is a fused ring sharing one or more heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, a bicyclic heterocycle does not include bridging bicyclic and spirobicyclic structures. In some embodiments, one ring of a bicyclic heterocycle structure contains one or more heteroatoms. In some embodiments, both rings of a bicyclic structure contain one or more heteroatoms.

[0057] The term "aryl" refers to the cyclic aromatic hydrocarbon moiety having a monocyclic or bicyclic aromatic ring with 5 to 10 carbon ring atoms. Bicyclic aryl ring systems include fused bicycles with two fused five-membered aryl rings, fused bicycles with one five-membered aryl ring and one fused six-membered aryl ring, and fused bicycles with two fused six-membered aryl rings. The aryl group may be optionally substituted as described above.

[0058] The term “heteroaryl” is used in its conventional sense and refers to a monovalent aromatic group of a 5-, 6-, or 7-membered ring, including fused ring systems of 5 to 10 atoms (at least one of which is aromatic) 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, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cenolinyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purineyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazonyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanzopyridinyl. The heteroaryl group may optionally be independently substituted by one or more of the substituents described herein. The 5- or 6-membered heteroaryl group may be selected from the group consisting of: optionally substituted pyridyl, pyrimidinyl, thiazolyl, imidazolel, oxazolyl, isoxazolyl, pyrazolyl, pyridone, and benzimidazolel.

[0059] The term "fused bicyclic heteroaryl" refers to a structure having atoms arranged in two rings fused together, each ring having at least two atoms in total, and at least one ring being a heteroaryl ring. Non-limiting examples of bicyclic heteroaryls include bicyclic heteroaryls containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O.

[0060] The term "heteroatom" refers to an atom other than hydrogen or carbon. Non-limiting examples of heteroatoms include N, O, and S.

[0061] Some compounds disclosed herein have asymmetric carbon atoms (optical centers). Racemates, diastereomers, geometric isomers, regioisomers, and single isomers (e.g., individual enantiomers) are all intended to be covered within the scope of this disclosure.

[0062] The term "chirality" refers to a molecule that does not overlap with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0063] The term "chiral purity" refers to the molar purity of a chiral compound based on the total number of moles of the chiral compound.

[0064] The term "stereoisomer" refers to compounds that have the same chemical composition but different spatial arrangements of atoms or groups.

[0065] The term E / Z refers to the IUPAC isomerism convention, in which substituents at each end of a double bond are assigned priority based on their atomic numbers. If a higher-priority substituent is located on the same side of the bond, it is assigned Z, and if it is located on opposite sides of the bond, it is assigned E.

[0066] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are considered and included as compounds of this disclosure. When the stereochemistry is specified by a solid wedge or dashed line indicating a specific configuration, that stereoisomer is specified and defined. Unless otherwise stated, the use of a solid wedge or dashed line signifies relative stereochemistry.

[0067] The term "spirocyclic" refers to a bicyclic molecule in which two of its constituent ring parts share a common carbon atom.

[0068] The term "bridging" refers to a bicyclic molecule in which two of its constituent ring parts share two common, non-adjacent carbon atoms.

[0069] The term "fusion" refers to a bicyclic molecule in which two of its constituent ring parts share two common adjacent carbon atoms.

[0070] The term "substituent" refers to a group of atoms that replace a hydrogen atom on a parent molecule. The term "substituted" means that the specified group has one or more substituents. Where any group can have multiple substituents and a variety of possible substituents are provided, the substituents are chosen independently and need not be identical. The term "unsubstituted" means that the specified group does not have any substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected 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 substitutions, i.e., from substituents replacing one hydrogen atom to substituents replacing all hydrogen atoms. Examples of substituents include, but are not limited to, hydroxyl, alkyl, alkoxy, halogenated, haloalkyl, oxo, cyano, nitro, amino, monoalkylamino, dialkylamino, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl.

[0071] In the description of this article, if there is a difference between the structure described and its name, the structure described shall prevail.

[0072] The term "salt" refers to a salt comprising an active compound prepared with a relatively non-toxic acid or base (e.g., those pharmaceutically acceptable salts), depending on the specific substituents found on the compounds described herein. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a pure or suitable inert solvent containing a desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrazine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, triethanolamine, etc. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pure or suitable inert acid in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, phosphoric acid monohydrogen phosphate, phosphoric acid dihydrogen phosphate, sulfuric acid, hydrogen sulfide, hydrofluoric acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0073] The neutral form of the compounds disclosed herein can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (such as solubility in polar solvents), but for the purposes of this disclosure, these salts are otherwise equivalent to the parent form of the compound.

[0074] The term "subject" refers to animals, such as mammals, including but not limited to humans.

[0075] The term "teat, treating, and treatment" refers to any sign of success in the treatment or improvement of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameters such as relief; remission; reduction of symptoms or making the symptoms, injury, pathology, or condition more tolerable to the patient; reduction of the frequency or duration of symptoms or condition; or, in some cases, prevention of symptom onset. Treatment or improvement of symptoms can be based on any objective or subjective parameters, including, for example, the results of a physical examination.

[0076] The term "solid tumor" refers to a solid mass of cancer cells that grows in an organ system and can occur anywhere in the body, such as breast cancer.

[0077] The term "liquid tumor" refers to a tumor that occurs in the blood, bone marrow, or lymph nodes, and includes types of leukemia, lymphoma, and myeloma.

[0078] The term "pharmaceutically acceptable" refers to anionic, cationic, carrier, diluent, or excipient that is compatible with other components of a formulation and is harmless to its recipients.

[0079] The terms “effective dose,” “effective amount,” and “therapeutic effective amount” in the present disclosure of compounds or pharmaceutical compositions are amounts sufficient to affect one or more beneficial or desirable (including biochemical, histological, and / or behavioral symptoms) of a disease, its complications, and intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, a “therapeutic effective amount” refers to an amount of the applied compound that will alleviate, to some extent, one or more symptoms of the disease being treated. In relation to the treatment of cancer, a therapeutic effective amount refers to an amount that has the following effects: (1) reducing the size of a tumor, (2) inhibiting (i.e., to some extent slowing down, preferably stopping) tumor metastasis, (3) inhibiting (i.e., to some extent slowing down, preferably stopping) tumor growth or tumor invasiveness, (4) alleviating (or preferably eliminating) one or more cancer-related signs or symptoms to some extent, (5) reducing the dosage of other drugs required to treat the disease, (6) enhancing the effect of another drug, and / or (7) delaying the progression of the patient’s disease.

[0080] An effective dose may be administered once or multiple times. For the purposes of this disclosure, an effective dose of a compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventative or therapeutic treatment. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.

[0081] As used herein, the term "another anticancer therapeutic agent" means any one or more therapeutic agents other than the compounds disclosed herein, which are used or can be used to treat cancer.

[0082] The term "co-administration" means the simultaneous or separate sequential administration of a compound or its salt, as described herein, and one or more other active pharmaceutical ingredients, including chemotherapeutic agents. If the administrations are not simultaneous, the compounds should be administered close to each other in time. Furthermore, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered topically while another may be administered orally.

[0083] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to this disclosure. For example, a compound as described herein may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or in a single unit dosage form. Thus, single unit dosage forms comprising compounds of formula (I), (II), or (III), additional therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators are provided.

[0084] The term "IC" 50 "Inhibition concentration" refers to the half maximum inhibitory concentration of a substance required to inhibit a specific biological or biochemical function, as measured by appropriate assay methods.

[0085] The term "DC" 50 "" refers to the concentration of a substance required to achieve half the maximum protein degradation, as measured by appropriate assay methods.

[0086] Term "D" max "" refers to the maximum level of protein degradation observed in a substance titration, as measured by appropriate assay methods and at defined time points.

[0087] Compound of formula (I)

[0088] Some embodiments of this disclosure relate to compounds of formula (I):

[0089]

[0090] Each R 1 Independently selected from: halogen; cyano; C 1-6 Alkyl; hydroxyl; C 1-6 Halogenated alkyl; C 1-6 Alkoxy; OC 1-6 Halogenated alkyl groups; and -N(R) a (R) b In some embodiments, each R 1 Independently selected from: -CH3; -F; -Cl; and -OH. In some embodiments, each R 1 It is a halogen. In some embodiments, each R 1Independently selected from -F and -Cl. In some embodiments, each R 1 C 1-6 Alkyl group. In some embodiments, each R 1 For –F. In some embodiments, each R 1 For –Cl.

[0091] Each R a and R b Independently selected from H and optionally substituted C 1-6 Alkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted 3- to 8-membered heterocyclic alkyl groups. In some embodiments, R a and R b Both are hydrogen. In some embodiments, R a It is hydrogen and R b C 1-6 Alkyl (e.g., methyl). In some embodiments, R a and R b Both are C 1-6 Alkyl (e.g., methyl).

[0092] 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 some embodiments, p is 1 and R 1 For -F or -Cl. In some embodiments, p is 2 and each R 1 It is independently selected from -F and -Cl.

[0093] Each R 2 Independently selected from: halogen; cyano; oxo; optionally substituted C 1-6 Alkyl; C 1-6 Alkyl group; hydroxyl group; C 1-6 Halogenated alkyl; OC 1-6 Halogenated alkyl; optionally substituted C 3-8 Cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; optionally substituted 5- to 6-membered heteroaryl; and OC 3-6 Cycloalkyl. In some embodiments, each R 2Independently selected from: halogens; haloalkyl groups; optionally substituted C-type atoms. 1-4 Alkyl; C 3-6 cycloalkyl; and C 5-6 Aryl. In some embodiments, each R 2 Selected independently from: fluorine; chlorine; methyl; isopropyl; fluoromethyl; difluoromethyl; trifluoromethyl; methoxy; cyclohexyl; and phenyl.

[0094] 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.

[0095] R 3 Selected from hydrogen and C 1-4 Alkyl group. In some embodiments, R 3 It is hydrogen. In some embodiments, R is... 3 It is a methyl group.

[0096] Each R 4 Independently selected from: hydrogen; optionally substituted C 1-6 Alkyl; optionally substituted C 3-6 cycloalkyl; optionally substituted C 6-10 Aryl; optionally substituted 3- to 6-membered heterocyclic alkyl; and optionally substituted 5- to 6-membered heteroaryl. In some embodiments, R 4 It is hydrogen. In some embodiments, R is... 4 C is arbitrarily substituted 6-10 Aryl. In some embodiments, R 4 The phenyl group is optionally substituted.

[0097] 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, R 4 At least one of them is H.

[0098] A is selected from: (i) a 5-membered monocyclic heteroaryl; and (ii) a 6- to 10-membered fused bicyclic heteroaryl. In some embodiments, A is a 5-membered monocyclic heteroaryl. In some embodiments, A is a 6- to 10-membered fused bicyclic heteroaryl.

[0099] In some embodiments, A is selected from:

[0100] as well as

[0101] In some embodiments, A is selected from:

[0102]

[0103] as well as .

[0104] In some embodiments, A is selected from:

[0105] as well as .

[0106] In some embodiments, A is selected from:

[0107] as well as .

[0108] In some embodiments, A is selected from:

[0109] as well as .

[0110] In some embodiments, A is selected from:

[0111] as well as .

[0112] In some embodiments, A is selected from:

[0113] as well as .

[0114] In some embodiments, A is selected from:

[0115] as well as .

[0116] In some embodiments, A is selected from:

[0117] as well as .

[0118] In one embodiment, A is or In another embodiment, A is... In a specific embodiment, A is... And through 1 or 2 R 2 Replace, each R 2 Independently selected from: fluorine; chloro; methyl; isopropyl; fluoromethyl; difluoromethyl; trifluoromethyl; methoxy; cyclohexyl; and phenyl. In a specific embodiment, A is... And through 1 or 2 R 2 Replace, each R 2 Independently selected from: fluorine; chlorine; and methyl. In specific embodiments, Selected from , , , ;and .

[0119] In one embodiment, A is In a specific embodiment, A is the result of 1 or 2 R... 2 Replacement Each R 2 Independently selected from: fluorine; chloro; methyl; isopropyl; fluoromethyl; difluoromethyl; trifluoromethyl; fluoroethyl; difluoroethyl; trifluoroethyl; cyclobutyl and cyclohexyl. In specific embodiments, Selected from: as well as .

[0120] In some embodiments, the compound of formula (I) is the compound of formula (I-1). .

[0121] In some embodiments, the compound of formula (I) is the compound of formula (I-1). .

[0122] In some embodiments, the compound of formula (I) is a compound of formula (Ia).

[0123] In some embodiments, R 1 Selected from: -CH3; -F; -Cl; and –OH. In some embodiments, R 1 For –F or –Cl. In one embodiment, R 1 For –F. In another embodiment, R 1 For –Cl.

[0124] In some embodiments, the compound of formula (I) is a compound of formula (Ib).

[0125] In some embodiments, R 1 Selected from: -CH3; -F; -Cl; and –OH. In some embodiments, R 1 For –F or –Cl. In one embodiment, R 1 For –F. In another embodiment, R 1 For –Cl.

[0126] In some embodiments, the compound of formula (I) is a compound of formula (Ic).

[0127] In some embodiments, R 1 for

[0128] Selected from: -CH3; -F; -Cl; and –OH. In some embodiments, R 1 For –F or –Cl. In one embodiment, R 1 For –F. In another embodiment, R 1 For –Cl.

[0129] In some embodiments, the compound of formula (I) is a compound of formula (Id). In some embodiments, each R 1 Independently selected from: -CH3; -F; -Cl; and -OH. In some embodiments, each R 1 Independently selected from –F and –Cl. In one embodiment, each R 1 For –F. In another embodiment, each R 1 For –Cl. In one embodiment, an R 1 For -F and another R 1 It is -Cl.

[0130] In some embodiments, the compounds of formula (I) are selected from:

[0131]

[0132] In some embodiments, this disclosure includes a compound of formula (I) and a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) is characterized by an IC50 measured at 6 h by CDK2HiBiT assay. 50 Values ​​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 ranges constructed therefrom, such as about 10 µM to about 0.025 µM, about 1 µM to about 0.025 µM, or about 0.5 µM to about 0.025 µM. In some such embodiments, 6 h IC 50 Values ​​can 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. D was measured at 6 h using a CDK2 HiBiT assay. max The value 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 thereof, such as about 25% to about 70%, or about 45% to about 70%. In some such embodiments, 6 h D max It can be at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%.

[0134] In some embodiments, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) is characterized by an IC50 measured at 18 h by CDK2HiBiT assay. 50 Values ​​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 ranges constructed therefrom, such as about 10 µM to about 0.025 µM, about 1 µM to about 0.025 µM, or about 0.5 µM to about 0.025 µM. In some such embodiments, 18 h IC 50Values ​​can 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. D measured at 18 h was determined using a CDK2 HiBiT assay. max The value 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 thereof, such as about 25% to about 60% or about 40% to about 60%. In some such embodiments, 18 h D max It can be at least 50%, at least 55%, or at least 60%.

[0135] In some embodiments, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) is characterized by CDK2 DC when measured by HiBiT assay. 50 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.

[0136] In some embodiments, HiBiT assays were performed in HEK293 cells.

[0137] Compound of formula (II)

[0138] Some embodiments of this disclosure relate to compounds of formula (II):

[0139] .

[0140] Y is an optionally substituted monocyclic C 3-6 Cycloalkyl or optionally substituted monocyclic 3- to 5-membered heterocyclic alkyl groups. In some embodiments, Y is a monocyclic C 3-6 Cycloalkyl. In some embodiments, Y is cyclobutyl. In some embodiments, Y is cyclopentyl. In some embodiments, Y is a monocyclic 3- to 5-membered heterocyclic alkyl group. In some embodiments, Y is an azacyclobutane. In any such embodiments, Y is optionally substituted, for example, hydroxylated or halogenated. In some embodiments, Y is optionally monosubstituted with a hydroxyl or halogen.

[0141] Each R 1 Independently selected from: halogen; cyano; C 1-6 Alkyl; hydroxyl; and C 1-6 Halogenated alkyl groups. In some embodiments, each R 1 Independently selected from: -CH3; -F; -Cl; and –OH. In some embodiments, each R 1It is a halogen. In some embodiments, each R 1 Selected from -F and -Cl. In some embodiments, each R 1 C 1-6 Alkyl group. In some embodiments, each R 1 For –F. In some embodiments, each R 1 For –Cl.

[0142] 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 some embodiments, p is 1 and R 1 For -F or –Cl. In some embodiments, p is 2 and each R 1 It is independently selected from -F and –Cl.

[0143] Each R 2 Independently selected from: halogen; cyano; oxo; optionally substituted C 1-6 Alkyl; C 1-6 Alkyl group; hydroxyl group; C 1-6 Halogenated alkyl; OC 1-6 Halogenated alkyl; optionally substituted C 3-8 Cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; optionally substituted 5- to 6-membered heteroaryl; and OC 3-6 cycloalkyl, NR 2a R 2b In some embodiments, each R 2 Independently selected from: halogens; haloalkyl groups; OC 1-6 Halogenated alkyl; optionally substituted C 1-4 Alkyl; C 3-6 cycloalkyl; oxo; and C 1-4 alkoxy groups; and N(C) 1-6 Alkyl)2. In some embodiments, each R 2 Independently selected from: fluorine; chlorine; trifluoromethyl; cyclopropyl; and methoxy. In some embodiments, each R 2a and R 2b Independently selected from H and optionally substituted C 1-6 Alkyl, or R 2a and R 2bTogether with the nitrogen atoms to which they are attached, they form optionally substituted 3- to 8-membered heterocyclic alkyl groups;

[0144] 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.

[0145] R 3 It is hydrogen or C 1-4 Alkyl group. In some embodiments, R 3 It is hydrogen. In some embodiments, R is... 3 It is a methyl group.

[0146] L 3 For a key or connector, the connector is selected from: optionally substituted -C 1-4 Alkylene; optionally substituted -OC 1-4 Alkylene; optionally substituted -C(O)OC 1-4 Alkylene-; and -C(O)-. L 3 For a key or connector, the connector is selected from: unreplaced -C 1-4 Alkylene-; unsubstituted -OC 1-4 Alkylene-; and unsubstituted -C(O)OC 1-4 Alkylene-. L 3 Selected from: Unreplaced -C 1-4 Alkylene-; unsubstituted -OC 1-4 Alkylene-; and unsubstituted -C(O)OC 1-4 Alkylene-. In some embodiments, L 3 As a key. In some embodiments, L 3 For unreplaced -C 1-4 Alkylene-. In some embodiments, L 3 Methylene. In some embodiments, L 3 For unreplaced -OC 1-4 Alkylene-. In some embodiments, L 3 It is an O-methylene group. In some of these L... 3 In the embodiment, -OC 1-4 Alkylene - in orientation In some embodiments, -OC 1-4 Alkylenes are in the opposite orientation. In some embodiments, L 3For unsubstituted -C(O)OC 1-4 Alkylene-. In some embodiments, L 3 It is -C(O)O-methylene-. In some embodiments, L 3 It is -C(O)-. In some L 3 In the embodiment, -C(O)OC 1-4 Alkylene - in orientation In some embodiments, -C(O)OC 1-4 Alkylenes are in the opposite orientation. In any such embodiment, L 3 Optional substitution.

[0147] B is selected from: (i) C 6-10 (ii) aryl; (iii) 5- to 10-membered heteroaryl; and (iv) 5- to 10-membered fused bicyclic heterocyclic alkyl. In some embodiments, B is selected from:

[0148]

[0149] In some embodiments, B is selected from:

[0150]

[0151] In some embodiments, B is selected from:

[0152]

[0153] In some embodiments, B is selected from:

[0154] In one embodiment, B is... In another embodiment, B is... In another embodiment, B is... In some embodiments, R 2 It is a haloalkyl group (e.g., -CF3). In some embodiments, q is 1. In some embodiments, R 2 It is a haloalkyl group (e.g., -CF3), and q is 1.

[0155] In some embodiments, B is selected from: as well as In one embodiment, B is... In another embodiment, B is... In another embodiment, B is... In another embodiment, B is... In some embodiments, R 2 It is a haloalkyl group (e.g., -CF3). In some embodiments, q is 1. In some embodiments, R 2 It is a haloalkyl group (e.g., -CF3), and q is 1.

[0156] In some embodiments, B is or In one embodiment, B is... In another embodiment, B is... In some embodiments, R 2 It is a haloalkyl group (e.g., -CF3). In some embodiments, q is 1. In some embodiments, R 2 It is a haloalkyl group (e.g., -CF3), and q is 1.

[0157] In some embodiments, B is selected from:

[0158] as well as .

[0159] In some embodiments, B is selected from:

[0160] as well as .

[0161] In some such embodiments, each R 2 Independently selected from: halogen; cyano; optionally substituted C 1-6 Alkyl; C 1-6 Alkyl group; hydroxyl group; C 1-6 Halogenated alkyl; OC 1-6 Halogenated alkyl; optionally substituted aryl; and optionally substituted C 3-8 cycloalkyl; in some such embodiments, each R 2 Selected independently from: halogen; C 1-4 Halogenated alkyl; cyano; OC 1-4 Halogenated alkyl; optionally substituted C 1-4 Alkyl; optionally substituted aryl; and optionally substituted C 3-6 Cycloalkyl. In some embodiments, each R 2 It is independently selected from: fluorine; chlorine; O-trifluoromethyl; methyl; fluorine; chlorine; cyano; difluoromethyl; trifluoromethyl; cyclopropyl; and aryl.

[0162] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0163] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0164] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0165] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0166] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0167] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0168] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0169] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0170] In some embodiments, -B-(R 2 )q is .

[0171] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0172] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0173] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0174] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0175] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0176] In some embodiments, -B-(R 2 )q is selected from: as well as .

[0177] For compound formula (II), when (i) L 3 When (i) L is a bond and (ii) B is a phenyl group, q is 1, 2, or 3. In some embodiments, when (i) L 3 When (i) is a bond and (ii) B is a phenyl group, then B is a substituted phenyl group. In some other embodiments, when (i) L 3 When (i) B is a phenyl group and (ii) B is a para-substituted phenyl group, then B is a para-substituted phenyl group. In some other embodiments, when (i) L 3 When (i) B is a phenyl group and (ii) B is a meta-substituted phenyl group, then B is a meta-substituted phenyl group. In some other embodiments, when (i) L 3 When (ii) B is a phenyl group and is a phenyl group, B is an ortho-substituted phenyl group.

[0178] In some embodiments, the compound of formula (II) is a compound of formula (II-a). In some embodiments, R 1 Selected from: -CH3; -F; and -Cl. In some embodiments, R 1 For –F or –Cl. In one embodiment, R 1 For –F. In another embodiment, R 1 For –Cl.

[0179] In some embodiments, the compound of formula (II) is a compound of formula (II-b). In some embodiments, R 1 Selected from: -CH3; -F; and -Cl. In some embodiments, R 1 For –F or –Cl. In one embodiment, R 1 For –F. In another embodiment, R 1 For –Cl.

[0180] In some embodiments, the compound of formula (II) is a compound of formula (II-c). In some embodiments, R 1 The derivative is selected from: -CH3; -F; and -Cl. In some embodiments, R 1 For –F or –Cl. In one embodiment, R 1 For –F. In another embodiment, R 1 For –Cl.

[0181] In some embodiments, the compound of formula (II) is a compound of formula (II-d). In some embodiments, each R 1 Independently selected from: -CH3; -F; and -Cl. In some embodiments, each R 1 Independently selected from –F and –Cl. In one embodiment, each R 1 For –F. In another embodiment, each R 1 For –Cl. In one embodiment, an R 1 For -F and another R 1 It is -Cl.

[0182] In some embodiments, the compounds of formula (II) are selected from:

[0183]

[0184] In some embodiments, the compound of formula (II) is a pharmaceutically acceptable salt.

[0185] In some embodiments, the compound of formula (II) (or a pharmaceutically acceptable salt thereof) is characterized by an IC50 concentration measured at 6 h by CDK2 HiBiT assay. 50 Values ​​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, or less than 0.020 µM, and any ranges constructed therefrom, such as about 10 µM to about 0.020 µM, about 1 µM to about 0.020 µM, or about 0.5 µM to about 0.020 µM. In some such embodiments, 6 h IC 50 The value can 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, D measured at 6 h is determined by CDK2 HiBiT. max The value 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 thereof, such as about 25% to about 65% or about 40% to about 65%. In some such embodiments, 6 h D max It can be at least 50%, at least 55%, at least 60%, or at least 65%.

[0186] In some embodiments, the compound of formula (II) (or a pharmaceutically acceptable salt thereof) is characterized by an IC50 concentration measured at 18 h by CDK2 HiBiT assay. 50 Values ​​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 ranges constructed therefrom, such as about 10 µM to about 0.05 µM, about 1 µM to about 0.05 µM, or about 0.5 µM to about 0.05 µM. In some such embodiments, 18 h IC 50 Values ​​can 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. D measured at 18 h was determined using a CDK2 HiBiT assay. maxThe value 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 thereof, such as about 25% to about 60% or about 40% to about 60%. In some such embodiments, 18 h D max It can be at least 50%, at least 55%, or at least 60%.

[0187] In some embodiments, the compound of formula (II) (or a pharmaceutically acceptable salt thereof) is characterized by CDK2 DC when measured by HiBiT assay. 50 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.

[0188] In some embodiments, HiBiT assays were performed in HEK293 cells.

[0189] In some embodiments, the compound of formula (II) is characterized in that, when measured by HiBiT assay, CDK2D max It must be at least 50%, at least 60%, or at least 70%.

[0190] In some embodiments, the compound of formula (II) is characterized in that, when measured by HiBiT assay, CDK2DC 50 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.

[0191] In some embodiments, HiBiT assays were performed in HEK293 cells.

[0192] Compound of formula (III)

[0193] Some embodiments of this disclosure relate to compounds of formula (III):

[0194]

[0195] Y is an optionally substituted monocyclic C 3-6 Cycloalkyl or optionally substituted monocyclic 3- to 5-membered heterocyclic alkyl groups.

[0196] Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Halogenated alkyl groups.

[0197] p is an integer selected from 0, 1, 2, and 3.

[0198] Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, OC 3-6 Cycloalkyl.

[0199] q is an integer selected from 0, 1, 2 and 3.

[0200] R 3 It is hydrogen or C 1-4 alkyl.

[0201] L 3 For a key or connector, the connector is selected from optionally substituted -C 1-4 Alkylene-, optionally substituted -OC 1-4 Alkylene-, optionally substituted -C(O)OC 1-4 Alkylene- and -C(O)-.

[0202] C is connected to L 3 3- to 6-membered heterocyclic alkyl groups with nitrogen heteroatoms 。

[0203] In some embodiments of equation (III), Y is a single-ring C 3-6 Cycloalkyl. In some embodiments, Y is cyclobutyl.

[0204] In some embodiments of formula (III), L 3 Selected from the bond and -C(O)-.

[0205] In some embodiments of formula (III), L 3 As a key. In some embodiments, L 3 L is a bond, and Y is a cyclobutyl group. In some embodiments, L 3 As the key, and C is the eigenvalue of -(R) 2 ) q Replacement In some embodiments, L 3 The bond is Y, which is cyclobutyl, and C is -(R 2 )q Replacement .

[0206] In some embodiments of formula (III), L 3 It is -C(O)-.

[0207] In some embodiments of equation (III), C is selected from... as well as In some embodiments, C is In some embodiments, C is .

[0208] In some embodiments of equation (III), each R 2 Independently selected from halogens, oxidants, and C 1-6 Halogenated alkyl groups. In some embodiments, each R 2 It is a halogen. In some embodiments, each R 2 For oxygenation. In some embodiments, each R... 2 C 1-6 Halogenated alkyl groups.

[0209] In some embodiments of equation (III), C-(R 2 ) q Selected from:

[0210] as well as .

[0211] In some embodiments, the compound of formula (III) is selected from:

[0212]

[0213] In some embodiments, the compound of formula (III) is selected from:

[0214]

[0215] In some embodiments, the compound of formula (III) is selected from:

[0216]

[0217] In some embodiments, the compound of formula (III) is a pharmaceutically acceptable salt.

[0218] In some embodiments, the compound of formula (III) (or a pharmaceutically acceptable salt thereof) is characterized by an IC50 concentration measured at 6 h by CDK2 HiBiT assay. 50Values ​​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, or less than 0.020 µM, and any ranges constructed therefrom, such as about 10 µM to about 0.020 µM, about 1 µM to about 0.020 µM, or about 0.5 µM to about 0.020 µM. In some such embodiments, 6 h IC 50 The value can 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, D measured at 6 h is determined by CDK2 HiBiT. max The value 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 thereof, such as about 25% to about 65% or about 40% to about 65%. In some such embodiments, 6 h D max It can be at least 50%, at least 55%, at least 60%, or at least 65%.

[0219] In some embodiments, the compound of formula (III) (or a pharmaceutically acceptable salt thereof) is characterized by an IC50 concentration measured at 18 h by CDK2 HiBiT assay. 50 Values ​​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 ranges constructed therefrom, such as about 10 µM to about 0.05 µM, about 1 µM to about 0.05 µM, or about 0.5 µM to about 0.05 µM. In some such embodiments, 18 h IC 50 Values ​​can 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. D measured at 18 h was determined using a CDK2 HiBiT assay. max The value 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 thereof, such as about 25% to about 60% or about 40% to about 60%. In some such embodiments, 18 h Dmax It can be at least 50%, at least 55%, or at least 60%.

[0220] In some embodiments, the compound of formula (III) (or a pharmaceutically acceptable salt thereof) is characterized by CDK2 DC when measured by HiBiT assay. 50 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.

[0221] In some embodiments, HiBiT assays were performed in HEK293 cells.

[0222] In some embodiments, the compound of formula (III) is characterized by CDK2D when measured by HiBiT assay. max It must be at least 50%, at least 60%, or at least 70%.

[0223] In some embodiments, the compound of formula (III) is characterized in that, when measured by HiBiT assay, CDK2DC 50 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.

[0224] In some embodiments, HiBiT assays were performed in HEK293 cells.

[0225] Pharmaceutical Composition

[0226] In some embodiments, pharmaceutical compositions of compounds of formula (I), formula (II), and formula (III) are provided. In such embodiments, the pharmaceutical composition comprises (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof; or (iii) a combination of a compound of formula (III) or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient.

[0227] In some embodiments, pharmaceutical compositions of compounds of formula (I) and formula (II) are provided. In such embodiments, the pharmaceutical composition comprises (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

[0228] The pharmaceutical compositions of this disclosure may be in the following forms: tablets, pills, capsules, suppositories, powders, enteric-coated or other protected formulations (e.g., bound to an ion exchange resin or packaged in lipid-protein vesicles), sustained-release formulations, solutions, suspensions, elixirs, aerosols, etc. In practice of the methods of this disclosure, a therapeutically effective amount of any of the compounds of this disclosure or any combination of the compounds of this disclosure or their pharmaceutically acceptable salts is administered via any commonly used and acceptable method known in the art. For example, the compounds or compositions of this disclosure may be administered orally (e.g., orally), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., via suppositories or washes), percutaneously (e.g., via electroporation), or by inhalation (e.g., via aerosols), and in solid, liquid, or gaseous dosage forms, including tablets and suspensions. This administration may be performed at will in a single-unit dosage form and in a continuous treatment manner, or in a single-dose treatment manner.

[0229] Suitable excipients are known to those skilled in the art and are described in detail in, for example: (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, but are not limited to, carriers, diluents, adjuvants, and mediators. Non-limiting examples include buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, and flavorings.

[0230] Compositions comprising compounds of formula (I), (II), or (III) may be formulated as pharmaceutical compositions according to standard pharmaceutical practices. Typical formulations are prepared by mixing the compounds disclosed herein with one or more excipients.

[0231] When the pharmaceutical compositions according to this disclosure are prepared into formulations for oral administration, the carriers and / or diluents to be used may include, for example, but not limited to: cellulose and cellulose derivatives (e.g., microcrystalline cellulose); calcium silicate; corn starch; sugars (e.g., lactose, sucrose, glucose, mannitol, and combinations thereof); calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, and combinations thereof. Formulations for oral administration may also include, for example, but not limited to: polymers (e.g., hydrophilic polymers such as polyvinylpyrrolidone); antioxidants; preservatives; wetting agents; lubricants; flow aids; processing aids; granulating agents; dispersants; colorants; and flavoring agents.

[0232] Compressed tablets can be prepared in a suitable tableting apparatus by compressing an active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more of a carrier, binder, lubricant, inert diluent, preservative, surfactant, dispersant, and inert liquid diluent. Tablets may optionally be coated or scored. Tablets can be coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, time-delaying coating materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes, and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0233] When the pharmaceutical composition according to this disclosure is prepared into an injection formulation, the carrier to be used may include, for example, but not limited to, water, saline, aqueous glucose solution, aqueous sugar solution, alcohol, glycol (e.g., polyethylene glycol 400), ether, oil, fatty acid, fatty acid ester, glycerol ester, surfactant, suspending agent, emulsifier, and combinations thereof.

[0234] The pharmaceutical composition may further include pharmaceutical additives such as preservatives, stabilizers, wetting agents or emulsifiers, salts for regulating osmotic pressure, buffers, etc.

[0235] In some embodiments, a pharmaceutical composition comprising a compound of formula (I), a compound of formula (II), or a compound of formula (III) or a pharmaceutically acceptable salt thereof further comprises an additional therapeutic agent.

[0236] combination therapy

[0237] The compounds disclosed herein can be administered in combination with other additional therapeutic agents, such as, for example, but not limited to, standard care agents suitable for a particular cancer.

[0238] The compounds described herein, or their pharmaceutically acceptable salts, may be used alone or in combination with other pharmaceutical agents for therapeutic purposes. For example, a second agent in a pharmaceutical combination formulation or dosing regimen may have an activity complementary to that of the compounds described herein, such that they do not adversely affect each other. The compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt may be co-administered with a chemotherapeutic agent to treat proliferative diseases and cancer.

[0239] These additional agents may be administered separately from the compounds described herein or their pharmaceutically acceptable salts as part of a multiple-dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed in a single composition with the compounds as described herein. If administered as part of a multiple-dosing regimen, the two active agents may be administered simultaneously, sequentially, or at intervals (typically within five hours of each other).

[0240] The amounts of the compounds and other therapeutic agents of the present invention (in those compositions comprising other therapeutic agents as described above) that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. In some embodiments, compositions as described herein are formulated such that a dose of the present invention of 0.01 to 100 mg / kg body weight / day can be administered.

[0241] Generally, any agent that is active against the disease or condition being treated can be used concurrently. Examples of such agents can be found in Cancer Principles and Practice of Oncology (VTDevita and S. Hellman (eds.), p. 6). (Published February 15, 2001, by Lippincott Williams & Wilkins Publishers). Based on the specific characteristics of the drugs and diseases involved, those skilled in the art will be able to identify which combination of drugs will be useful.

[0242] In some embodiments, the treatment method comprises the co-administration of a compound as described herein or a pharmaceutically acceptable salt thereof with at least one chemotherapeutic agent. The term "chemotherapeutic agent" is a pharmaceutical agent used to treat cancer and includes, but is not limited to, cytotoxic agents such as radioactive isotopes (e.g., At...). 211 I 131 I 125 Y 90 Re 186 Re 188 、Sm 153 Bi 212 P 32Pb 212 (and radioactive isotopes of Lu); growth inhibitors; antimicrotubule agents; platinum analogs; topoisomerase II inhibitors; antimetabolites; topoisomerase I inhibitors; hormones and hormone analogs; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; apoptosis-promoting agents; cell cycle signal transduction inhibitors; nitrogen mustard; alkylating agents; toxoids or taxanes; aromatase inhibitors; pigment protein enediyne antichromophores; mitomycin; antihormonal agents; antiandrogens; protein kinase inhibitors; lipid kinase inhibitors; antisense oligonucleotides; tyrosine kinase inhibitors; Raf-1 inhibitors; EGFR inhibitors; camptothecin derivatives; anthracycline antibiotics; nucleoside metabolism inhibitors and other CDK inhibitors.

[0243] Treatment

[0244] In some embodiments, the compounds of this disclosure may be administered as a single agent. In some embodiments, the compounds of this disclosure may be administered in combination with at least one other therapeutic agent.

[0245] In some embodiments, this document provides a method for treating a disease, ailment, or condition in a subject who requires such treatment, 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.

[0246] In some embodiments, this document provides a method for treating a CDK2-mediated disorder in a subject with such need, the method comprising administering to the person 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.

[0247] In some embodiments, this document provides a method for 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.

[0248] In some embodiments, this document provides a method for selectively reducing CDK2 levels 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 GSPT1 levels in the subject are not reduced.

[0249] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a disease, ailment or condition of a subject in need of such treatment.

[0250] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a CDK2-mediated disorder in a subject with such need.

[0251] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for the degradation of CDK2 in a subject.

[0252] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for selectively reducing CDK2 levels in a subject, wherein GSPT1 levels in the subject are not reduced.

[0253] A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to treat a disease, ailment or condition in a subject who requires such treatment.

[0254] A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to treat a CDK2-mediated disorder in a subject who requires such treatment.

[0255] A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to degrade CDK2 in a subject.

[0256] Compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof or pharmaceutical compositions as described herein are used to selectively reduce CDK2 levels in subjects without reducing GSPT1 levels in the subjects.

[0257] In some embodiments, this document provides a method for treating a disease, ailment, or condition in a subject who requires such treatment, 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.

[0258] In some embodiments, this document provides a method for treating a CDK2-mediated disorder in a subject with such need, the method comprising administering to the person a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0259] In some embodiments, this document provides a method for 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.

[0260] In some embodiments, this document provides a method for selectively reducing CDK2 levels 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, wherein GSPT1 levels in the subject are not reduced.

[0261] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a disease, ailment or condition of a subject in need of such treatment.

[0262] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a CDK2-mediated disorder in a subject who requires such treatment.

[0263] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for the degradation of CDK2 in a subject.

[0264] Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein in the manufacture of a medicament for selectively reducing CDK2 levels in a subject, wherein GSPT1 levels in the subject are not reduced.

[0265] A compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to treat a disease, ailment or condition in a subject who requires such treatment.

[0266] The compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to treat a CDK2-mediated disorder in a subject who requires such treatment.

[0267] Compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to degrade CDK2 in a subject.

[0268] Compound of formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, used to selectively reduce CDK2 levels in subjects without reducing GSPT1 levels in subjects.

[0269] In some embodiments, the disease 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; esophageal cancer; eye cancer; head cancer; kidney cancer; liver cancer; lymph node cancer; lung cancer; upper respiratory and digestive tract cancer; oral cancer; oropharyngeal cancer; laryngeal cancer; hypopharyngeal cancer; salivary gland cancer; cervical cancer; thyroid cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; laryngeal cancer; uterine cancer; neuroblastoma; meningioma; hemangiopericytoma; leiomyoma; leukemia; lymphoma; and myeloma.

[0270] In some embodiments, the cancer is selected from: hormone receptor-positive breast cancer; estrogen receptor-positive breast cancer; triple-negative breast cancer; multiple brain metastases; glioblastoma multiforme; glioblastoma; brainstem glioma; malignant glioma; anaplastic astrocytoma; anaplastic oligodendroglioma; neuroendocrine carcinoma; metastatic hepatocellular carcinoma; Kaposi's sarcoma; malignant melanoma; malignant mesothelioma; malignant pleural effusion mesothelioma syndrome; peritoneal carcinoma; papillary serous carcinoma; gynecological 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-dependent 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 Cellular immunoblastic lymphoma; small non-cleavage cell lymphoma; human lymphocytic leukemia / lymphoma; adult T-cell lymphoma; peripheral T-cell lymphoma; cutaneous T-cell lymphoma; mantle cell lymphoma; Hodgkin lymphoma; non-Hodgkin lymphoma; AIDS-related lymphoma; follicular lymphoma; small lymphocytic lymphoma; large B-cell lymphoma rich in T cells / histocytes; transformed lymphoma; primary mediastinal (thymic) large B-cell lymphoma; splenic marginal zone lymphoma; Richter's transformation; lymph node marginal zone lymphoma; ALK-positive large B-cell lymphoma; indolent lymphoma; acute myeloid leukemia; acute lymphoblastic leukemia; adult T-cell lymphoma. Cellular leukemia; chronic lymphocytic leukemia; small lymphocytic lymphoma; hairy cell leukemia; myeloproliferative disorders; chronic myeloid leukemia; acute monocytic leukemia; myelodysplastic syndrome; human lymphotropic virus type 1 leukemia; mastocytosis; B-cell acute lymphoblastic leukemia; and multiple myeloma.

[0271] Exemplary cancers include, but are not limited to, leukemia (e.g., acute myeloid 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., gastric adenocarcinoma), kidney cancer (e.g., renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), 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).

[0272] In some embodiments, the cancer is ovarian cancer, stomach cancer, uterine cancer, esophageal cancer, lung cancer, or breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is lung cancer.

[0273] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is HR+, and the subject in need has progressed while using a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is HER2+, and the subject has progressed while using trastuzumab.

[0274] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is NSCLC, and the subject has progressed while using an epidermal growth factor receptor (EGFR) inhibitor.

[0275] In some embodiments, treatment may be administered after one or more symptoms have appeared. Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0276] The administration of the compounds disclosed herein can be achieved by any method capable of delivering the compounds to the site of action. These methods include oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), local administration, and rectal administration.

[0277] Dosing regimens can be adjusted to provide the optimal desired response. For example, a single dose can be administered, several doses can be administered over time, or the dose can be proportionally reduced or increased depending on the urgency of the treatment situation. Each unit dose may contain a predetermined amount of a compound of formula (I), formula (II), or formula (III), which is calculated to bind with the drug carrier to produce the desired therapeutic effect. The specifications of the dosage unit form of this disclosure are influenced by: (i) the unique characteristics of the specific active compound formula, (ii) the specific therapeutic or preventive effect to be achieved, and (iii) pharmacokinetic factors related to the drug and associated excipients, as well as the disease to be treated.

[0278] Therefore, based on the disclosure provided herein, those skilled in the art will understand that dosages and administration regimens can be adjusted according to methods known in the therapeutic field. That is, the maximum tolerable dose can be readily determined, and the effective amount to provide a detectable therapeutic benefit to the patient can also be determined. Dosage values ​​can vary depending on the type and severity of the condition to be relieved and can include single or multiple doses. It should be further understood that, for any particular subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration, and the dosage ranges listed herein are merely exemplary and not intended to limit the scope or practice of the claimed compositions. For example, dosages can be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Therefore, this disclosure covers intra-patient dose escalation as determined by those skilled in the art. Determining appropriate dosages and regimens for administering chemotherapeutic agents is well known in the relevant art and will be understood by those skilled in the art to be included once the teachings disclosed herein are provided.

[0279] The amount of the compound of this disclosure administered will depend on the subject being treated, the severity of the disease or condition, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. However, the effective dose is in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, as a single dose or divided dose. For a 70 kg person, this equates to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, for example by dividing such larger doses into several smaller doses administered throughout the day.

[0280] While certain dosages and administration regimens are disclosed herein, the disclosure is not limited to the dosages and administration regimens that may be provided to patients when implementing this disclosure.

[0281] In some embodiments, a method is provided for degrading CDK2 in a subject with cancer. This method includes administering to the subject an effective amount of: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as described elsewhere herein.

[0282] In some embodiments, a method of treating cancer in a subject with cancer is provided. This method includes administering to the subject an effective amount of: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as described elsewhere herein.

[0283] In some embodiments, a method of treating a solid tumor is provided. This method includes administering to a subject an effective amount of: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as described elsewhere herein.

[0284] In some embodiments, a method for treating a liquid tumor is provided. This method includes administering to a subject an effective amount of: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a compound of formula (III) or a pharmaceutically acceptable salt thereof; or (iv) a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as described elsewhere herein.

[0285] Example

[0286] Table 1 below lists the compounds of formula (I) prepared and characterized by NMR and / or mass spectrometry, where “Ex” refers to the example compound number.

[0287] Table 1

[0288]

[0289] Table 2 below lists the compounds of formula (II) prepared and characterized by NMR and / or mass spectrometry, where “Ex” refers to the example compound number.

[0290] Table 2

[0291]

[0292] The following examples show the NMR and / or mass spectrometry results for compounds of formula (I) 65-97, 99-107, 109-114 and 212, compounds of formula (II) 116-151, 153-183, 185-191, 193-203, 213-219 and 221-229, and compounds of formula (III) 204-211.

[0293] Compound Synthesis

[0294] Example 1

[0295] Preparation of intermediate 1A

[0296] General scheme for preparing intermediate 1A (“Int-1A”)

[0297]

[0298] Step 1: Preparation of 3-(6-bromo-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0299]

[0300] 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) were added to a solution of methyl 5-bromo-2-(bromomethyl)benzoate (350 g, 1.14 mol, 1.00 eq) in MeCN (2.45 L). The mixture was stirred at 80.0 °C for 12 h. The filter cake was concentrated under pressure to give a residue to the title compound as a coarse gray solid (250 g, 773 mmol, 68.0% yield).

[0301] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-carboxynitrile

[0302]

[0303] A mixture of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione (100 g, 309 mmol, 1.00 eq) and Zn(CN)₂ (36.8 g, 313 mmol, 1.01 eq) in DMF (700 mL) was degassed and purged three times with N₂, followed by the addition of triphenylphosphine palladium (34.9 g, 30.2 mmol, 0.10 eq). The mixture was stirred at 100 °C for 12 h 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 give the title compound as a coarse gray solid (35.0 g, 129 mmol, 42.0% yield).

[0304] Step 3: Preparation of 3-(6-(aminomethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0305]

[0306] A mixture of 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-carboxynitrile (65.0 g, 241 mmol, 1.00 eq) in MeOH (420 mL) and HCl (12 M, 60.3 mL) was added with Raney nickel (4.14 g, 48.2 mmol) and purged three times with H2. The mixture was stirred at 25 °C for 12 h under an H2 atmosphere (50 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a crude green solid (65.0 g, 238 mmol, 98.7% yield).

[0307] Step 4: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)tert-butyl carbamate (Int-1A)

[0308]

[0309] A mixture of 3-(6-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (65 g, 237 mmol, 1.00 eq), TEA (72.2 g, 713 mmol, 99.3 mL, 3.00 eq), and Boc2O (62.2 g, 285 mmol, 65.5 mL, 1.20 eq) in MeOH (70.0 mL) was degassed and purged three times with N2. The mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 0:1). The product was further purified after mixing with other batches (51.3 g). The combined substances were purified by reversed-phase HPLC to give the title compound as a white solid (25.0 g, 62.8 mmol, 46.3% yield). 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)+.

[0310] Example 2

[0311] Preparation of compounds 1-4, 7, 9-16, 18, 19, 21-32 of formula (I) and compounds 40, 41, 43-47 and 51-53 of formula (II).

[0312] Compound "IC" is prepared according to the following scheme. For compounds 1-4, 7, 9-16, 18, 19, 21-32 of formula (I), the "R" part of compound IC in the following scheme corresponds to the part in formula (I). For compounds 40, 41, 43-47 and 51-53 of formula (II), the “R” part of compound IC in the following schemes corresponds to the part in formula (II). .

[0313] In the general scheme, "Int-2B" refers to intermediate 2B, "Int1" refers to intermediate 1, and "Int-2B" refers to intermediate 2B.

[0314]

[0315] Step 1: Preparation of 3-(6-(aminomethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione hydrogen chloride (Int-1B)

[0316]

[0317] To a solution of ((2-(2,6-dioxadiazin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate tert-butyl ester (37 mg, 0.100 mmol, 1.00 eq) in DCM (1 mL), HCl-dioxane (1 mL, 4 M) was added. The mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a crude residue, which was used in the next step.

[0318] Step 2: Preparation of 3-(6-(aminomethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (Int1)

[0319]

[0320] 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrogen (31 mg, 0.100 mmol, 1.00 eq) was dissolved in CH3CN (1 mL), and the pH of the solution was adjusted to pH 7 with DIEA. Then, additional DIEA (0.300 mmol, 3.00 eq) was added to obtain a solution of the title compound, which was then used for the next step.

[0321] Steps 3a / b: Preparation of compound IC

[0322]

[0323] At 0 °C, TEA or pyridine (0.600 mmol, 6.00 eq) was added to a solution of alcohol IA (0.300 mmol, 3.00 eq) in DCM (1 mL), followed by a solution of 4-nitrophenyl chloroformate (0.300 mmol, 3.00 eq) in DCM (0.5 mL). The reaction mixture was stirred at 30 °C for 2 to 16 h. The reaction mixture was concentrated under reduced pressure to give crude carbonate IB. Then, a solution of Int-1B in CH3CN (1 mL) was added, and the mixture was stirred at 30 °C for 2 to 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound.

[0324] Example 3

[0325] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(p-tolyl)cyclobutyl ester (compound 39)

[0326]

[0327] Step 1: Preparation of 1-(3-(benzyloxy)cyclobutyl)-4-methylbenzene

[0328]

[0329] N-[(3-benzyloxycyclobutylene)amino]-4-methylbenzenesulfonamide (4.14 g, 12.03 mmol, 1.5 eq) was added to a suspension of p-tolueneboronic acid (1.09 g, 8.02 mmol, 1 eq) and cesium carbonate (7.89 g, 24.05 mmol, 3 eq) in 1,4-dioxane (50 mL). The reaction mixture was stirred at 100 °C under N2 for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the 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 rapid chromatography (0% to 10% petroleum ether solution of EtOAc) to give 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).

[0330] Step 2: Preparation of 3-(p-Tolyl)cyclobutanol

[0331]

[0332] To a solution of 1-(3-(benzyloxy)cyclobutyl)-4-methylbenzene (0.89 g, 3.53 mmol, 1 eq) in 1,4-dioxane (20 mL), 10% Pd / C (0.38 g) and 20% Pd / (OH)₂ (0.5 g) were added. The suspension was stirred at 25 °C in H₂ for 16 h. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0% to 15% EtOAc in petroleum ether solution) to give the title compound (300 mg, 52% yield) as a yellow oil.

[0333] Step 3: Preparation of (3-(p-Tolyl)cyclobutyl)nitrobenzene carbonate 4-nitrobenzene

[0334]

[0335] At 0 °C, 4-nitrophenol chloromethyl ester (161.52 mg, 0.80 mmol, 1.3 eq.) was added to a solution of 3-(p-tolyl)cyclobut-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 (5 mL). The reaction mixture was stirred at 25 °C under N2 for 16 h. 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 give the title compound (201.77 mg, crude) as a yellow oil. It was used directly in the next step without further purification.

[0336] Step 4: Preparation of 3-(p-Tolyl)cyclobutyl carbamate ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate)

[0337]

[0338] Add 3-[6-(aminomethyl)-1-oxo-isoindololin-2-yl]piperidin-2,6-dione (168.46 mg, 0.62 mmol, 1 eq.) and Et3N (0.26 mL, 1.85 mmol, 3 eq.) to a solution of (3-(p-tolyl)cyclobutyl)carbonate 4-nitrobenzene (201.77 mg, 0.62 mmol, 1 eq.) in DMF (3 mL). The mixture was then stirred at 25 °C for 16 h. The reaction mixture 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 preparative HPLC (Xtimate C18 150*40mm*10um, water (0.225% FA)-ACN, 58% to 88%) to give 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).

[0339] Example 4

[0340] Preparation of N-[[2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindoline-5-yl]methyl]carbamate [3-(o-tolyl)cyclobutyl] ester (compound 42)

[0341]

[0342] Step 1: Preparation of 1-(3-benzyloxycyclobutyl)-2-methylbenzene

[0343]

[0344] N-[(3-benzyloxycyclobutylene)amino]-4-methylbenzenesulfonamide (5.07 g, 14.71 mmol, 2.00 eq.) and Cs₂CO₃ (4.82 g, 14.71 mmol, 2.00 eq.) were added to a solution of 2-methylphenylboronic acid (1.0 g, 7.36 mmol, 1.00 eq.) in 1,4-dioxane (30 mL) at 25 °C under N₂. The mixture was then stirred at 100 °C under N₂ for 16 h. The reaction mixture was then concentrated under vacuum. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give the title compound as a white solid (700 mg, 38% yield).

[0345] Step 2: Preparation of 3-(o-tolyl)cyclobutanol

[0346]

[0347] 10% Pd / C (120.0 mg) was added to a stirred solution of 1-(3-benzyloxycyclobutyl)-2-methylbenzene (600.0 mg, 2.38 mmol, 1 eq.) in 1,4-dioxane (20 mL), and the reaction mixture was stirred at 25 °C under H2 (15 psi) for 3 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give the title compound (330 mg, 86%) as a light oil.

[0348] Step 3: Preparation of [3-(o-tolyl)cyclobutyl]carbonate (4-nitrophenyl) ester

[0349]

[0350] To a solution of 3-(o-tolyl)cyclobutanol (100.0 mg, 0.62 mmol, 1.00 eq.) in DCM (2 mL), 4-dimethylaminopyridine (7.53 mg, 0.06 mmol, 0.1 eq.) and pyridine (0.15 mL, 1.85 mmol, 3.00 eq.) were added. Then, 4-nitrophenylcarbonyl chloride (124.24 mg, 0.62 mmol, 1.00 eq.) was added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. Subsequently, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated to give a yellow oily crude title compound (120 mg, crude). The crude product can be used directly in the next step without further purification.

[0351] Step 4: Preparation of N-[[2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindoline-5-yl]methyl]carbamate[3-(o-tolyl)cyclobutyl] ester]

[0352]

[0353] Et3N (0.08 mL, 0.55 mmol, 2.00 eq.) and 3-[6-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (112.71 mg, 0.41 mmol, 1.50 eq.) were added to a solution of (4-nitrophenyl)[3-(o-tolyl)cyclobutyl]carbonate (90.0 mg, 0.27 mmol, 1.00 eq.) in DMF (2 mL) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated. The resulting residue was purified by preparative HPLC (Welch Xtimate C18 150*30mm*5µm / water(FA)-CAN, 0% to 60%) to give the title compound as a white solid (38.6 mg, 30% yield). LCMS (ESI): m / z 462.3 (M+H) + . 1 H 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 = 7.6 Hz, 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).

[0354] Example 5

[0355] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (4-chlorobenzo[d]thiazolyl)methyl ester (compound 5)

[0356]

[0357] Step 1: Preparation of (4-chlorobenzo[d]thiazolyl)methanol

[0358]

[0359] A mixture of 2-bromo-4-chlorobenzo[d]thiazole (1.0 g, 4.02 mmol, 1.00 eq.), (tributyltinyl)methanol (1.1 g, 4.43 mmol, 1.10 eq.), 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 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by column chromatography (0% to 30% EtOAc in petroleum ether solution) to give the title compound as a white solid (180.0 mg, 22% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.08 (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).

[0360] Step 2: Preparation of (4-nitrophenyl)carbonate (4-chlorobenzo[d]thiazolyl-2-yl)methyl ester

[0361]

[0362] DMAP (3.0 mg, 0.03 mmol, 0.10 eq.) and pyridine (0.06 mL, 0.76 mmol, 3.00 eq.) were added to a mixture of 4-chlorobenzo[d]thiazolyl-2-yl)methanol (50.0 mg, 0.25 mmol, 1.00 eq.) in DCM (5 mL). Then, 4-nitrophenylcarbonyl chloride (61.0 mg, 0.30 mmol, 1.20 eq.) was added to the mixture. The mixture was stirred at 25 °C for 16 h. The reaction was concentrated to give the title compound (90.0 mg, 98% yield) as a yellow oil. The crude product was used directly for the next step without purification. LCMS (ESI): m / z 365.0 (M+H) + .

[0363] Step 3: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (4-chlorobenzo[d]thiazolyl)methyl ester

[0364]

[0365] To a mixture of (4-nitrophenyl)carbonate (4-chlorobenzo[d]thiazolyl-2-yl)methyl ester (90.0 mg, 0.25 mmol, 1.00 eq.) in DMF (2 mL), 3-(6-(aminomethyl)-1-oxoisoindoline-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.) were added, and the mixture was stirred at 20 °C for 16 h. The mixture was purified by preparative HPLC (Xtimate C18150*40mm*10µm; water (FA)-ACN; 33 / 63) to give the title product (29.0 mg, 23% yield) as a 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).

[0366] Example 6

[0367] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 6)

[0368]

[0369] Step 1: Preparation of 2-bromo-4-phenylcyclohexane-1-one

[0370]

[0371] 4-Phenylon-1-one (3.0 g, 17.23 mmol) was added to a solution of bromine (0.95 mL, 17.23 mmol) in MeOH (30 mL). The resulting mixture was stirred at -10 °C for 0.5 h, and then at 25 °C for 16 h. The reaction mixture was extracted with EtOAc (50 mL × 3) and washed with brine (70 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (2 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0372] Step 2: Preparation of ethyl 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0373]

[0374] Add ethyl amino(thio)acetate (1052 mg, 7.9 mmol) to a solution of 2-bromo-4-phenyl-cyclohexanone (2000.0 mg, 7.9 mmol) in EtOH (10 mL). Stir the resulting reaction mixture at 90 °C for 3 h under N2. After cooling to room temperature, pour the reaction mixture into ice water (25 mL) and extract with EtOAc (20 mL × 3). Wash the combined organic layers with brine (100 mL), dry with Na2SO4, filter, and concentrate. Purify the residue by column chromatography (0% to 25% (75% ethyl acetate in ethanol) petroleum ether solution) to give ethyl 6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-carboxylate (550 mg, 24% yield) as a yellow solid. 1 H 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).

[0375] Step 3: Preparation of (6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0376]

[0377] A solution of ethyl 6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-carboxylate (450.0 mg, 1.57 mmol) in MeOH (5 mL) was degassed three times with N2 and then cooled to 0 °C. NaBH4 (118 mg, 3.13 mmol) was added and the reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched at 0 °C with NH4Cl solution (5 mL). The mixture was extracted with EtOAc (10 mL × 3), the combined organic layers were washed with brine (10 mL), filtered, and concentrated to give the title compound (300 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0378] Step 4: Preparation of ((6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl)nitrobenzene carbonate 4-nitrobenzene

[0379]

[0380] Pyridine (0.15 mL, 1.83 mmol) and N,N-dimethylpyridine-4-amine (0.01 mL, 0.06 mmol) were added 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 (2 mL). Then, 4-nitrophenylcarbonyl chloride (246.47 mg, 1.22 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was then diluted with water (10 mL) and extracted with DCM (20 mL × 3). The organic matter was washed with brine (20 mL × 3), dried over sodium sulfate, filtered, and concentrated to give the title compound (200 mg, 80% yield) as a yellow oil. The crude product was used directly in the next step without further purification.

[0381] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester)

[0382]

[0383] DIEA (0.25 mL, 1.46 mmol) was added to a mixture of 3-[6-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidin-2,6-dione; hydrochloride (150.9 mg, 0.490 mmol) in DMF (0.60 mL) at 25 °C. After stirring at 25 °C for 10 min, methyl carbonate (4-nitrophenyl)(6-phenyl-4,5,6,7-tetrahydro-1,3-benzothiazolyl-2-yl) (200.0 mg, 0.4900 mmol) was added. The resulting mixture was stirred at 25 °C for 1 h under N2. The reaction mixture was purified by preparative HPLC (acetonitrile 58-88 / 0.225% / FA aqueous solution) to give the title compound as a yellow solid (14.5 mg, 5.4% yield). LCMS (ESI): m / z 545.1 (M+H) + . 1H NMR (400MHz, 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).

[0384] Example 7

[0385] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 8)

[0386]

[0387] Step 1: Preparation of 2-bromo-4,4-difluorocyclohexane-1-one

[0388]

[0389] Br2 (0.41 mL, 7.46 mmol, 1.00 eq.) was added to a solution of 4,4-difluorocyclohexane-1-one (1.00 g, 7.46 mmol, 1.00 eq.) in MeOH (20.00 mL) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h, and then stirred at 25 °C for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with DCM (25 mL × 3). The combined organic phases were washed with brine (25 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the title compound (1.00 g, crude) as a yellow oil.

[0390] Step 2: Preparation of ethyl 6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0391]

[0392] Ethyl amino(thio)acetate (500.10 mg, 3.76 mmol, 1.00 eq.) was added to a solution of 2-bromo-4,4-difluorocyclohexanone (800.00 mg, 3.76 mmol, 1.00 eq.) in EtOH (13.00 mL) under N2. The reaction mixture was stirred at 90 °C for about 3 h under N2. The reaction mixture was extracted with DCM (25 mL × 3) and washed with brine (25 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC (acetonitrile 38-68 / 0.225% / FA aqueous solution) to give the title compound as a white solid (190 mg, 20.5% yield). LCMS (ESI): m / z 248.0 (M+H) + .

[0393] Step 3: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0394]

[0395] Sodium borohydride (51.00 mg, 1.35 mmol, 2.05 eq.) was slowly added to a solution of ethyl 6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-carboxylate (162.00 mg, 0.66 mmol, 1.00 eq.) in THF (2.00 mL) and MeOH (2.00 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (100.00 mg, quantified) as a yellow oil. LCMS (ESI): m / z 205.8 (M+H) + 1 H 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).

[0396] Step 4: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methyl(4-nitrophenyl)carbonate

[0397]

[0398] To a solution of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (100.00 mg, 0.49 mmol, 1.00 eq.) in DCM (2.00 mL), 4-dimethylaminopyridine (5.90 mg, 0.05 mmol, 0.10 eq.) and pyridine (0.12 mL, 1.46 mmol, 3.00 eq.) were added. 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 25 °C for 5 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (5 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (287.00 mg, crude) as a yellow oil. LCMS (ESI): m / z 371.0 (M+H)+ 。

[0399] Step 5: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methyl(4-nitrophenyl)carbonate

[0400]

[0401] DIPEA (0.03 mL, 0.19 mmol, 3.00 eq.) was added to a solution of (4-nitrophenyl)carbonate (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (47.80 mg, 0.13 mmol, 2.00 eq.) and 3-[6-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; hydrochloride (20.00 mg, 0.06 mmol, 1.00 eq.) in DMF (1.00 mL) at 25 °C. The mixture was stirred at 25 °C under N2 for 16 h. The resulting residue was purified by reversed-phase chromatography (Welch Xtimate C18 150*30mm*5um / water(FA)-ACN) to give the title compound as a white solid (4.50 mg, 13% yield). 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).

[0402] Example 8

[0403] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(2-methoxyphenyl)cyclobutyl ester (compound 48)

[0404]

[0405] Step 1: Preparation of 3-phenylcyclopentan-1-one

[0406]

[0407] Cs₂CO₃ (12.9 g, 39.48 mmol, 3.00 eq.) was added to a mixture of N-[(3-benzyloxycyclobutylene)amino]-4-methylbenzenesulfonamide (9.1 g, 26.32 mmol, 2.00 eq.) and (2-methoxyphenyl)boronic acid (2.0 g, 13.16 mmol, 1.00 eq.) in 1,4-dioxane (4 mL) at 25 °C. The mixture was then stirred at 100 °C for 16 h under N₂. After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The organic layers were mixed, dried with anhydrous sodium sulfate, and then concentrated under vacuum. The resulting residue was purified by column chromatography (2% ethyl acetate in petroleum ether solution) to give the title compound as a white oil (800 mg, 23% yield).

[0408] Step 2: Preparation of 3-phenylcyclopentan-1-ol

[0409]

[0410] 1-(3-(benzyloxy)cyclobutyl)-2-methoxybenzene (100.0 mg, 0.40 mmol, 1.00 eq.) was added to a solution of Pd / C (169 mg, 0.16 mmol, 0.40 eq.) in 1,4-dioxane (5 mL), and the mixture was stirred at 25 °C for 3 h under H2 (15 psi). The mixture was then filtered, and the filtrate was concentrated. The residue was purified by chromatography (0% to 5% EtOAc in petroleum ether solution) to give the title compound (51.6 mg, 80% yield) as a white oil. 1 H 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).

[0411] Step 3: Preparation of 3-(2-methoxyphenyl)cyclobutyl(4-nitrophenyl) carbonate

[0412]

[0413] Add pyridine (73.14 mg, 0.92 mmol, 3.00 eq.) and DMAP (3.77 mg, 0.03 mmol, 0.10 eq.) to a solution of 3-(2-methoxyphenyl)cyclobut-1-ol (50 mg, 0.31 mmol, 1.00 eq.) in DCM (2 mL) and then add 4-nitrophenylcarbonyl chloride (93.18 mg, 0.46 mmol, 1.50 eq.) at 0 °C. Incubate the mixture at 25 °C. Stir for 2 h. Then, dilute the reaction mixture with water (5 mL) and extract with DCM (5 mL × 3). Wash the organic matter with brine (10 mL × 3), dry over sodium sulfate, filter, and concentrate to give the crude title compound (80 mg, crude product). The crude product will be used directly in the next step without further purification.

[0414] Step 4: Preparation of 3-(2-methoxyphenyl)cyclobutyl 2-carbamate ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate

[0415]

[0416] At 25 °C, 3-(6-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (254.7 mg, 0.93 mmol, 4.00 eq.) and Et3N (0.06 mL, 0.47 mmol, 2.00 eq.) were added to a solution of 3-(2-methoxyphenyl)cyclobutyl(4-nitrophenyl) carbonate (80.0 mg, 0.23 mmol, 1.00 eq.) in DMF (2 mL). The mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The mixture was then purified by preparative HPLC (water (0.225% FA)-ACN, 37% to 67%) to give the title compound as a white solid (14.9 mg, 13% yield). 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).

[0417] Example 9

[0418] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(2-(trifluoromethyl)phenyl)cyclobutyl ester (compound 49)

[0419]

[0420] Step 1: Preparation of 1-(3-(benzyloxy)cyclobutyl)-2-(trifluoromethyl)benzene

[0421]

[0422] 1-Bromo-2-(trifluoromethyl)benzene (140 mg, 0.62 mmol, 1.5 eq.) and NiCl2 .A mixture of glycol dimethyl ether (9.1 mg, 0.04 mmol, 0.10 eq.) in DME (2 mL) was stirred for 5 min. This mixture was then transferred dropwise at 20 °C 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). All the above procedures were performed in a glove box. The reaction mixture was then stirred at 20 °C for 16 h using a Lumidox screening kit. Water (10 mL) was then added and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (0% to 2% ethyl acetate in petroleum ether) to give the title compound (130 mg, crude) as a yellow oil. 1 HNMR (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).

[0423] Step 2: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobut-1-ol

[0424]

[0425] 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) and DMF (3 mL), 1-(3-(benzyloxy)cyclobutyl)-2-(trifluoromethyl)benzene (170.0 mg, 0.56 mmol, 1.00 eq.) was added, and the mixture was stirred at 25 °C for 16 h under H₂ (15 psi). The residue was purified by column chromatography (0% to 5% EtOAc in petroleum ether solution) to give the title compound (36 mg, 30% yield) as a white oil.

[0426] Step 3: Preparation of (3-(2-(trifluoromethyl)phenyl)cyclobutyl)nitrobenzene carbonate 4-nitrobenzene

[0427]

[0428] Pyridine (39.5 mg, 0.50 mmol, 3.00 eq.) and DMAP (2.08 mg, 0.02 mmol, 0.10 eq.) were added to a solution of 3-(2-(trifluoromethyl)phenyl)cyclobut-1-ol (36 mg, 0.17 mmol, 1.00 eq.) in DCM (2 mL). Then, 4-nitrophenylcarbonyl chloride (50.34 mg, 0.25 mmol, 1.50 eq.) was added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then diluted with water (5 mL) and extracted with DCM (5 mL × 3). The organic matter was washed with brine (10 mL × 3), dried over sodium sulfate, filtered, and concentrated to give the crude compound. The crude product was used directly in the next step without further purification.

[0429] Step 4: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobutyl ester of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate

[0430]

[0431] At 25 °C, 3-(6-(aminomethyl)-1-oxoisoquinoline-2(1H)-yl)piperidin-2,6-dione (71.7 mg, 0.26 mmol, 2.00 eq.) and Et3N (39.8 mg, 0.47 mmol, 2.00 eq.) were added to a solution of (3-(2-(trifluoromethyl)phenyl)cyclobutyl)carbonate 4-nitrobenzene (50.0 mg, 0.13 mmol, 1.00 eq.) in DMF (2 mL). The resulting reaction mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The reaction mixture was then purified by preparative HPLC (water (0.225% FA)-ACN, 39% to 69%) to give the title compound as a white solid (4.6 mg, 6% yield). LCMS (ESI): m / z 516.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ10.99 (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).

[0432] Example 10

[0433] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(4-(trifluoromethyl)phenyl)cyclobutyl ester (compound 50)

[0434]

[0435] Step 1: Preparation of N'-(3-(benzyloxy)cyclobutylene)-4-methylbenzenesulfonylhydrazine

[0436]

[0437] 3-(benzyloxy)cyclobut-1-one (10.0 g, 56.75 mmol, 1.00 eq.) was added to a solution of TosNHNH2 (10.57 g, 56.75 mmol, 1.00 eq.) in MeOH (100 mL) at 25 °C. A crude product was immediately produced. After stirring at 25 °C for 10 min, the reaction mixture was concentrated. The residue was dried under vacuum to give the title compound (19 g, crude product) as a yellow solid.

[0438] Step 2: Preparation of 1-(3-(benzyloxy)cyclobutyl)-4-(trifluoromethyl)benzene

[0439]

[0440] N'-(3-(benzyloxy)cyclobutylene)-4-methylbenzenesulfonylhydrazine (3.63 g, 10.53 mmol, 2.00 eq.) and Cs₂CO₃ (3.45 g, 10.53 mmol, 2.00 eq.) were added to a solution of (4-(trifluoromethyl)phenyl)boronic acid (1.0 g, 5.27 mmol, 1.00 eq.) in 1,4-dioxane (30 mL) at 25 °C under N₂. The mixture was then stirred at 100 °C for 16 h 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 give the title compound (230 mg, 14%) as a white solid.

[0441] Step 3: Preparation of 3-(4-(trifluoromethyl)phenyl)cyclobut-1-ol

[0442]

[0443] 10% Pd / C (40.0 mg) was added 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), and the reaction mixture was stirred at 25 °C for 16 h under H2 (15 psi). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the 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).

[0444] Step 4: Preparation of (3-(4-(trifluoromethyl)phenyl)cyclobutyl)nitrobenzene carbonate 4-nitrobenzene

[0445]

[0446] Add 4-dimethylaminopyridine (5.65 mg, 0.05 mmol, 0.1 eq.) and pyridine (0.11 mL, 1.39 mmol, 3.00 eq.) to a solution of 3-(4-(trifluoromethyl)phenyl)cyclobut-1-ol (100.0 mg, 0.46 mmol, 1.00 eq.) in DCM (3 mL). Then add 4-nitrophenylcarbonyl chloride (121.2 mg, 0.60 mmol, 1.20 eq.) at 0 °C. Stir the mixture at 25 °C for 4 h. Dilute the reaction mixture with H2O (10 mL) and extract with DCM (10 mL × 3). Wash the organic matter with brine (10 mL × 3), dry to Na2SO4, filter, and concentrate to give a yellow oily crude title compound (170 mg, crude). The crude product can be used directly in the next step without further purification.

[0447] Step 5: Preparation of 3-(4-(trifluoromethyl)phenyl)cyclobutyl 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate

[0448]

[0449] Et3N (0.19 mL, 1.34 mmol, 3.00 eq.) and 3-(6-(aminomethyl)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (165.72 mg, 0.54 mmol, 1.20 eq.) were added to a solution of (3-(4-(trifluoromethyl)phenyl)cyclobutyl)carbonate 4-nitrobenzene (170.0 mg, 0.45 mmol, 1.00 eq.) in DMF (3 mL) at 25 °C. The solution was then stirred at 25 °C for 16 h. The resulting residue was purified by preparative HPLC (Welch Ultimate C18 150*30mm*5µm / water(FA)-CAN, 0% to 60%) to give the title compound as a white solid (109.5 mg, 46% yield). LCMS (ESI): m / z 516.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ8.05 (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).

[0450] Example 11

[0451] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 17)

[0452]

[0453] Step 1: Preparation of 2-bromo-4,4-dimethylcyclohexane-1-one

[0454]

[0455] Br2 (4.35 mL, 7.46 mmol, 1.00 eq.) was added to a solution of 4,4-dimethylcyclohexane-1-one (10.00 g, 79.24 mmol, 1.00 eq.) in MeOH (75.00 mL) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h, and then stirred at 25 °C for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic phases were washed with brine (80 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the title compound (12.50 g, quantitative) as a yellow oil. LCMS (ESI): m / z 206.9 (M+H) + .

[0456] Step 2: Preparation of ethyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0457]

[0458] 2-Amino-2-thioacetic acid ester (649.30 mg, 4.88 mmol, 1.00 eq.) was added to a solution of 2-bromo-4,4-dimethylcyclohexane-1-one (1.00 g, 4.88 mmol, 1.00 eq.) in EtOH (10.00 mL) under N2. The reaction mixture was stirred at 90 °C for 3 h under N2. After cooling to room temperature, the reaction mixture was extracted with DCM (25 mL × 3) and washed with brine (25 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (0.85 g, quantitative) as a white solid.

[0459] Step 3: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0460]

[0461] Sodium borohydride (0.52 g, 13.75 mmol, 1.90 eq.) was slowly added to a solution of ethyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-carboxylate (1.73 g, 7.23 mmol, 1.00 eq.) in THF (7.00 mL) and MeOH (7.00 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The solution was purified by column chromatography (0% to 60% petroleum ether solution of EtOAc) to give the title compound (1.30 g, 91% yield) as a white solid. LCMS (ESI): m / z 197.9 (M+H) + .

[0462] Step 4: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methyl(4-nitrophenyl)carbonate

[0463]

[0464] Pyridine (0.25 mL, 3.04 mmol, 3.00 eq.) and DMAP (12.38 mg, 0.10 mmol, 0.10 eq.) were added 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). Then, 4-nitrophenyl chloroformate (245.18 mg, 1.22 mmol, 1.20 eq.) was added to the above reaction mixture at 0 °C. The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The organic matter was washed with brine (20 mL × 3), dried over sodium sulfate, filtered, and concentrated to give the title compound as a yellow oil (367 mg, 99% yield). The crude product was used directly in the next step without further purification.

[0465] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0466]

[0467] Et3N (0.31 mL, 2.21 mmol, 4.00 eq) and (4-nitrophenyl)carbonate (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2-yl)methyl ester (200.0 mg, 0.55 mmol, 1.00 eq) were added to a solution of 3-[5-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidine-2,6-dione (226.23 mg, 0.83 mmol, 1.50 eq.) in DMF (2.0 mL) at 0 °C. The solution was then stirred at 25 °C for 16 h. The mixture was purified by preparative HPLC (acetonitrile 58-88 / 0.225% FA aqueous solution) to give the title compound as a white solid (115.8 mg, 41% yield). LCMS (ESI): m / z 497.2 (M+H) + . 1 H 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).

[0468] Example 12

[0469] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 20)

[0470]

[0471] Step 1: Preparation of 2-bromo-4-isopropylcyclohexane-1-one

[0472]

[0473] Br2 (3.4 g, 21.39 mmol, 1.00 eq) was added dropwise to a solution of 4-isopropylcyclohexane-1-one (3.0 g, 21.39 mmol, 1.00 eq) in MeOH (60 mL) at -10 °C. The mixture was stirred at -10 °C for 0.5 h, and then stirred at 25 °C for 16 h. The reaction mixture was then extracted with EtOAc (90 mL × 3) and washed with brine (90 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (4.8 g, crude) as a yellow oil. The crude product was used directly in the next step without purification.

[0474] Step 2: Preparation of ethyl 6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0475]

[0476] Ethyl amino(thio)ethyl acetate (2.92 g, 21.91 mmol, 1.00 eq) was added to a solution of 2-bromo-4-isopropylcyclohexane-1-one (4.8 g, 21.91 mmol, 1.00 eq) in EtOH (73 mL) at 25 °C. The resulting reaction mixture was stirred at 90 °C for 3 h 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 layers were mixed, dried with anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by preparative HPLC (water (0.225% FA)-ACN, 63% to 93%) to give the title compound as a white solid (554 mg, 10% yield). LCMS (ESI): m / z 254.0 (M+H) + . 1 H 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).

[0477] Step 3: Preparation of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0478]

[0479] LiAlH4 (134.8 mg, 3.55 mmol, 2.00 eq) was added to a solution of ethyl 6-isopropyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-carboxylate (450.0 mg, 1.78 mmol, 1.00 eq) in THF (5 mL) at 0 °C. After stirring at 25 °C for 2 h, the reaction was carried out at 0 °C with NaSO4. . Quench with 10H₂O until no more bubbles form. Then extract the reaction mixture with EtOAc (10 mL × 3). Combine the organic layers, wash with brine (15 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. Purify the residue by rapid chromatography (0% to 100% ethyl acetate in petroleum ether) to give the title compound (30 mg, 8% yield) as a yellow oil. 1 H 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).

[0480] Step 4: Preparation of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl(4-nitrophenyl)carbonate

[0481]

[0482] At 25 °C, 4-nitrophenylcarbonyl chloride (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) were added to a solution of (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (30.0 mg, 0.44 mmol, 1.00 eq) in DCM (2 mL). The resulting reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was then diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over sodium sulfate, filtered, and concentrated to give the title compound (50 mg, 94% yield) as a yellow oil. The crude product was used directly in the next step without further purification.

[0483] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0484]

[0485] Et3N (40.3 mg, 0.40 mmol, 3 eq) and 3-(6-(aminomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride (82.3 mg, 0.27 mmol, 2 eq) were added to a solution of (4-nitrophenyl)carbonate (6-isopropyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)-methyl ester (50.0 mg, 0.13 mmol, 1 eq) in DMF (2 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The mixture was then purified by preparative HPLC (water (0.225% FA)-ACN, 48% to 78%) to give the title compound as a white solid (33.5 mg, 45% yield). 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).

[0486] Example 13

[0487] Preparation of N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)-2-((1r,3r)-3-(2-(trifluoromethyl)phenyl)cyclobutyl)acetamide and N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)-2-((1s,3s)-3-(2-(trifluoromethyl)phenyl)cyclobutyl)acetamide (compounds 54 and 55)

[0488]

[0489] Step 1: Preparation of 1-(3-(benzyloxy)cyclobutyl)-2-(trifluoromethyl)benzene

[0490]

[0491] Add Ir[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) to a 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) to a stirred mixture. In a second vial, a mixture of NiCl2 glycol dimethyl ether (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 25 °C for 5 min. The mixture was then transferred to the first vial, and the reaction mixture was stirred at 25 °C under a 24 W blue LED for 16 h. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether solution, Rf = 0.6) to give the title compound (60 mg, 75% yield). 1 H 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).

[0492] Step 2: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclobut-1-ol

[0493]

[0494] Pd / C (600 mg, 0.56 mmol, 0.3 eq) and carbon-supported Pd(OH)₂ (240 mg, 0.34 mmol, 0.20 eq) were added 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) at 25 °C. The solution was then stirred at 25 °C for 4 h under H₂. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (0% to 20% ethyl acetate in petroleum ether solution) to give the title compound (200 mg, 47% yield). 1 H 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).

[0495] Step 3: N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)-2-((1r,3r)-3-(2-(trifluoromethyl)phenyl)cyclobutyl)acetamide

[0496]

[0497] Preparation of N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)-2-((1s,3s)-3-(2-(trifluoromethyl)phenyl)cyclobutyl)acetamide

[0498]

[0499] CDI (30 mg, 0.19 mmol, 1.00 eq) was added to a solution of 3-(2-(trifluoromethyl)phenyl)cyclobut-1-ol (40 mg, 0.19 mmol, 1.00 eq) in THF (1 mL), and the mixture was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindoline-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 (0.05 mL, 0.37 mmol, 2.00 eq) in DMF (1 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was then purified by preparative HPLC (C18 150*30mm, water (HCl)-ACN, 40% to 70%) to give a yellow solid N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)-2-((1r,3r)-3-(2-(trifluoromethyl)phenyl)cyclobutyl)acetamide (tentative) (4.5 mg, 4.5% yield). 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 further yielded a yellow solid N-((2-(2,6-dioxadiepidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)-2-((1s,3s)-3-(2-(trifluoromethyl)phenyl)cyclobutyl)acetamide (tentative) (1.7 mg, 1.6% yield). 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).

[0500] Example 14

[0501] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindole-5-yl)methyl)carbamate 3-(1-methyl-1H-indole-4-yl)cyclobutyl ester (compound 56)

[0502]

[0503] Step 1: Preparation of 4-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H-indole

[0504]

[0505] Add 3-((tert-butyldimethylsilyl)oxy)cyclobut-1-ol (1.86 g, 9.2 mmol, 1.5 eq) to a mixture of 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-tetrafluoroborate (4.84 g, 12.24 mmol, 2 eq) in 1,4-dioxane (40 mL). Stir the mixture at 20 °C under N2 for 5 min, and then add pyridine (0.79 mL, 9.8 mmol, 1.6 eq). Stir the mixture at 20 °C under N2 for 10 min. The solution was then added to 4-bromo-1H-indole (1.2 g, 6.12 mmol, 1 eq), quinine ring (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) was mixed in DMA (40 mL), stirred at 900 rpm, and irradiated for 2 h in a PennOC integrated photoreactor at 100% light intensity and a maximum fan speed of 1500 rpm under a 450 nm blue LED module. The reaction mixture was extracted with ethyl acetate (50 mL × 3) and washed with brine (30 mL × 2). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (0% to 6% ethyl acetate in petroleum ether) to give the title compound (1.74 g, 94% yield) as a brown oil. LCMS (ESI): m / z 302.0 (M+H) + .

[0506] Step 2: Preparation of 3-(1H-indol-4-yl)cyclobut-1-ol

[0507]

[0508] A solution of 1 M TBAF in THF (6.2 mL, 6.2 mmol, 1.1 eq) was added to a solution of 4-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H-indole (1.7 g, 5.64 mmol, 1 eq) in THF (15 mL), and the resulting solution was stirred at 20 °C for 1 h. The reaction mixture was concentrated and purified by column chromatography (0% to 30% (75% ethyl acetate in ethanol) petroleum ether solution) to give the title compound (370 mg, 1.98 mmol, 35% yield) as a brown oil. LCMS (ESI): m / z 187.9 (M+H) + .

[0509] Step 3: Preparation of 3-(1-methyl-1H-indol-4-yl)cyclobut-1-ol

[0510]

[0511] To a solution of 3-(1H-indol-4-yl)cyclobut-1-ol (190.0 mg, 1.01 mmol, 1 eq) in DMF (3 mL), KI (33.69 mg, 0.20 mmol, 0.2 eq), K₂CO₃ (154.27 mg, 1.12 mmol, 1.1 eq) and MeI (69.49 μL, 1.12 mmol, 1.1 eq) were added. The mixture was stirred at 25 °C for 16 h. The mixture was then diluted with ethyl acetate (20 mL) and washed with H₂O (10 mL × 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether solution) to give the title compound (40 mg, 20% yield) as a white solid (a mixture of cis and trans isomers). LCMS (ESI): m / z 202.1 (M+H) + .

[0512] Step 4: Preparation of 3-(1-methyl-1H-indole-4-yl)cyclobutyl carbamate ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindole-5-yl)methyl)carbamate

[0513] CDI (41.9 mg, 0.26 mmol, 1.3 eq) was added to a solution of 3-(1-methyl-1H-indol-4-yl)cyclobut-1-ol (40.0 mg, 0.20 mmol, 1 eq) in THF (1 mL), and the solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of 3-(6-(aminomethyl)-1-oxoisoindololin-2-yl)piperidin-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 (1 mL). The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Xtimate C18 150*40mm*5um, water (HCl)-ACN, 27% to 57%) to give the title compound as a white solid (35 mg, 35% yield). 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).

[0514] Example 15

[0515] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (1R,3S)-3-(2-(trifluoromethyl)phenyl)cyclohexyl ester (compound 57)

[0516]

[0517] Step 1: Preparation of 3-(2-(trifluoromethyl)phenyl)cyclohexane-1-one

[0518]

[0519] Isopropyl magnesium chloride (22.22 mL, 44.44 mmol, 2.00 eq) (2 M THF solution) was added to a solution of 1-bromo-2-(trifluoromethyl)benzene (5.0 g, 22.22 mmol, 1.00 eq) in THF (50 mL) at -78 °C under N2. The solution was then stirred at room temperature for 16 h, followed by the addition of CuI (2.12 g, 11.11 mmol, 0.50 eq). After stirring at room temperature for 1 min, cyclohexyl-2-en-1-one (2.58 mL, 26.67 mmol, 1.20 eq) was added and stirred for 30 min. The mixture was diluted with water (40 mL). The aqueous phase was concentrated and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (50 mL), 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 give the title compound as a yellow oil (800 mg, 15% yield). 1 H 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).

[0520] Step 2: Preparation of (1S,3R)-3-(2-(trifluoromethyl)phenyl)cyclohexane-1-ol

[0521]

[0522] Sodium borohydride (1.06 g, 28.02 mmol, 8.00 eq) was slowly added to a solution of 3-(2-(trifluoromethyl)phenyl)cyclohexane-1-one (800.0 mg, 3.3 mmol, 1.00 eq) in MeOH (8 mL) at 0 °C. The mixture was stirred at 0 °C for 5 min. The mixture was stirred at 25 °C for 16 h. The reaction was quenched by adding saturated NH4Cl solution (15 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were 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 give the title compound (500 mg, 62% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ7.62 (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).

[0523] Step 3: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (1R,3S)-3-(2-(trifluoromethyl)phenyl)cyclohexyl ester)

[0524]

[0525] CDI (86.3 mg, 0.53 mmol) was added to a solution of (1S,3R)-3-(2-(trifluoromethyl)phenyl)cyclohexane-1-ol (100.0 mg, 0.410 mmol, 1.00 eq) in THF (2 mL), and the solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of 3-(6-(aminomethyl)-1-oxoisoindoline-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) in DMF (2 mL). The reaction mixture was then stirred at 25 °C for 16 h. The compound was then purified by preparative HPLC (acetonitrile 40% to 70% / 0.225% hydrochloric acid aqueous solution) to give the title compound as a white solid (54 mg, 24% yield). LCMS (ESI): m / z 544.2 (M+H) + . 1 H 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).

[0526] Example 16

[0527] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(2-fluorophenyl)cyclobutyl ester (compound 58)

[0528]

[0529] Step 1: Preparation of 3-(2-fluorophenyl)cyclobut-1-ol

[0530]

[0531] Pyridine (0.15 mL, 1.83 mmol, 1.6 eq) was added to a mixture of cyclobutane-1,3-diol (177 mg, 2.00 mmol, 1.75 eq), 5,7-di-tert-butyl-3-phenyl-1,3-benzoxazole-3-ammonium; trifluoroborane; and fluoride (904 mg, 2.29 mmol, 2.0 eq) in 1,4-dioxane (4 mL). The mixture was stirred at 20 °C for 5 min under nitrogen. The solution was then added to a mixture of 1-bromo-2-fluorobenzene (200 mg, 1.14 mmol, 1.0 eq), quinine ring (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 and irradiated for 2 h in a PennOC integrated photoreactor at 100% light intensity and a maximum fan speed of 1500 rpm under a 450 nm blue LED module. The mixture was then extracted with EtOAc (40 mL) and washed with brine (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the title compound (70 mg, 37% yield) as a yellow oil.

[0532] Step 2: Preparation of 3-(2-fluorophenyl)cyclobutyl(4-nitrophenyl) carbonate

[0533]

[0534] Step 3: Preparation of 3-(2-fluorophenyl)cyclobutyl carbamate ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate)

[0535]

[0536] Et3N (0.2 mL, 1.25 mmol, 3.0 eq) was added to a mixture of (4-nitrophenyl)carbonate 3-(2-fluorophenyl)cyclobutyl ester (138 mg, 0.42 mmol, 1.0 eq) and 3-(6-(aminomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride (168 mg, 0.54 mmol, 1.3 eq) in DMF (2 mL), and the mixture was stirred at 40 °C for 16 h. The mixture was then concentrated. The residue was purified by preparative HPLC (Welch Xtimate C18 150*30 mm*5 μm, water (FA)-CAN, 36% to 66%) to give the title compound as a yellow solid (102.7 mg, 52% yield). LCMS (ESI): m / z 466.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.99 (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).

[0537] Example 17

[0538] Preparation of 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-N-(quinoline-6-yl)acrylamide (compound 33)

[0539]

[0540] Step 1: Preparation of 5-bromospiro[2.5]octane-6-one

[0541]

[0542] Br2 (3.54 g, 22.15 mmol, 1.00 eq) was added to a solution of spiro[2.5]octane-6-one (2.5 g, 20.13 mmol, 1.00 eq) in MeOH (30 mL) at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction was quenched with H2O (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, and concentrated to give the title compound (2.7 g, crude) as a yellow oil, which was used directly in the next step.

[0543] Step 2: Preparation of ethyl 5,7-dihydro-4H-spiro[benzo[d]thiazole-6,1'-cyclopropane]-2-carboxylate

[0544]

[0545] At 20 °C, ethyl amino(thio)acetate (1.77 g, 13.3 mmol, 4.00 eq) was added to a solution of 5-bromospiro[2.5]octane-6-one (2.7 g, 13.3 mmol, 1.00 eq) in MeOH (25.0 mL), and the mixture was stirred at 90 °C under N2 for 12 h. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (0% to 20% ethyl acetate in petroleum ether) to give the title compound (600 mg, 19% yield). LCMS (ESI): m / z 237.9 (M+H) + .

[0546] Step 3: Preparation of (5,7-dihydro-4H-spiro[benzo[d]thiazol-6,1'-cyclopropane]-2-yl)methanol

[0547]

[0548] Ethyl 5,7-dihydro-4H-spiro[benzo[d]thiazol-6,1'-cyclopropane]-2-carboxylate (500.0 mg, 1.69 mmol, 1.00 eq) was added fractionally to a solution of 5,7-dihydro-4H-spiro[benzo[d]thiazol-6,1'-cyclopropane]-2-carboxylate (20 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with H₂O (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (0% to 40% ethyl acetate in petroleum ether) to give the title compound (90 mg, 27% yield). LCMS (ESI): m / z 195.9 (M+H) + .

[0549] Step 4: Preparation of (4-nitrophenyl)carbonate (5,7-dihydro-4H-spiro[benzo[d]thiazol-6,1'-cyclopropane]-2-yl)methyl ester

[0550]

[0551] Pyridine (0.11 mL, 1.38 mmol, 3.00 eq) and DMAP (5.63 mg, 0.05 mmol, 0.01 eq) were added to a solution of (5,7-dihydro-4H-spiro[benzo[d]thiazol-6,1'-cyclopropane]-2-yl)methanol (90.0 mg, 0.46 mmol, 1.00 eq) in DCM (10.0 mL). Then, 4-nitrophenyl chloroformate (139.34 mg, 0.69 mmol, 1.50 eq) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. Afterward, the reaction mixture was diluted with water (25 mL) and extracted with DCM (10 mL × 3). The organic matter was washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated to give a yellow oily title compound (120 mg, 33% yield). The crude product was used directly in the next step without further purification.

[0552] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (5,7-dihydro-4H-spiro[benzo[d]thiazo-6,1'-cyclopropane]-2-yl)methyl ester

[0553]

[0554] Et3N (0.06 mL, 0.46 mmol, 3.00 eq) and 3-[6-(aminomethyl)-1-oxo-isoindol-2-yl]piperidine-2,6-dione (62.79 mg, 0.23 mmol, 1.50 eq) were added to a solution of (4-nitrophenyl)carbonate (5,7-dihydro-4H-spiro[benzo[d]thiazolyl-6,1'-cyclopropane]-2-yl) in DMF (10.0 mL) at 0 °C. The mixture was stirred at 25 °C under N2 for 16 h. The reaction mixture was then diluted with water (5 mL) and extracted with DCM (10 mL × 3). The organic matter was washed with brine (10 mL × 3), dried over sodium sulfate, filtered, and concentrated to obtain a crude product. This crude product was purified by preparative HPLC (Gilson 281 (Boston Green ODS) C18 150*30mm*3um, water (0.225% FA)-ACN, 36% to 65%) to give the title compound as a white solid (21 mg, 28% yield). LCMS (ESI): m / z 495.1 (M+H) + . 1 H 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 = 8.4Hz, 4H).

[0555] Example 18

[0556] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (4-methylbenzo[d]thiazolyl)methyl ester (compound 34)

[0557]

[0558] Step 1: Preparation of (4-methylbenzo[d]thiazolyl)methanol

[0559]

[0560] Pd(PPh3)4 (202.6 mg, 0.18 mmol, 0.08 eq), CuI (83.5 mg, 0.44 mmol, 0.20 eq), and tributyltin-methylethanol (774.20 mg, 2.41 mmol, 1.00 eq) were added 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) at 25 °C under N2. The reaction mixture was stirred at 100 °C for 16 h 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 phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the title compound as a yellow solid (24.50 mg, 6.2% yield). LCMS (ESI): m / z 180.1 (M+H) + .

[0561] Step 2: Preparation of (4-nitrophenyl)carbonate (4-methylbenzo[d]thiazolyl-2-yl)methyl ester

[0562]

[0563] Pyridine (0.06 mL, 0.69 mmol, 3.00 eq) and 4-dimethylaminopyridine (2.80 mg, 0.02 mmol, 0.10 eq) were added to a suspension of 4-nitrophenyl chloroformate (55.40 mg, 0.27 mmol, 1.20 eq) in DCM (2.00 mL) at 25 °C 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 25 °C under N2. The reaction was stirred at 25 °C for 16 h. The solvent was concentrated by Speedvac. The crude product was used directly in the next step without further purification.

[0564] Step 3: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (4-methylbenzo[d]thiazolyl)methyl ester

[0565]

[0566] Et3N (0.10 mL, 0.69 mmol, 3.00 eq) and (4-nitrophenyl)carbonate (4-methylbenzo[d]thiazolyl-2-yl)methyl ester (78.80 mg, 0.23 mmol, 1.00 eq) were added to a solution of 3-[6-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidine-2,6-dione (62.50 mg, 0.23 mmol, 1.00 eq) in DMF (4.00 mL) at 25 °C under N2. The mixture was then stirred at 40 °C for 16 h. The resulting residue was purified by reversed-phase chromatography (Welch Xtimate C18 150*30mm*5um / water(FA)-ACN) to give the title compound as a white solid (11.00 mg, 9.3% yield). LCMS (ESI): m / z 479.2 (M+H) + . 1 H 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).

[0567] Example 19

[0568] Preparation of N-[[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-3-oxo-isoindoline-5-yl]methyl]carbamate (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazolyl-2-yl)methyl ester (compound 35)

[0569]

[0570] Step 1: Preparation of 3-bromo-2-fluoro-6-methylbenzaldehyde

[0571]

[0572] A mixture of 3-bromo-2-fluorobenzaldehyde (5.0 g, 24.63 mmol, 1.00 eq), 2-aminobenzenesulfonic acid (1.92 g, 11.08 mmol, 0.45 eq), potassium methyl trifluoroborate (12.0 g, 98.52 mmol, 4.00 eq), 1-fluoro-2,4,6-trimethylpyridine tetrafluoroborate (1.12 g, 49.26 mmol, 2.00 eq), and Pd(OAc)₂ (553 mg, 2.46 mmol, 0.10 eq) in a mixture of TFA (6.7 mL) and HFIP (60 mL) was degassed three times under an Ar atmosphere. The mixture was stirred at 20 °C for 20 min, then heated to 90 °C for 24 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by column chromatography (2% to 5% ethyl acetate in petroleum ether solution) to give a colorless oily mixture of the title compound and the starting material (approximately 1:1, 1.7 g). LCMS (5-95AB / 1.5 min) showed 43% 3-bromo-2-fluoro-6-methylbenzaldehyde and 49% 3-bromo-2-fluoro-benzaldehyde. The crude product was used directly in the next step.

[0573] Step 2: Preparation of 3-bromo-2-fluoro-6-methylbenzoic acid

[0574]

[0575] NaH₂PO₄ (9.07 g, 75.56 mmol, 4.00 eq) was added in a single batch to a stirred solution of 3-bromo-2-fluoro-6-methylbenzaldehyde (4.10 g, 18.89 mmol, 1.00 eq) in THF (100 mL), water (50 mL), and t-BuOH (25 mL) at -5 °C. NaClO₂ (6.83 g, 75.56 mmol, 4.00 eq) was then added in portions. After the addition, the mixture was stirred at -5 °C for one hour. 2-Methyl-2-butene (9.27 g, 132.23 mmol, 7.00 eq) was added dropwise to the reaction mixture while maintaining the temperature below 0 °C. After the addition, the mixture was stirred at 0 °C for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and 2M HCl solution (20 mL), and the layers were separated. The organic phase was concentrated to give a colorless, oily mixture of the title compound and 3-bromo-2-fluoro-6-methylbenzoic acid (approximately 1:1, 5.0 g). LCMS showed 40% of the desired product and 42% of 3-bromo-2-fluorobenzoic acid. The mixture was difficult to separate by column chromatography and was used directly in the next step.

[0576] Step 3: Preparation of N-[[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-6-quinolinyl]methyl]tert-butyl carbamate

[0577]

[0578] A mixture of 3-bromo-2-fluoro-6-methylbenzoic acid and 3-bromo-2-fluorobenzoic acid (5.0 g, 21.46 mmol, 1.00 eq) in MeOH (10 mL) was carefully added to SOCl2 (3.11 mL, 42.91 mmol, 2.00 eq). The mixture was then heated to 75 °C for 12 h. The mixture was concentrated to a 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-methylbenzoic acid (2.0 g) as a white solid. 3-Bromo-2-fluoro-6-methylbenzoic acid (1.2 g, 5.15 mmol, 1.00 eq) was dissolved in DMF (10 mL), followed by the addition of Cs₂CO₃ (2.52 g, 7.72 mmol, 1.50 eq), and 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 25 °C for 16 h under a nitrogen atmosphere. The mixture was then poured into water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with brine (10 mL × 2), dried, filtered, and concentrated. The residue was purified by column chromatography (5% ethyl acetate in petroleum ether) to give the title compound as a white solid (750 mg, 59% yield). LCMS (ESI): m / z 249.0 (M+H) + . 1 H 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).

[0579] Step 4: Preparation of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate

[0580]

[0581] 2,2'-Azobis(2-methylpropionitrile) (49.85 mg, 0.30 mmol, 0.10 eq) was added to a mixture of methyl 3-bromo-2-fluoro-6-methylbenzoate (750.0 mg, 3.04 mmol, 1.00 eq) and 1-bromo-2,5-pyrrolidone (594.32 mg, 3.34 mmol, 1.10 eq) in a DCE (10 mL) at 25 °C. The reaction mixture was then stirred at 90 °C for 16 h under a N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by column chromatography (2% ethyl acetate in petroleum ether solution) to give the title compound as a white solid (950 mg, 2.91 mmol, 96% yield). 1 H 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).

[0582] Step 5: Preparation of 3-(6-bromo-7-fluoro-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0583]

[0584] At 25 °C, 3-aminopiperidine-2,6-dione hydrochloride (576 mg, 3.5 mmol, 1.20 eq) and DIEA (2.89 mL, 17.49 mmol, 6.00 eq) were added to a solution of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate (950.0 mg, 2.91 mmol, 1.00 eq) in MeCN (10 mL). The mixture was stirred at 80 °C for 20 h. After cooling to room temperature, the mixture was concentrated. The residue was dissolved in 1 M HCl solution (10 mL) and EtOAc (10 mL). The mixture was filtered, and the filter cake was washed with water (10 mL × 2) to give the title compound as a blue solid (690 mg, 2.02 mmol, 69% yield). 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).

[0585] Step 6: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-carboxynitrile

[0586]

[0587] 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) were added to a solution of 3-(6-bromo-7-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione (400.0 mg, 1.17 mmol, 1.00 eq) in DMF (5 mL) at 25 °C. The mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting solution was filtered through diatomaceous earth, cooled to room temperature, filtered again, and the filter cake was washed with ethyl acetate (10 mL × 2) and MeOH (10 mL × 2). The combined organic layers were concentrated to a residue and ground with ethyl acetate (10 mL). The solid was filtered and washed with water (5 mL × 2) to give the title compound as a gray solid (260 mg, 77% yield). LCMS (ESI): m / z 288.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ11.03 (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).

[0588] Step 7: Preparation of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride

[0589]

[0590] A mixture of PdCl2 (200.0 mg, 1.13 mmol, 1.2 eq) and 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-3-oxo-isoindoline-5-carboxynitrile (260.0 mg, 0.91 mmol, 1.00 eq) in MeOH (20 mL) was stirred at 20 °C for 5 h under a H2 atmosphere (15 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (100 mg, 32% yield). LCMS (ESI): m / z 583.3 (2M+H) + . 1 H 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, 13.2Hz, 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).

[0591] Step 8: Preparation of N-[[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-3-oxo-isoindoline-5-yl]methyl]carbamate (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazolyl-2-yl)methyl ester

[0592]

[0593] 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), 4-nitrophenyl chloroformate (123 mg, 0.61 mmol, 1.20 eq) and DIEA (0.34 mL, 2.03 mmol, 4.00 eq) were added. After stirring at 25 °C for 2 h, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate (10 mL) and washed with brine (5 mL × 2). The organic phase was concentrated to give a yellow oily (4-nitrophenyl)carbonate (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2-yl) methyl ester (150 mg, crude), which was absorbed with DMF (5 mL). The solution was supplemented with methyl (6,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-2-yl) carbonate (199 mg, 0.55 mmol, 1.20 eq) and Et3N (0.32 mL, 2.29 mmol, 5.00 eq). The resulting reaction mixture was stirred at 20 °C for 16 h. The mixture was then purified by preparative HPLC (column: Xtimate C18 150*40mm*10µm; water (FA)-ACN; ACN: 7% to 37%) to give the title compound as a white solid (106 mg, 0.20 mmol, 45% yield). LCMS (ESI): m / z 515.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.06 (t, J = 5.6Hz, 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).

[0594] Example 20

[0595] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (7-fluorobenzo[d]thiazolyl)methyl ester (compound 36)

[0596]

[0597] Step 1: Preparation of 7-fluorobenzo[d]thiazole-2-thiol

[0598]

[0599] O-ethyl dithiocarbonate (14.9 g, 92.94 mmol, 1.2 eq) was added to a solution of 2,3-difluoroaniline (10.0 g, 77.45 mmol, 1.0 eq) in DMF (100 mL) at 25 °C. The mixture was stirred at 120 °C for 3 h. After cooling to room temperature, water (100 mL) was added to precipitate the title compound (28 g, 98% yield) as a grayish-white powder. 1 H NMR (400MHz, DMSO-d6) δ 7.48 - 7.42 (m, 1H), 7.23 - 7.12 (m, 2H).

[0600] Step 2: Preparation of 2-bromo-7-fluorobenzo[d]thiazole

[0601]

[0602] Bromine (32 mL, 589.14 mmol, 11 eq) was added to a solution of 7-fluoro-1,3-benzothiazol-2-thiol (10 g, 53.98 mmol, 1.0 eq) in CHCl3 (100 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. It was then slowly added to water (100 mL) and stirred for another 20 min. The mixture was filtered to remove the paste-like solid. The organic phase was separated, dried, and evaporated to leave a brown solid. The brown solid was dissolved in diethyl ether and filtered. The residue was washed with ether, and the filtrate and washes were combined and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give the title compound (4 g, 32% yield) as a yellow solid.

[0603] Step 3: Preparation of (7-fluorobenzo[d]thiazolyl)methanol

[0604]

[0605] Pd(PPh3)4 (797 mg, 0.69 mmol, 0.08 eq) and tributyltinylmethanol (3.1 g, 9.48 mmol, 1.1 eq) were added 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). The mixture was stirred at 100 °C for 16 h under N2. The mixture was then quenched with KF solution (50 mL). The mixture was extracted with DCM (40 mL × 3), washed with water (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to give the title compound as a white solid (300 mg, 19% yield). 1 H 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).

[0606] Step 4: Preparation of (4-nitrophenyl)carbonate (7-fluorobenzo[d]thiazolyl-2-yl)methyl ester

[0607]

[0608] Pyridine (0.14 mL, 1.67 mmol, 3.0 eq) and DMAP (14 mg, 0.11 mmol, 0.2 eq) were added to a solution of (7-fluorobenzo[d]thiazolyl)methanol (100 mg, 0.56 mmol, 1.0 eq) in DCM (2 mL), followed by the addition of 4-nitrophenyl carbon chloride (147 mg, 0.73 mmol, 1.3 eq). The resulting mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to give the title compound (190 mg, crude) as a yellow solid. This was used directly in the next step without further purification.

[0609] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (7-fluorobenzo[d]thiazolyl)methyl ester

[0610]

[0611] To a mixture of (4-nitrophenyl)carbonate (7-fluorobenzo[d]thiazolyl-2-yl)methyl ester (190 mg, 0.55 mmol, 1.0 eq) in DMF (2 mL), 3-(6-(aminomethyl)-1-oxoisoindol-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) were added, and the mixture was stirred at 40 °C for 16 h. The mixture was then purified by preparative HPLC (Welch Xtimate C18150*30mm*5µm, water (FA)-CAN, 38% to 68%) to give the title compound as a yellow solid (42.2 mg, 16% yield). LCMS (ESI): m / z 482.9 (M+H) + . 1 H 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).

[0612] Example 21

[0613] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (7-methylbenzo[d]thiazolyl)methyl ester (compound 37)

[0614]

[0615] Step 1: Preparation of (7-chlorobenzo[d]thiazolyl)methanol

[0616]

[0617] Tributyltinylmethanol (2.8 g, 8.85 mmol, 1.0 eq), CuI (307 mg, 1.61 mmol, 0.2 eq), and Pd(PPh3)4 (744 mg, 0.64 mmol, 0.08 eq) were added to a mixture of 2-bromo-7-chlorobenzo[d]thiazole (2 g, 8.05 mmol, 1.1 eq), CuI (307 mg, 1.61 mmol, 0.2 eq), and the mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then quenched by adding KF solution (50 mL). The mixture was extracted with DCM (30 mL × 3), washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to give the title compound as a white solid (340 mg, 21% yield). 1 H 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).

[0618] Step 2: Preparation of (7-methylbenzo[d]thiazolyl)methanol

[0619]

[0620] Xphos (48 mg, 0.10 mmol, 0.2 eq) and Pd2(dba)3 (46 mg, 0.05 mmol, 0.1 eq) were added to a solution of (7-chlorobenzo[d]thiazolyl-2-yl)methanol (100 mg, 0.50 mmol, 1.0 eq), trimethylborooxane (0.42 mL, 1.5 mmol, 3.0 eq), K3PO4 (319 mg, 1.5 mmol, 3.0 eq) in 1,4-dioxane (3 mL). The resulting reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated and purified by preparative TLC (10% MeOH in DCM solution) to give the title compound as a white solid (50 mg, 56% yield). LCMS (ESI): m / z 180.1 (M+H) + .

[0621] Step 3: Preparation of (4-nitrophenyl)carbonate (7-methylbenzo[d]thiazolyl)methyl ester

[0622]

[0623] Pyridine (0.07 mL, 0.84 mmol, 3.0 eq), 4-nitrophenyl carbon chloride (74 mg, 0.36 mmol, 1.3 eq), and DMAP (7 mg, 0.06 mmol, 0.2 eq) were added to a solution of (7-methylbenzo[d]thiazolyl)methanol (50 mg, 0.28 mmol, 1.3 eq) in DCM (2 mL), and the mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to give the title compound (90 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification.

[0624] Step 4: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (7-methylbenzo[d]thiazolyl)methyl ester

[0625]

[0626] To a mixture of (4-nitrophenyl)carbonate (7-methyl-1,3-benzothiazol-2-yl)methyl ester (90 mg, 0.26 mmol, 1.0 eq) in DMF (2 mL), 3-(6-(aminomethyl)-1-oxoisoindol-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) were added, and the mixture was stirred at 40 °C for 16 h. The mixture was then purified by preparative HPLC (Welch Xtimate C18150*30mm*5µm, water (FA)-CAN, 38% to 68%) to give the title compound as a white solid (42.6 mg, 34% yield). 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).

[0627] Example 22

[0628] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (7-chlorobenzo[d]thiazolyl)methyl ester (compound 38)

[0629]

[0630] Step 1: Preparation of (7-chlorobenzo[d]thiazolyl)methanol

[0631]

[0632] Tributyltinylmethanol (285 mg, 0.89 mmol, 1.1 eq) and Pd(PPh3)4 (75 mg, 0.06 mmol, 0.08 eq) were added 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). The mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then quenched with KF solution (10 mL). The mixture was extracted with DCM (30 mL x 3), washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to give the title compound as a white solid (340 mg, 21% yield). LCMS (ESI): m / z 200.1 (M+H) + .

[0633] Step 2: Preparation of (4-nitrophenyl)carbonate (7-chlorobenzo[d]thiazolyl-2-yl)methyl ester

[0634]

[0635] Pyridine (0.05 mL, 0.60 mmol, 3.0 eq), 4-nitrophenyl carbonate (53 mg, 0.26 mmol, 1.3 eq), and DMAP (5 mg, 0.04 mmol, 0.2 eq) were added to a solution of (7-chloro-1,3-benzothiazol-2-yl)methanol (40 mg, 0.20 mmol, 1.3 eq) in DCM (2 mL), and the mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to give the title compound (70 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification.

[0636] Step 3: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate (7-chlorobenzo[d]thiazolyl)methyl ester

[0637]

[0638] To a mixture of (4-nitrophenyl)carbonate (7-chloro-1,3-benzothiazol-2-yl)methyl ester (70 mg, 0.19 mmol, 1.0 eq) in DMF (1 mL), 3-(6-(aminomethyl)-1-oxoisoindol-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) were added, and the mixture was stirred at 40 °C for 16 h. The mixture was then purified by preparative HPLC (Welch Xtimate C18150*30mm*5µm, water (FA)-CAN, 38% to 68%) to give the title compound as a yellow solid (13.1 mg, 13% yield). 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).

[0639] Example 23

[0640] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindole-5-yl)methyl)carbamate 3-(1-methyl-1H-indole-7-yl)cyclobutyl ester (compound 59)

[0641]

[0642] Step 1: Preparation of 7-bromo-1-methyl-1H-indole

[0643]

[0644] 7-Bromo-1H-indole (9.0 g, 45.91 mmol, 1.00 eq) and NaH (2.1 g, 52.5 mmol, 1.10 eq) were added in THF (150 mL). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. 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. The reaction mixture was then 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 (petroleum ether solution of 0% to 80% ethyl acetate) to give 7-bromo-1-methyl-1H-indole (9.2 g, 95% yield) as a white solid.

[0645] Step 2: Preparation of 3-(1-methyl-1H-indol-7-yl)cyclobut-1-ol

[0646]

[0647] A mixture of cyclobutane-1,3-diol (147 mg, 1.66 mmol, 1.75 eq), 5,7-di-tert-butyl-3-phenyl-1,3-benzoxazol-3-onium, trifluoroborane, and fluoride (752 mg, 1.9 mmol, 2 eq) in dioxane (4 mL) was stirred at 20 °C under N2 for 5 min, and a solution of pyridine (0.12 mL, 1.5 mmol, 1.6 eq) in dioxane (4 mL) was added. The resulting reaction mixture was stirred at 20 °C under N2 for 10 min. The filtrate was then added to a mixture of 7-bromo-1-methyl-1H-indole (200 mg, 0.95 mmol, 1 eq), quinine ring (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 and irradiated for 2 h in a PennOC integrated photoreactor at 100% light intensity and a maximum fan speed of 1500 rpm under a 450 nm blue LED module. The reaction mixture 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 preparative TLC (50% EtOAc in petroleum ether solution) to give 3-(1-methyl-1H-indol-7-yl)cyclobut-1-ol (80 mg, 42% yield) as a yellow oil. LCMS (ESI): m / z 202.0 (M+H) + .

[0648] Step 3: Preparation of (4-nitrophenyl)carbonate 3-(1-methyl-1H-indole-7-yl)cyclobutyl ester

[0649]

[0650] DMAP (5 mg, 0.04 mmol, 1 eq) and pyridine (0.1 mL, 1.19 mmol, 3 eq) were added to a solution of 3-(1-methyl-1H-indol-7-yl)cyclobut-1-ol (80 mg, 0.39 mmol, 1 eq) in DCM (2 mL). Then, 4-nitrophenyl carbon chloride (96 mg, 0.48 mmol, 1.2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reactants were diluted with water (5 mL) and extracted with DCM (5 mL × 2). The organic matter was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (140 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0651] Step 4: Preparation of 3-(1-methyl-1H-indole-7-yl)cyclobutyl carbamate ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindole-5-yl)methyl)carbamate

[0652]

[0653] Add (4-nitrophenyl)carbonate 3-(1-methyl-1H-indolin-7-yl)cyclobutyl ester (140.0 mg, 0.38 mmol, 1 eq) to a mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidin-2,6-dione; hydrochloride (236 mg, 0.76 mmol, 2 eq), TEA (0.16 mL, 1.15 mmol, 3 eq) in DMF (3 mL), and stir the mixture at 25 °C for 2 h under N2 atmosphere. TLC (50% ethyl acetate in petroleum ether solution, Rf=0.3) indicated that the reaction was complete. The crude product was purified by preparative HPLC (acetonitrile 40% to 70% / / 0.225% FA aqueous solution) to give N-[[2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindol-5-yl]methyl]carbamate [3-(1-methylindol-7-yl)cyclobutyl] ester (14.4 mg, 7.5% yield) as a white solid. LCMS (ESI): m / z 501.1 (M+H) + . 1HNMR (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).

[0654] Example 24

[0655] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(benzo[d]thiazolyl)cyclobutyl ester (compound 60)

[0656]

[0657] Step 1: Preparation of 3-(benzo[d]thiazolyl-7-yl)cyclobut-1-ol

[0658]

[0659] Pyridine (0.12 mL, 1.49 mmol, 1.6 eq) was added to a mixture of cyclobutane-1,3-diol (144 mg, 1.63 mmol, 1.75 eq), 5,7-di-tert-butyl-3-phenyl-1,3-benzoxazol-3-onium, trifluoroborane and fluoride (739 mg, 1.87 mmol, 2.0 eq) in 1,4-dioxane (4 mL), and the mixture was stirred at 20 °C for 5 min under nitrogen. The solution was then added to a mixture of 7-bromobenzo[d]thiazole (200 mg, 0.93 mmol, 1.0 eq), quinine ring (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 and irradiated for 2 h in a PennOC integrated photoreactor at 100% light intensity and a maximum fan speed of 1500 rpm under a 450 nm blue LED module. The mixture was then extracted with EtOAc (40 mL) and washed with brine (10 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the title compound (60 mg, 31% yield) as a yellow oil. LCMS (ESI): m / z 205.7 (M+H) + .

[0660] Step 2: Preparation of (4-nitrophenyl)carbonate 3-(benzo[d]thiazolyl-7-yl)cyclobutyl ester

[0661]

[0662] 4-Nitrophenylcarbon chloride (77 mg, 0.38 mmol, 1.3 eq) was added to a solution of 3-(benzo[d]thiazolyl-7-yl)cyclobut-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). The mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to give the title compound (108 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification.

[0663] Step 3: Preparation of 3-(benzo[d]thiazolyl)cyclobutyl ester of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate

[0664]

[0665] Et3N (0.12 mL, 0.87 mmol, 3.0 eq) was added to a mixture of (4-nitrophenyl)carbonate 3-(benzo[d]thiazolyl-7-yl)cyclobutyl ester (108 mg, 0.29 mmol, 1.0 eq) and 3-(6-(aminomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride (91 mg, 0.29 mmol, 1.0 eq) in DMF (2 mL), and the mixture was stirred at 40 °C for 16 h. The mixture was then purified by preparative HPLC (Welch Xtimate C18150*30 mm*5 μm, water (FA)-CAN, 38% to 68%) to give the title compound as a yellow solid (13.6 mg, 10% yield). 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).

[0666] Example 25

[0667] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (1S,3S)-3-(benzo[d]thiazolyl)cyclobutyl ester (compound 61)

[0668]

[0669] Step 1: Preparation of (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobut-1-ol and (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobut-1-ol

[0670]

[0671] A mixture of cyclobutane-1,3-diol (90.0 mg, 1.02 mmol, 1.75 eq) and NHC (462.0 mg, 1.17 mmol, 2.00 eq) in 1,4-dioxane (4 mL) was stirred at 20 °C for 5 minutes under N2. Then, a solution of pyridine (0.08 mL, 0.94 mmol, 1.60 eq) (1 mL of dioxane solution) was added dropwise, and the mixture was stirred at 20 °C for 5 minutes. The solution was then added to a mixture of 4-bromobenzo[d]thiazole (0.07 mL, 0.58 mmol, 1.00 eq), quinine ring (113.0 mg, 1.02 mmol, 1.75 eq), Ir(ppy)2(dtbbpy)PF6 (8.0 mg, 0.01 mmol, 0.015 eq) and NiBr2.dtbbpy (14.0 mg, 0.03 mmol, 0.05 eq) in DMF (4 mL). The mixture was stirred at 900 rpm at 20 °C and irradiated for 2 h in a PennOC integrated photoreactor at 100% light intensity and a maximum fan speed of 1500 rpm under a 450 nm blue LED module. 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% to 50% petroleum ether solution of EtOAc) to give (1s,3s)-3-(benzo[d]thiazol-4-yl)cyclobut-1-ol (70.0 mg, 37% yield) and (1r,3r)-3-(benzo[d]thiazol-4-yl)cyclobut-1-ol (70.0 mg, 37% yield) as colorless oils.

[0672] (1s,3s)-3-(benzo[d]thiazo-4-yl)cyclobut-1-ol: 1 H 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).

[0673] (1r,3r)-3-(benzo[d]thiazo-4-yl)cyclobut-1-ol:1 H 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).

[0674] Step 2: Preparation of (4-nitrophenyl)carbonate (1s,3s)-3-(benzo[d]thiazolyl-4-yl)cyclobutyl ester

[0675]

[0676] DMAP (4.0 mg, 0.03 mmol, 0.10 eq) and pyridine (0.08 mL, 1.02 mmol, 3.00 eq) were added to a mixture of (1s,3s)-3-(benzo[d]thiazolyl-4-yl)cyclobut-1-ol (70.0 mg, 0.34 mmol, 1.00 eq) in DCM (5 mL). Then, 4-nitrophenylcarbonyl chloride (82.0 mg, 0.41 mmol, 1.20 eq) was added at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction was concentrated to give the title product (120.0 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0677] Step 3: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (1s,3s)-3-(benzo[d]thiazo-4-yl)cyclobutyl ester

[0678]

[0679] To a mixture of (4-nitrophenyl)carbonate (1s,3s)-3-(benzo[d]thiazolyl-4-yl)cyclobutyl ester (126.0 mg, 0.34 mmol, 1.00 eq), Et3N (0.14 mL, 1.02 mmol, 3.00 eq) in DMF (2 mL), 3-(6-(aminomethyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione hydrochloride (210.0 mg, 0.68 mmol, 2.00 eq) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was purified by preparative HPLC (C18 150 × 30 mm, water (FA)-ACN; 35 / 65) to give the title product (94.0 mg, 54% yield) as a yellow solid. LCMS (ESI): m / z 505.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 10.99 (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).

[0680] Example 26

[0681] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (1r,3r)-3-(benzo[d]thiazolyl)cyclobutyl ester (compound 62)

[0682]

[0683] Step 1: Preparation of (4-nitrophenyl)carbonate (1r,3r)-3-(benzo[d]thiazolyl-4-yl)cyclobutyl ester

[0684]

[0685] DMAP (3.0 mg, 0.02 mmol, 0.10 eq) and pyridine (0.06 mL, 0.73 mmol, 3.00 eq) were added to a mixture of (1r,3r)-3-(benzo[d]thiazolyl-4-yl)cyclobut-1-ol (50.0 mg, 0.24 mmol, 1.00 eq) in DCM (5 mL). Then, 4-nitrophenylcarbonyl chloride (59.0 mg, 0.29 mmol, 1.05 eq) was added at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to give the title product (90.0 mg, 99% yield) as a yellow oil. The crude product was used directly in the next step without further purification.

[0686] Step 2: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (1r,3r)-3-(benzo[d]thiazo-4-yl)cyclobutyl ester

[0687]

[0688] To a mixture of (4-nitrophenyl)carbonate (1r,3r)-3-(benzo[d]thiazolyl-4-yl)cyclobutyl ester (90.0 mg, 0.24 mmol, 1.00 eq), Et3N (0.10 mL, 0.73 mmol, 3.00 eq) in DMF (1 mL), 3-(6-(aminomethyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione hydrochloride (150.0 mg, 0.49 mmol, 2.00 eq) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was purified by preparative HPLC (C18 150 × 30 mm, water (FA)-ACN; 35 / 65) to give 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).

[0689] Example 27

[0690] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate 3-(2,6-difluorophenyl)cyclobutyl ester (compound 63)

[0691]

[0692] Step 1: Preparation of 3-(2,6-difluorophenyl)cyclobut-1-ol

[0693]

[0694] A solution of 5,7-di-tert-butyl-3-phenyl-1,3-benzoxazol-3-onium; 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 in a glove box at 25 °C for 5 minutes. Then, a solution of pyridine (0.13 mL, 1.66 mmol, 1.6 eq) in 1,4-dioxane (4 mL) was added to the above solution, and the resulting mixture was stirred at 25 °C for 10 minutes. After filtration, the filtrate was added in a glove box to a mixture of 2-bromo-1,3-difluorobenzene (200.0 mg, 1.04 mmol, 1 eq), quinine ring (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). The mixture was then stirred at 900 rpm and irradiated for 2 h at 100% light intensity under a 450 nm blue LED module with a maximum fan speed of 1500 rpm in a PennOC integrated photoreactor. The reaction mixture was diluted with 10 mL of H₂O and extracted with 10 mL of EtOAc (3 times). The organic matter was washed with 20 mL of brine, dried over Na₂SO₄, filtered, and concentrated. The residue was subjected to preparative TLC (30% ethyl acetate in petroleum ether solution, R...). f = 0.5) purification to give the title compound (20 mg, 9.4% yield) as a yellow oil. 1 H 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).

[0695] Step 2: Preparation of (4-nitrophenyl)carbonate 3-(2,6-difluorophenyl)cyclobutyl ester

[0696]

[0697] Add 4-dimethylaminopyridine (1.33 mg, 0.01 mmol, 1.00 eq) and pyridine (0.03 mL, 0.33 mmol, 3.00 eq) to a total solution of 3-(2,6-difluorophenyl)cyclobutanol (20.0 mg, 0.11 mmol, 1.00 eq) in DCM (2 mL). Then add 4-nitrophenylcarbonyl chloride (26.26 mg, 0.13 mmol, 1.20 eq) at 0 °C. Stir the mixture at 25 °C for 4 h. Dilute the reaction mixture with water (10 mL) and extract with DCM (10 mL × 3). Wash the organic matter with brine (10 mL × 3), dry over sodium sulfate, filter, and concentrate the filtrate to give the crude title compound (30 mg, crude product) as a yellow oil. The crude product will be used directly in the next step without further purification.

[0698] Step 3: Preparation of 3-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate cyclobutyl ester

[0699]

[0700] Et3N (0.04 mL, 0.26 mmol, 3.00 eq) and 3-[6-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidin-2,6-dione hydrochloride (53.2 mg, 0.17 mmol, 2.00 eq) were added to a solution of [3-(2,6-difluorophenyl)cyclobutyl](4-nitrophenyl)carbonate 4-nitrophenyl (30.0 mg, 0.09 mmol, 1.00 eq) in DMF (2 mL) at 25 °C. The solution was then stirred at 25 °C for 16 h. The reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150*30mm*5um / water(FA)-CAN, 36% to 66%) to give 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).

[0701] Example 28

[0702] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindole-5-yl)methyl)carbamate 3-(1H-indole-7-yl)cyclobutyl ester (compound 64)

[0703]

[0704] Step 1: Preparation of 7-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H-indole

[0705]

[0706] Add pyridine (0.33 mL, 4.08 mmol, 1.60 eq) to a mixture of 3-[tert-butyl(dimethyl)silyl]oxycyclobutanol (774.22 mg, 3.83 mmol, 1.50 eq), 5,7-di-tert-butyl-3-phenyl-1,3-benzoxazole-3-ammonium; trifluoroborane; fluoride (2016.12 mg, 5.1 mmol, 2 eq) in 1,4-dioxane (10 mL), and stir the mixture at 20 °C under N2 for 5 minutes. The solution was then added to a mixture of 7-bromo-1H-indole (500.0 mg, 2.55 mmol, 1.00 eq), quinine ring (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 and irradiated for 2 h in a PennOC integrated photoreactor at 100% light intensity and a maximum fan stirring rate of 1500 rpm under a 450 nm blue LED module. The reaction mixture was then 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 over Na₂SO₄, and concentrated to obtain a crude product, which was purified by column chromatography (0% to 2% petroleum ether solution of EtOAc) to give the title compound (760 mg, crude) as a grayish-yellow oil. The crude product was used directly in the next step without further purification.

[0707] Step 2: Preparation of 3-(1H-indol-7-yl)cyclobut-1-ol

[0708]

[0709] Add TBAF (2.77 mL, 2.77 mmol, 1.10 eq) to a solution of tert-butyl-[3-(1H-indol-4-yl)cyclobutoxy]-dimethylsilane (760 mg, 2.52 mmol, 1 eq) in THF (2 mL). Incubate the resulting solution at 20 °C. oThe mixture was stirred at 0.5 h at 100°C. The reaction mixture was then concentrated. The residue was purified by column chromatography (0% to 2% MeOH in DCM solution) to give the title compound (120 mg, 25%) as a pale yellow oil.

[0710] Step 3: Preparation of (4-nitrophenyl)carbonate 3-(1H-indole-7-yl)cyclobutyl ester

[0711]

[0712] To a solution of 4-nitrophenyl chloroformate (129.18 mg, 0.64 mmol, 1.20 eq) in DCM (4 mL), 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) were added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was then concentrated to give a crude product, which was purified by silica gel column chromatography (0% to 5% EtOAc in petroleum ether) to give the title compound (25.5 mg, 11%) as a pale yellow solid. LCMS (ESI): m / z 352.9 (M+H) + .

[0713] Step 4: Preparation of 3-(1H-indole-7-yl)cyclobutyl 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindole-5-yl)methyl)carbamate

[0714]

[0715] Add 3-[6-(aminomethyl)-1-oxo-isoindolinlin-2-yl]piperidine-2,6-dione (55.85 mg, 0.2 mmol, 1.2 eq) to a mixture of (4-nitrophenyl)carbonate [3-(1H-indol-7-yl)cyclobutyl] ester (60.0 mg, 0.17 mmol, 1 eq) and Et3N (0.07 mL, 0.51 mmol, 3 eq) in DMF (3 mL). Stir the mixture at 25 °C for 16 h under a nitrogen atmosphere. The reaction mixture was then purified by preparative HPLC (Gilson 281 (Boston Green ODS) C18 150*30mm*3um, water (0.225% FA)-ACN, 40% to 70%) to give the title compound as a white solid (25.5 mg, 30% yield). LCMS (ESI): m / z 487.1 (M+H) + . 1 HNMR (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).

[0716] Example 29

[0717] Preparation of 3-(6-(aminomethyl)-4-chloro-1-oxoisoindololin-2-yl)piperidine-2,6-dione hydrochloride (INT2)

[0718]

[0719] Step 1: Preparation of 3-chloro-5-iodo-2-methylbenzoic acid

[0720]

[0721] NIS (2.44 g, 10.83 mmol, 1 eq) was added to a solution of methyl 3-chloro-2-methylbenzoate (2.0 g, 10.83 mmol, 1 eq) in H₂SO₄ (15 mL). The reaction was stirred at 25 °C for 16 h. Ice water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was 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 give the title compound (2.8 g, 87.2% yield) as a yellow solid. 1 H 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).

[0722] Step 2: Preparation of methyl 3-chloro-5-iodo-2-methylbenzoate

[0723]

[0724] SOCl2 (1.37 mL, 18.89 mmol, 2 eq) was added to a mixture of 3-chloro-5-iodo-2-methylbenzoic acid (2.8 g, 9.44 mmol, 1 eq) in MeOH (20 mL). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give the title compound as a colorless oil (2 g, 6.44 mmol, 68.2% yield). 1 H NMR (400 MHz, CDCl3) δ7.94 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 3.83 (s, 3H), 2.47 (s,3H).

[0725] Step 3: Preparation of methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate

[0726]

[0727] Step 4: Preparation of 3-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0728]

[0729] DIEA (5.37 mL, 30.82 mmol, 3 eq) was added to a solution of methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (4.0 g, 10.27 mmol, 1 eq), 3-aminopiperidin-2,6-dione, and methyl hydrochloride (2.2 g, 13.35 mmol, 1.3 eq) in ACN (50 mL) at 25 °C. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was ground with ethyl acetate (20 mL) and then with water (20 mL) to give the title compound (3.7 g, 9.15 mmol, 89% yield) as a purple solid. LCMS (ESI): m / z 405.0 (M+H) + . 1 H 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).

[0730] Step 5: Preparation of tert-butyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)carbamate

[0731]

[0732] Under N2 atmosphere, a mixture of 3-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)piperidin-2,6-dione (2.0 g, 4.94 mmol, 1 eq), Catacxium A Pd G3 (330 mg, 0.49 mmol, 0.1 eq), potassium 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 100 °C in a microwave oven for 1 h. The organic layer was concentrated under vacuum. The mixture was diluted with ethyl acetate (5 mL) and water (5 mL) and then filtered to give the title compound as a gray solid (1.5 g, 3.68 mmol, 74.4% yield). LCMS (ESI): m / z 460.2 (M+H) + 。

[0733] Step 6: Preparation of 3-(6-(aminomethyl)-4-chloro-1-oxoisoindololin-2-yl)piperidine-2,6-dione hydrochloride

[0734]

[0735] A solution of 1,4-dioxane in 4 M HCl (5 mL) was added to a mixture of N-[[7-chloro-2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindoline-5-yl]methyl]carbamate (1.5 g, 3.68 mmol, 1 eq) in DCM (5 mL). The reaction mixture was stirred at 25 °C for 4 h. The mixture was concentrated under vacuum to give the title compound as a yellow solid (1 g, 2.91 mmol, 79% yield). LCMS (ESI): m / z 444.2 (M+H) + .

[0736] Example 30

[0737] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (INT3)

[0738]

[0739] Step 1: Preparation of 3-bromo-2-hydroxy-6-methylbenzaldehyde

[0740]

[0741] MgCl₂ (7.64 g, 80.2 mmol) was added 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 (400 mL), 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 cooled to 25 °C and slowly poured into 600 mL of 3M HCl solution, and the mixture was stirred for 15 min. The mixture was extracted with ethyl acetate (3 × 200 mL), dried over Na₂SO₄, and concentrated. The residue was purified by rapid column chromatography (0% to 2% ethyl acetate in petroleum ether solution) to give the title compound as a yellow oil (7.2 g, 62.6% yield).

[0742] Step 2: Preparation of 3-bromo-2-methoxy-6-methylbenzaldehyde

[0743]

[0744] K₂CO₃ (18.51 g, 133.93 mmol, 2 eq) and iodomethane (4.38 mL, 70.31 mmol, 1 eq) were added to a solution of 3-bromo-2-hydroxy-6-methylbenzaldehyde (14.4 g, 66.96 mmol, 1 eq) in DMF (150 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was filtered, and the cake was washed with ethyl acetate (100 mL) and the mixture was concentrated. The residue was diluted with ethyl acetate (100 mL) and washed with brine (2 × 60 mL), dried over Na₂SO₄, and concentrated. The residue was purified by rapid column chromatography (100% petroleum ether) to give the title compound (14 g, 91.3% yield) as a colorless oil. 1 H 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).

[0745] Step 3: Preparation of 3-bromo-2-methoxy-6-methylbenzoic acid

[0746]

[0747] At 0 °C, NaH₂PO₄ (14.67 g, 122.23 mmol) and NaClO₂ (22.1 g, 244.46 mmol, 4 eq) were added 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 butanol (27.5 mL). The mixture was stirred at 25 °C for 1 h. 2-Methylbutanol (30 g, 427.82 mmol, 7 eq) was added, and the mixture was stirred at 25 °C for 30 min. The reaction mixture was poured into water (200 mL) and the pH was adjusted to 9–10 with 1 M NaOH solution. The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The aqueous phase was adjusted to pH 5–6 with 1 M HCl solution. The aqueous phase was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by rapid column chromatography (10% to 25% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (10.2 g, 68.1% yield). 1 H 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).

[0748] Step 4: Preparation of methyl 3-bromo-2-methoxy-6-methylbenzoate

[0749]

[0750] Iodimethane (1.57 mL, 25.3 mmol, 1 eq) was added 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) at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was filtered and the filter 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 layers were washed with brine (4 × 70 mL), dried over Na₂SO₄, and concentrated. The residue was purified by rapid column chromatography (0% to 1% ethyl acetate in petroleum ether solution) to give the title compound (5.85 g, 89% yield) as a pale 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).

[0751] Step 5: Preparation of methyl 3-bromo-6-(bromomethyl)-2-methoxybenzoate

[0752]

[0753] AIBN (1.09 g, 4.52 mmol, 0.2 eq) and NBS (4.42 g, 24.84 mmol, 1.1 eq) were added 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) at 25 °C. The mixture was stirred at 90 °C for 2 h under N2 (15 psi). The mixture was concentrated and the residue was purified by rapid column chromatography (100% petroleum ether) to give the title compound (7 g, 91.7% yield) as a colorless oil. 1 H 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).

[0754] Step 6: Preparation of 3-(6-bromo-7-methoxy-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0755]

[0756] To a solution of methyl 3-bromo-6-(bromomethyl)-2-methoxybenzoate (7.0 g, 20.71 mmol, 1 eq) in acetonitrile (80 mL), 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) were added. The reaction mixture was stirred at 90 °C for 16 h under N2 (15 psi). The reaction mixture was concentrated and the residue was purified by rapid column chromatography (0% to 100% (ethanol:ethyl acetate = 1:3) in petroleum ether, followed by 10% to 20% dichloromethane in methanol) to give a crude product. The crude product was diluted with water (30 mL) and ethyl acetate (60 mL) and stirred for 20 min. After filtration, the cake was washed with ethyl acetate (50 mL) and concentrated to give the title compound as a light brown solid (3.2 g, 43.7% yield). LCMS (ESI): m / z 353.0, 355.0 [M + H] + .

[0757] Step 7: ((2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxoisoindoline-5-yl)methyl)tert-butyl carbamate

[0758]

[0759] CataCXium A Pd G3 (95 mg, 0.14 mmol, 0.1 eq) was added to a mixture of 3-(6-bromo-7-methoxy-1-oxoisoindoline-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 trifluoroborate (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (671.26 mg, 2.83 mmol, 2 eq) in 1,4-dioxane (8 mL) and water (0.8 mL). The resulting mixture was then microwaved at 100 °C for 1 h under a nitrogen atmosphere. The solution was diluted with water (5 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (10% to 50% petroleum ether solution of ethyl acetate:ethanol = 3:1) to give the title compound as a yellow solid (530 mg, 92% yield). LCMS (ESI): m / z 426.0 [M + H] + .

[0760] Step 8: 3-(6-(aminomethyl)-7-hydroxy-1-oxoisoindoline-2-yl)piperidine-2,6-dione

[0761]

[0762] BBr3 (0.12 mL, 1.24 mmol) was added to a solution of ((2-(2,6-dioxopiperidin-3-yl)-4-methoxy-3-oxoisoindoline-5-yl)methyl)carbamate tert-butyl ester (100.0 mg, 0.25 mmol) in DCM (4.5 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with dichloromethane (15 mL) and slowly added to water (10 mL). After separation, the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The aqueous phase was freeze-dried to give the crude title compound (65 mg, 90% yield) as a white solid. LCMS (ESI): m / z 290.1 ​​[M + H] + .

[0763] Example 31

[0764] Preparation of tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)cyclobutoxy)silane (Int4)

[0765]

[0766] Step 1: Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)cyclobut-1-ol

[0767]

[0768] At 0 °C, a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)methane (21.13 g, 78.84 mmol) in THF (100 mL) was added to a solution of LDA (2 M THF) in THF (200 mL). The mixture was stirred at 0 °C for 1 h. Then, a solution of 2-(chloromethyl)ethylene oxide (5.62 mL, 65.7 mmol) in THF (100 mL) was added at 0 °C, and the resulting mixture was stirred at 25 °C for 1 h. Then, CuCl (1.30 g, 13.14 mmol) was added, and the mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The mixture was quenched with NH4Cl solution, extracted with ethyl acetate (300 mL × 2), washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 20%) to give the title compound (19 g, 95.93 mmol) as a yellow oil. 1 H 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).

[0769] Step 2: Preparation of tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptacyclopentan-2-yl)cyclobutoxy)silane (INT5)

[0770]

[0771] Imidazole (6.87 g, 100.97 mmol), DMAP (1.23 g, 10.10 mmol), and tert-butylchlorodimethylsilane (9.13 g, 60.58 mmol) were added to a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclobut-1-ol (10.0 g, 50.49 mmol) in dichloromethane (120 mL) at 0 °C, and the mixture was then stirred at 25 °C for 16 h. The crude product was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 10%) to give the title compound (9.50 g, 60% yield) as a colorless oil. 1 H 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).

[0772] Example 32

[0773] Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol (Int5)

[0774]

[0775] Step 1: Preparation of 2-bromo-4,4-dimethylcyclohexanone

[0776]

[0777] At 0 °C, a solution of 4,4-dimethylcyclohexanone (20.00 g, 158.48 mmol, 1.00 eq) in dichloromethane (500 mL) was supplemented with 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). The mixture was stirred at 40 °C for 4 h. The reaction mixture was quenched by adding water (300 mL) and extracted with dichloromethane (200 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (36.4 g, crude) as a 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)

[0778] Step 2: Preparation of ethyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0779]

[0780] A solution of 2-bromo-4,4-dimethylcyclohexanone (36.30 g, 177.00 mmol, 1.00 eq) and ethyl 2-amino-2-thioethyl (23.57 g, 177.00 mmol, 1.00 eq) in ethanol (500 mL) was stirred at 90 °C for 6 h. The solvent was concentrated under vacuum. The residue was purified by rapid chromatography on silica gel (ethyl acetate:petroleum ether = 2 / 1 to 3 / 2) to give the title compound (7.80 g, 18% yield) as a yellow oil. LCMS (ESI): m / z 240.0 (M+H) +

[0781] Step 3: Preparation of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0782]

[0783] A solution of 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylic acid ester (7.80 g, 32.59 mmol, 1.00 eq) in THF (80 mL) and methanol (80 mL) was slowly added to sodium tetrahydroborate (11.53 g, 304.78 mmol, 9.35 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was then stirred at 25 °C for 2 h. The reaction was quenched by adding 200 mL of water. The reaction mixture was extracted with EtOAc (300 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel (ethyl acetate: petroleum ether = 2 / 1 to 3 / 2) to give the title compound (3.8 g, 59% yield) as a yellow solid. 1HNMR (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).

[0784] Example 33

[0785] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 65)

[0786]

[0787] Step 1: Preparation of 2-bromo-5-methylcyclohexane-1-one

[0788]

[0789] Br2 (2.51 mL, 49.03 mmol) and AcOH (0.48 mL, 8.33 mmol) were added to a solution of 3-methylcyclohexanone (5.00 g, 44.58 mmol) in water (20 mL) at 5 °C. During the addition, the color of the solution changed from colorless to orange, and then to red. After complete addition, the reaction was stirred at 25 °C for 16 h. The reaction mixture was extracted with DCM (20 mL × 3) and washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether solution) to give the title compound (1.8 g, 21.1% yield) as a yellow oil. LCMS (ESI): m / z 191.0 (M+H) + .

[0790] Step 2: Preparation of ethyl 5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0791]

[0792] Ethyl amino(thio)acetate (1.25 g, 9.42 mmol, 1 eq) was added to a solution of 2-bromo-5-methyl-cyclohexanone (1.8 g, 9.42 mmol, 1 eq) in EtOH (20 mL) at 20 °C. The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was diluted with water (20 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed with brine (20 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (8% ethyl acetate in petroleum ether solution) to give the title compound (300 mg, 14% yield) as a yellow oil.

[0793] Step 3: Preparation of (5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0794]

[0795] NaBH4 (402 mg, 10.65 mmol) was slowly added to a solution of ethyl 5-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-carboxylate (400 mg, 1.78 mmol) in MeOH (4 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then at 25 °C 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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (50% ethyl acetate in petroleum ether solution) to give the title compound (167 mg, 51.3% yield) as a yellow oil. LCMS (ESI): m / z 184.2 (M+H) + .

[0796] Step 4: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0797]

[0798] CDI (57 mg, 0.35 mmol) was added 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). The reaction mixture was stirred at 25 °C for 2 h, and the resulting solution was then added to a mixture of 3-[6-(aminomethyl)-1-oxo-isoindoline-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 mixture was stirred at 25 °C for 16 h. The resulting residue was purified by reversed-phase chromatography (acetonitrile 35% to 65% / 0.1% aqueous HCl) to give the title compound as a white solid (7.4 mg, 0.01 mmol, 5.3% yield). 1 H 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).

[0799] Example 34

[0800] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester hydrochloride (compound 66)

[0801]

[0802] Step 1: Preparation of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0803]

[0804] NaBH4 (300 mg, 7.93 mmol, 4.66 eq) was slowly added to a solution of ethyl 6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-carboxylate (420 mg, 1.70 mmol, 1.00 eq) in THF (4 mL) and methanol (4 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then at 25 °C for 3 h. The reaction mixture was quenched with NH4Cl solution (3 mL), the solution was concentrated under vacuum, and the residue was purified by rapid silica gel chromatography (0% to 50% ethyl acetate in petroleum ether) to give the title compound (140 mg, 40% yield) as a yellow oil. LCMS (ESI): m / z 205.8 (M+H) +

[0805] Step 2: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester hydrochloride

[0806]

[0807] CDI (32 mg, 0.19 mmol, 1.00 eq) was added to a solution of (6,6-difluoro-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (40 mg, 0.19 mmol, 1.00 eq) in THF (2 mL). The solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of DBU (30 mg, 0.19 mmol, 1.00 eq), 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione hydrochloride (64 mg, 0.19 mmol, 1.00 eq) and TEA (39 mg, 0.39 mmol, 2.00 eq) in DMF (2 mL). The mixture was stirred at 25 °C for 12 h. The solution was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (HCl)-ACN, 30% to 60%) to give the title compound as a white solid (11 mg, 9% yield). 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).

[0808] Example 35

[0809] Preparation of (R)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindole-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 67) and (S)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindole-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 68)

[0810]

[0811] Step 1: (R)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindole-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester and (S)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindole-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0812]

[0813] The product was further purified by chiral SFC (column = DAICEL CHIRALCEL OJ; column size = 250 mm × 30 mm × 10 µm; detection wavelength = 220 nm; flow rate = 70 mL / min; mobile phase: A: CO2 B: ethanol (0.05% DEA); isocratic ratio: 50%) to obtain two provisional peaks:

[0814] Peak 1: (R)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (5 mg, 26.7% yield), white solid. LCMS (ESI): m / z 515.1 [M + H] + . 1 H 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).

[0815] Peak 2: (S)-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (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).

[0816] Example 36

[0817] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 69)

[0818]

[0819] Step 1: Preparation of 2-bromocyclohexyl-2-en-1-one

[0820]

[0821] A solution of dibromo (2.73 mL, 53.23 mmol, 1.2 eq) in dichloromethane (50 mL) was added dropwise over 3 h to a stirred solution of cyclohexane-2-en-1-one (5.05 mL, 52 mmol, 1.0 eq) in dichloromethane (120 mL). The solution was stirred at 0 °C for 3 h. Then, triethylamine (10.61 mL, 76.09 mmol, 1.5 eq) was added dropwise, and the mixture was stirred at 25 °C for 3 h. The reaction mixture was washed with 3% HCl and brine and dried over Na₂SO₄. The mixture was purified by rapid chromatography (0% to 10% ethyl acetate in petroleum ether solution) to give the title compound (7.50 g, 82% yield). 1 H 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).

[0822] Step 2: Preparation of 2-bromo-3-methylcyclohexane-1-one

[0823]

[0824] Trimethylaluminum (30 mL, 60 mmol, 1.5 eq) was added to a solution of triphenylphosphine (750 mg, 2.86 mmol, 0.1 eq) in toluene (50 mL) under N2 atmosphere. The solution was stirred at 25 °C for 0.5 h and then cooled to -60 °C. The solution was stirred for 5 min, and a 50 mL solution of 2-bromocyclohexane-2-en-1-one (7.5 g, 42.85 mmol, 1.0 eq) and copper(I) (250 mg, 1.75 mmol, 1.0 eq) in toluene was added dropwise. The mixture was stirred at -60 °C for 2 h and then heated to 25 °C for 16 h. The solution was diluted with tert-butyl methyl ether, the reactants were quenched with methanol (20 mL), and the mixture was washed with 2 M HCl and dried over Na2SO4. The organic layer was concentrated under vacuum. The residue was purified by rapid silica gel chromatography, eluted with petroleum ether solution of 0% to 20% ethyl acetate, to give the title compound (3.5 g, 43% yield).

[0825] 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

[0826]

[0827] Ethyl amino(thio)acetate (2.44 g, 18.32 mmol, 1.0 eq) was added to a mixture of 2-bromo-3-methylcyclohexanone (3.50 g, 18.32 mmol, 1.0 eq) in ethanol (50 mL) at 20 °C. The resulting mixture was then stirred at 90 °C for 3 h under a 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 layer was washed with brine (20 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 10% ethyl acetate in petroleum ether) to give 650 mg of the mixture as a yellow oil. The above product was further purified by chiral SFC (column = AICEL CHIRALCEL OJ; column size = 250 mm × 30 mm × 10 µm; detection wavelength = 220 nm; flow rate = 70 mL / min; mobile phase: A: CO2, B: ethanol (0.05% DEA); isocratic ratio: 50% B) to obtain:

[0828] Peak 1: Ethyl 7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate (200 mg, 0.89 mmol, 4.8% yield) as a white solid. 1 H 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).

[0829] Peak 2: Ethyl 4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate as a white solid (180 mg, 0.80 mmol, 4.4% yield). 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).

[0830] Step 4: Preparation of (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0831]

[0832] NaBH4 (269 mg, 7.10 mmol, 8.0 eq) was slowly added to a solution of ethyl 7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-carboxylate (200 mg, 0.89 mmol, 1.0 eq) in methanol (4 mL) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (3 mL), extracted with dichloromethane (10 mL × 3) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by TLC (0% to 30% ethyl acetate in petroleum ether solution) to give the title compound (100 mg, 0.55 mmol, 62% yield). LCMS (ESI): m / z 184.1 [M + H] + .

[0833] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0834]

[0835] CDI (42 mg, 0.26 mmol, 1.2 eq) was added to a solution of (7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (40 mg, 0.22 mmol, 1.0 eq) in THF (1 mL). The solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of 3-[6-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidine-2,6-dione (72 mg, 0.26 mmol, 1.2 eq) and DBU (0.03 mL, 0.22 mmol, 1.0 eq) and triethylamine (0.03 mL, 0.22 mmol, 1.0 eq) in DMF (1 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was then purified by preparative HPLC (C18 150 * 30 mm, water (HCl)-ACN, 25% to 55%) to give the title compound (10 mg, 0.02 mmol, 10% yield). 1 H 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).

[0836] Example 37

[0837] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 70)

[0838]

[0839] Step 1: Preparation of 2-bromocyclohexyl-2-en-1-one

[0840]

[0841] A solution of Br2 (2.73 mL, 53.23 mmol) in 50 mL of DCM was added to a stirred solution of cyclohexane-2-en-1-one (5.05 mL, 52.01 mmol) in 120 mL of DCM. The reaction mixture was stirred at 0 °C for 3 h, then TEA (10.61 mL, 76.09 mmol) was added, and the mixture was stirred at 25 °C for 3 h. The mixture was washed with 3% HCl and brine and dried over Na2SO4. The mixture was purified by silica gel rapid chromatography (10% ethyl acetate in petroleum ether) to give the title compound (7.5 g, 42.85 mmol, 82.4% yield) as a yellow oil. 1 HNMR (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).

[0842] Step 2: Preparation of 2-bromo-3-methylcyclohexane-1-one

[0843]

[0844] A solution of PPh3 (750 mg, 2.86 mmol) and CuBr (250 mg, 1.74 mmol) in toluene (50 mL) was stirred at 25 °C for 0.5 h under N2. The mixture was then cooled to -60 °C, and Me3Al (30 mL, 60 mmol) was added dropwise. The resulting mixture was stirred for 5 min, and then 2-bromocyclohexane-2-en-1-one (7.5 g, 42.85 mmol) was added dropwise to toluene (50 mL). The mixture was stirred at -60 °C for 2 h, and then stirred at 25 °C for 16 h. The solution was diluted with tert-butyl methyl ether, the reaction was quenched with methanol (20 mL), the mixture was washed with 2 M HCl, dried over Na2SO4, and the organic layer was concentrated under vacuum. The residue was purified by rapid silica gel chromatography, eluting with petroleum ether solution of 20% ethyl acetate to give the title compound as a white solid (3.5 g, 18.31 mmol, 42.7% yield). LCMS (ESI): m / z 191.0 (M+H) + .

[0845] Step 3: Preparation of ethyl 4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0846]

[0847] Ethyl amino(thio)acetate (2.44 g, 18.32 mmol) was added to a solution of 2-bromo-3-methyl-cyclohexanone (3.5 g, 18.32 mmol) in EtOH (50 mL) at 20 °C. The resulting mixture was then stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was diluted with water (20 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give 650 mg of crude product as a yellow oil. The mixture was purified by SFC to give the title compound as a white solid (200 mg, 0.88 mmol, 4.8% yield).

[0848] 1 H 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)+.

[0849] Step 4: Preparation of (4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0850]

[0851] NaBH4 (241 mg, 6.39 mmol) was added to a solution of ethyl 7-methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-carboxylate (180 mg, 0.80 mmol) in MeOH (4 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then stirred at 2 °C for 16 h. The reaction mixture was diluted with water (3 mL), extracted with dichloromethane (10 mL × 3), and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by TLC (petroleum ether solution of 30% ethyl acetate) to give the title compound (100 mg, 68.3% yield) as a yellow oil. LCMS (ESI): m / z 183.2 (M+H) + .

[0852] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl)carbamate (4-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0853]

[0854] CDI (53 mg, 0.33 mmol) was added 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), and the solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of DBU (0.03 mL, 0.22 mmol), 3-[6-(aminomethyl)-1-oxo-isoindoline-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 25 °C for 16 h. The resulting residue was purified by reversed-phase chromatography (acetonitrile 35% to 65% / 0.1% HCl aqueous solution) to give the title compound (17.3 mg, 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) + .

[0855] Example 38

[0856] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 71)

[0857]

[0858] Step 1: Preparation of methyl 1H-imidazolium-1-carboxylic acid (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl) ester

[0859]

[0860] CDI (36.98 mg, 0.23 mmol) was added to a mixture of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (45.0 mg, 0.23 mmol) in THF (1.5 mL) at 0 °C. The resulting mixture was then stirred at 0 °C for 1 h. The crude title compound was used directly in the next step.

[0861] Step 2: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0862]

[0863] At 25 °C, TEA (0.06 mL, 0.45 mmol, 2 eq) and DBU (0.03 mL, 0.22 mmol, 1 eq) were added to a mixture of 3-[6-(aminomethyl)-7-hydroxy-1-oxo-isoindoline-2-yl]piperidine-2,6-dione (64.54 mg, 0.22 mmol, 1 eq) in DMF (1 mL). At 25 °C, a mixture of methyl 1H-imidazolium-1-carboxylic acid (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl) ester (64.54 mg, 0.22 mmol) in THF (1 mL) was added to the reaction solution. The resulting mixture was then stirred at 25 °C for 16 h. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (31% to 62% aqueous HCl, acetonitrile) to give the title compound as a white solid (16.1 mg, 13% yield). LCMS (ESI): m / z 513.1 [M + H] + . 1 H 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).

[0864] Example 39

[0865] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 72)

[0866]

[0867] (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). Then triethylamine (0.24 mmol, 0.033 mL, 3 equiv.) was added, and the reaction was stirred at room temperature for 30 minutes.

[0868] To a separate vial containing 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindololin-2-yl]piperidin-2,6-dione; hydrochloride (26 mg, 0.080 mmol, 1.0 equiv.), add 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.). Then, add the activated alcohol solution to the reaction in one go, and flush the vial with excess THF (0.10 mL) to ensure complete transfer. Stir the reaction at room temperature until complete consumption of the starting material is observed by LCMS.

[0869] The reaction was quenched by adding a saturated aqueous solution of NH4Cl and extracted with DCM (3x). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (XSelect CSH Prep C18, column size 50 x 30 mm, 5 µm, pure water / ACN) to give the title compound as a white solid (19.98 mg, 53% yield). 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).

[0870] Example 40

[0871] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 73)

[0872]

[0873] Step 1: Preparation of 2-bromo-5,5-dimethylcyclohexanone

[0874]

[0875] NBS (7.26 g, 40.81 mmol, 1.0 eq) was added to a solution of 3,3-dimethylcyclohexanone (5.00 g, 39.62 mmol, 1.0 eq) in dichloromethane (50 mL). 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 with NaHCO3 (100 mL × 3). The organic layers were combined to give the title compound (8.00 g, 39.0 mmol, 98.5% yield) as a yellow oil.

[0876] Step 2: Preparation of ethyl 5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[0877]

[0878] 2-Amino-2-thio-ethyl acetate (6.75 g, 50.71 mmol, 1.3 eq) was added to a mixture of 2-bromo-5,5-dimethyl-cyclohexanone (8.00 g, 39.01 mmol, 1.0 eq) in ethanol (20 mL) at 20 °C. The resulting mixture was then stirred at 90 °C for 12 h. The reaction mixture was concentrated to dryness. The resulting residue was purified by reversed-phase chromatography (0% to 10% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (750 mg, 8% yield). 1 H 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).

[0879] Step 3: Preparation of (5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[0880]

[0881] NaBH4 (252 mg, 6.69 mmol, 8.0 eq) was slowly added to a solution of ethyl 5,5-dimethyl-6,7-dihydro-4H-1,3-benzothiazol-2-carboxylate (200 mg, 0.84 mmol, 1.0 eq) in methanol (4 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was then stirred at 25 °C for 16 h. The reaction mixture was diluted with water (3 mL), extracted with dichloromethane (20 mL × 3) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by TLC (30% ethyl acetate in petroleum ether solution) to give 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).

[0882] Step 4: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0883]

[0884] CDI (73 mg, 0.46 mmol, 1.0 eq) was added to a solution of (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 h. The mixture was then added to a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindoline-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), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under vacuum and purified by preparative HPLC (Xtimate C18 150 * 40 mm * 10 μm, water (0.05% HCl)-ACN, 40% to 70%), and lyophilized to give the title compound as a white solid (30.5 mg, 19.4% yield). 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) + .

[0885] Example 41

[0886] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate ((S)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 74)

[0887]

[0888] Step 1: Preparation of 1H-imidazolium-1-carboxylic acid (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0889]

[0890] CDI (66.09 mg, 0.41 mmol) was added to a solution of (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (49.8 mg, 0.27 mmol) in THF (1 mL), and the solution was stirred at 25 °C for 2 h. The product did not require purification and was used directly in the next step.

[0891] Step 2: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate ((S)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0892]

[0893] 1H-imidazol-1-carboxylic acid (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (60.95 mg, 0.2500 mmol) was added to a mixture of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione (68.0 mg, 0.2500 mmol), DBU (0.05 mL, 0.33 mmol), and triethylamine (0.08 mL, 0.55 mmol) in DMF (1 mL). The mixture was stirred at 25 °C for 16 h. The organic layer was concentrated under vacuum and purified by preparative HPLC (acetonitrile 25-55 / 0.225% HCl aqueous solution) to give N-[[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-3-oxo-isoindoline-5-yl]methyl]carbamate [(7R)-7-methyl-4,5,6,7-tetrahydro-1,3-benzothiazolyl-2-yl]methyl ester (30.2 mg, 0.0591 mmol, 21.6% yield). LCMS (ESI): m / z 501.0 [M+H] + . 1 H 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).

[0894] Example 42

[0895] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate((R)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 75)

[0896]

[0897] 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

[0898]

[0899] (7-Methyl-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)methanol (300.0 mg, 1.64 mmol) was further purified by chiral SFC (column = DAICEL CHIRALCEL OJ; column size = 250 mm × 30 mm × 10 µm; detection wavelength = 220 nm; flow rate = 70 mL / min; mobile phase: A: CO2 B: ethanol (0.01% NH3.H2O); isocratic ratio: 15%) to obtain two provisional peaks:

[0900] Peak 1: (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol (145 mg, 48.3% yield) as a white solid. 1 H 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).

[0901] Peak 2: (S)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol (140 mg, 0.76 mmol, 47% yield) as a white solid. 1 H 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).

[0902] Step 2: Preparation of 1H-imidazolium-1-carboxylic acid (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0903]

[0904] CDI (66 mg, 0.41 mmol, 1.5 eq) was added to a solution of (R)-(7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (50 mg, 0.27 mmol, 1 eq) in THF (1 mL), and the solution was stirred at 25 °C for 2 h. The product was used directly in the next step.

[0905] Step 3: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate ((R)-7-methyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0906]

[0907] A mixture of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindol-2-yl)piperidin-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) was added to a solution of 3-phenylcyclobutyl)imidazolium-1-carboxylate (76 g, 0.27 mmol, 1 eq), and stirred at 25 °C for 16 h. The organic layer was concentrated under vacuum and purified by preparative HPLC (acetonitrile 25-55 / 0.225% HCl aqueous solution) to give the title compound as a white solid (19 mg, 14% yield). 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).

[0908] Example 43

[0909] Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindololin-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 76)

[0910]

[0911] Step 1: Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[0912]

[0913] CDI (36 mg, 0.22 mmol, 1.1 eq) was added to a solution of (6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (40 mg, 0.21 mmol, 1 eq) in THF (1 mL), and the solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindoline-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, 2 eq) in DMF (2 mL), and the mixture was stirred at 25 °C for 16 h. The residue was purified by preparative HPLC (Xtimate C18 150*30 mm, water (0.225% HCl)-ACN, 40% to 70%) to give the title compound as a white solid (5.2 mg, 0.01 mmol, 11% yield). LCMS (ESI): m / z 549.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 8.11 (t, J = 5.6Hz, 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).

[0914] Example 44

[0915] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 77)

[0916] For this example, the same sequence of steps as compound 88 is followed, except that 4-methylpiperidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[0917] Step 1: Preparation of 4-methyl-1-nitrosoperpiperidine-2-carboxylic acid

[0918]

[0919] The reaction was carried out with 4-methylpiperidine-2-carboxylic acid salt at 1.35 mmol to give 98.9 mg (43% yield) of 4-methyl-1-nitrosopiperidinidine-2-carboxylic acid as a white solid, which could be used immediately without further purification. LCMS (ESI): m / z 173.050 (M+H) + .

[0920] Step 2: Preparation of 5-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[0921]

[0922] The reaction was carried out with 4-methyl-1-nitrosoperpiperidine-2-carboxylic acid at a scale of 0.57 mmol. The reaction was purified by silica gel column chromatography (0% to 80% iPrOAc in heptane solution) to give 69.2 mg (78% yield) of 5-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-onthium-3-ol salt as a white solid. LCMS (ESI): m / z 155.1 (M+H) + .

[0923] Step 3: Preparation of ethyl 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[0924]

[0925] The reaction was carried out on a 0.45 mmol scale with 5-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 40% iPrOAc in heptane) to give 26.7 mg (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) + .

[0926] Step 4: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[0927]

[0928] The reaction was carried out with ethyl 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.125 mmol. 19.1 mg (92% yield) of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil was obtained, which could be used without further purification. LCMS (ESI): m / z 167.100 (M+H) + .

[0929] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[0930]

[0931] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.080 mmol. After preparative HPLC (Triart C18, column size 100 x 30 mm, 5 µm, pure water / ACN), 10.32 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (27% yield). 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).

[0932] Example 45

[0933] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 78)

[0934] For this example, the same sequence of steps as compound 88 is followed, except that 5-methylpiperidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[0935]

[0936] Step 1: Preparation of 5-methyl-1-nitrosoperpiperidine-2-carboxylic acid

[0937]

[0938] The reaction was carried out at a scale of 1.39 mmol with 5-methylpiperidine-2-carboxylic acid salt to give 130 mg (54% yield) of 5-methyl-1-nitrosopiperidin-2-carboxylic acid as a grayish-white semi-solid, which could be used without further purification. LCMS (ESI): m / z 173.050 (M+H) + .

[0939] Step 2: Preparation of 6-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[0940]

[0941] The reaction was carried out with 5-methyl-1-nitrosoperpiperidine-2-carboxylic acid at a scale of 0.76 mmol. The reaction was purified by silica gel column chromatography (0% to 80% iPrOAc in heptane solution) to give 102.6 mg (88% yield) of 6-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-onthium-3-olate as a white solid. LCMS (ESI): m / z 155.050 (M+H) + .

[0942] Step 3: Preparation of ethyl 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[0943]

[0944] The reaction was carried out on a 0.67 mmol scale with 6-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 40% iPrOAc in heptane) to give 58.9 mg (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) + .

[0945] Step 4: Preparation of (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[0946]

[0947] The reaction was carried out with 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.16 mmol. 24.5 mg (92% yield) of (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil was obtained, which could be used without further purification. LCMS (ESI): m / z 167.100 (M+H) + .

[0948] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[0949]

[0950] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.080 mmol. After preparative HPLC (Triart C18, column size 100 x 30 mm, 5 µm, pure water / ACN), 12.53 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (32% yield). LCMS (ESI): m / z 484.20 (M+H) + . 1 H 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).

[0951] Example 46

[0952] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 79)

[0953] For this example, the same sequence of steps as compound 88 is followed, except that 3-methyl-piperidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[0954]

[0955] Step 1: Preparation of 3-methyl-1-nitrosoperpiperidine-2-carboxylic acid

[0956]

[0957] The reaction was carried out at a scale of 1.06 mmol with 3-methylpiperidine-2-carboxylic acid salt to give 90.2 mg (50% yield) of 3-methyl-1-nitrosopiperidin-2-carboxylic acid as a grayish-white solid, which could be used without further purification. LCMS (ESI): m / z 173.100 (M+H) + .

[0958] Step 2: Preparation of 4-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[0959]

[0960] The reaction was carried out with 3-methyl-1-nitrosoperpiperidine-2-carboxylic acid at a scale of 0.524 mmol. The reaction was purified by silica gel column chromatography (0% to 75% iPrOAc in heptane solution) to give 78.4 mg (97% yield) of 4-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-onthium-3-ol salt as a white solid. LCMS (ESI): m / z 155.100 (M+H) + .

[0961] Step 3: Preparation of ethyl 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[0962]

[0963] The reaction was carried out at a scale of 0.51 mmol using 4-methyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 30% iPrOAc in heptane) to give 33.7 mg (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) + .

[0964] Step 4: Preparation of (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[0965]

[0966] The reaction was carried out with ethyl 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.153 mmol. 25.2 mg (99% yield) of (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol as a clear oil was obtained, which could be used without further purification. LCMS (ESI): m / z 167.100 (M+H) + .

[0967] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[0968]

[0969] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.080 mmol. Following preparative HPLC (Triart C18, column size 100 x 30 mm, 5 µm, pure water / ACN), 12.11 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (31% yield). 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).

[0970] Example 47

[0971] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 80)

[0972] For this example, the same sequence of steps as for compound 88 is followed, except that 4,4-difluoropiperidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[0973]

[0974] Step 1: Preparation of 4,4-difluoro-1-nitrosoperpiperidine-2-carboxylic acid

[0975]

[0976] The reaction was carried out at a scale of 0.94 mmol with 4,4-difluoro-1-nitrosopiperidin-2-carboxylic acid to give 180.5 mg (99% yield) of 4,4-difluoro-1-nitrosopiperidin-2-carboxylic acid as a grayish-white solid, which could be used immediately without further purification. LCMS (ESI): m / z 195.000 (M+H) + .

[0977] Step 2: Preparation of 5,5-difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[0978]

[0979] The reaction was carried out with 4,4-difluoro-1-nitrosoperpiperidine-2-carboxylic acid at a scale of 0.93 mmol. The reaction was purified by silica gel column chromatography (0% to 70% iPrOAc in heptane solution) to give 159.2 mg (97% yield) of 5,5-difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-onthium-3-ol salt as a white solid. LCMS (ESI): m / z 177.050 (M+H) + .

[0980] Step 3: Preparation of ethyl 5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[0981]

[0982] The reaction was carried out at a scale of 0.90 mmol using 5,5-difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 55% iPrOAc in heptane) to give 118.2 mg (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) + .

[0983] Step 4: Preparation of (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[0984]

[0985] The reaction was carried out with ethyl 5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.16 mmol. 29.4 mg (98% yield) of a clear oil of (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol was obtained, which could be used without further purification. LCMS (ESI): m / z 189.050 (M+H) + .

[0986] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[0987]

[0988] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.080 mmol. Following preparative HPLC (Triart C18, column size 100 x 30 mm, 5 µm, pure water / ACN), 11.12 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (5,5-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (28% yield). LCMS (ESI): m / z 506.16 (M+H) + . 1 H 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).

[0989] Example 48

[0990] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 81)

[0991] For this example, the same sequence of steps as for compound 88 is followed, except that 5,5-difluoropiperidine-2-carboxylic acid is used instead of 3-methylpyrrolidine-2-carboxylic acid salt in the first step.

[0992]

[0993] Step 1: Preparation of 5,5-difluoro-1-nitrosoperpiperidine-2-carboxylic acid

[0994]

[0995] The reaction was carried out on a 1.51 mmol scale with 5,5-difluoropiperidine-2-carboxylic acid to give 265 mg (90% yield) of 5,5-difluoro-1-nitrosopiperidinidine-2-carboxylic acid as a yellow solid, which could be used immediately without further purification. LCMS (ESI): m / z 195.050 (M+H) + .

[0996] Step 2: Preparation of 6,6-difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[0997]

[0998] The reaction was carried out with 5,5-difluoro-1-nitrosopiperidin-2-carboxylic acid at a scale of 1.37 mmol. The reaction was purified by silica gel column chromatography (0% to 70% iPrOAc in heptane solution) to give 216 mg (90% yield) of 6,6-difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-onthium-3-ol salt as a white solid. LCMS (ESI): m / z 177 (M+H) + .

[0999] Step 3: Preparation of ethyl 6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[1000]

[1001] The reaction was carried out at a scale of 1.23 mmol using 6,6-difluoro-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 30% iPrOAc in heptane) to give 139.7 mg (50% yield) of ethyl 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) + .

[1002] Step 4: Preparation of (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[1003]

[1004] The reaction was carried out with ethyl 6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.16 mmol. 31.7 mg (110% yield) of a clear oil of (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol was obtained, which could be used without further purification. LCMS (ESI): m / z 189.000 (M+H) + .

[1005] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[1006]

[1007] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.080 mmol. Following preparative HPLC (Triart C18, column size 100 x 30 mm, 5 µm, pure water / ACN), 7.43 mg of ((2-(2,6-dioxoperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (6,6-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (18% yield). 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).

[1008] Example 49

[1009] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 82)

[1010] For this example, the same sequence of steps as for compound 88 is followed, except that 3,3-dimethylpiperidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[1011]

[1012] Step 1: Preparation of 3,3-dimethyl-1-nitrosoperpiperidine-2-carboxylic acid

[1013]

[1014] The reaction was carried out with 3,3-dimethylpiperidine-2-carboxylic acid salt at 0.95 mmol to give 124.1 mg (70% yield) of 3,3-dimethyl-1-nitrosopiperidin-2-carboxylic acid as a white solid, which could be used immediately without further purification. LCMS (ESI): m / z 187.050 (M+H) + .

[1015] Step 2: Preparation of 4,4-dimethyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[1016]

[1017] The reaction was carried out with 3,3-dimethyl-1-nitrosoperpiperidine-2-carboxylic acid at a scale of 0.67 mmol. The reaction was purified by silica gel column chromatography (0% to 70% iPrOAc in heptane solution) to give 96.6 mg (86% yield) of 4,4-dimethyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-onthium-3-ol salt as a white solid. LCMS (ESI): m / z 169.050 (M+H) + .

[1018] Step 3: Preparation of ethyl 4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[1019]

[1020] The reaction was carried out at a scale of 0.57 mmol using 4,4-dimethyl-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 45% iPrOAc in heptane) to give 65.7 mg (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) + .

[1021] Step 4: Preparation of (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[1022]

[1023] The reaction was carried out with ethyl 4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.16 mmol. 28.6 mg (99% yield) of a clear oil of (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol was obtained, which could be used without further purification. LCMS (ESI): m / z 181.100 (M+H) + .

[1024] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[1025]

[1026] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.08 mmol. Following preparative HPLC (Gemini-NX C18, column size 50 x 30 mm, 5 µm, pure water / ACN), 11.02 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (28% yield). LCMS (ESI): m / z 498.22 (M+H) + . 1 H 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).

[1027] Example 50

[1028] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 83)

[1029] For this example, the same sequence of steps as compound 88 is followed, except that 3-tert-butylpiperidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[1030]

[1031] Step 1: Preparation of 3-(tert-butyl)-1-nitrosoperpiperidine-2-carboxylic acid

[1032]

[1033] The reaction was carried out at a scale of 0.95 mmol with 3-tert-butylpiperidine-2-carboxylic acid salt to give 203 mg (100% yield) of 3-(tert-butyl)-1-nitrosopiperidin-2-carboxylic acid as a yellow oil, which could be used immediately without further purification. LCMS (ESI): m / z 215.050 (M+H) + .

[1034] Step 2: Preparation of 4-(tert-butyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[1035]

[1036] The reaction was carried out with 3-(tert-butyl)-1-nitrosoperpiperidine-2-carboxylic acid at a scale of 0.95 mmol. The reaction was purified by silica gel column chromatography (0% to 70% iPrOAc in heptane solution) to give 174.6 mg (94% yield) of 4-(tert-butyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-on-3-ol salt as a white solid. LCMS (ESI): m / z 197.050 (M+H) + .

[1037] Step 3: Preparation of ethyl 4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[1038]

[1039] The reaction was carried out at a scale of 0.89 mmol using 4-(tert-butyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 45% iPrOAc in heptane) to give 41.1 mg (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) + .

[1040] Step 4: Preparation of (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[1041]

[1042] The reaction was carried out with ethyl 4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.164 mmol. 31.5 mg (92% yield) of a clear oil of (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol was obtained, which could be used without further purification. LCMS (ESI): m / z 209.100 (M+H) + .

[1043] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[1044]

[1045] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.08 mmol. Following preparative HPLC (Gemini-NX C18, column size 50 x 30 mm, 5 µm, pure water / ACN), 13.18 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (4-(tert-butyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (31% yield). 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 = 12.8Hz, 1H), 1.59 – 1.45 (m, 1H), 0.94 (s, 9H).

[1046] Example 51

[1047] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 84)

[1048] For this example, the same sequence of steps as compound 88 is followed, except that 3-(trifluoromethyl)piperidine-2-carboxylic acid is used instead of 3-methylpyrrolidine-2-carboxylic acid salt in the first step.

[1049]

[1050] Step 1: Preparation of 1-nitroso-3-(trifluoromethyl)piperidine-2-carboxylic acid

[1051]

[1052] The reaction was carried out with 3-(trifluoromethyl)piperidine-2-carboxylic acid at a scale of 0.95 mmol to give 114.2 mg (53% yield) of 1-nitroso-3-(trifluoromethyl)piperidine-2-carboxylic acid as a yellow oil, which could be used directly without further purification. LCMS (ESI): m / z 227.00 (M+H) + .

[1053] Step 2: Preparation of 4-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[1054]

[1055] The reaction was carried out with 1-nitroso-3-(trifluoromethyl)piperidine-2-carboxylic acid at a scale of 0.50 mmol. The reaction was purified by silica gel column chromatography (0% to 80% iPrOAc in heptane) to give 89.3 mg (85% yield) of 4-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridin-8-on-3-ol salt as a white solid. LCMS (ESI): m / z 209.000 (M+H) + .

[1056] Step 3: Preparation of ethyl 4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate

[1057]

[1058] The reaction was carried out at a scale of 0.43 mmol using 4-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 40% iPrOAc in heptane) to give 103.9 mg (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) δ6.85 (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).

[1059] Step 4: Preparation of (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol

[1060]

[1061] The reaction was carried out with ethyl 4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-carboxylate at a scale of 0.16 mmol. 33.8 mg (96% yield) of a clear oil of (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol was obtained, which could be used without further purification. LCMS (ESI): m / z 221.100 (M+H) + .

[1062] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester

[1063]

[1064] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.08 mmol. After preparative HPLC (Gemini-NX C18, column size 50 x 30 mm, 5 µm, 0.1% formic acid aqueous solution / ACN), 8.22 mg of ((2-(2,6-dioxoperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)carbamate (4-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester was obtained as a white solid (19% yield). 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 = 7.7Hz, 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).

[1065] Example 52

[1066] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester hydrochloride (compound 85)

[1067]

[1068] Step 1: Preparation of ((3,3-dimethylcyclohexyl-1-en-1-yl)oxy)trimethylsilane

[1069]

[1070] A solution of 3-methylcyclohexane-2-en-1-one (5.15 mL, 45.39 mmol) in THF (20 mL) and a solution of TMSCl (5.42 g, 49.93 mmol) in THF (15 mL) were added to a solution of copper iodide (I) (0.08 mL, 2.27 mmol) in THF (30 mL) at -60 °C under N2 (15 psi), and the mixture was stirred at -60 °C for 15 min. Methylmagnesium bromide (22.7 mL, 68.09 mmol) was added at -60 °C, and the mixture was stirred at -60 °C for 1 h. The mixture was then heated to 25 °C and stirred for 1 h, and slowly quenched with a saturated NH4Cl solution (60 mL). The mixture was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by rapid column chromatography (100% petroleum ether) to give the title compound as a colorless oil (3.45 g, 38% yield). 1 H 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).

[1071] Step 2: Preparation of 2-bromo-3,3-dimethylcyclohexane-1-one

[1072]

[1073] Methyllithium (9.45 mL, 15.12 mmol) was added to a solution of ((3,3-dimethylcyclohexyl-1-en-1-yl)oxy)trimethylsilane (2.0 g, 10.08 mmol) in THF (30 mL) at 0 °C under N2 (15 psi) and the mixture was stirred at 0 °C for 10 min. The mixture was cooled to -60 °C and Br2 (0.52 mL, 10.08 mmol) was slowly added to THF (10 mL). The mixture was stirred at -60 °C for 1 min, and then rapidly quenched at -60 °C under N2 (15 psi) with a saturated NaHCO3 solution (20 mL). The mixture was extracted with ethyl acetate (3 × 70 mL), and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by rapid column chromatography (0% to 100% ethyl acetate in petroleum ether solution) to give the title compound as a colorless oil (1.8 g, 87% yield). 1 HNMR (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).

[1074] Step 3: Preparation of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[1075]

[1076] Ethyl 2-amino-2-thioethyl (909.05 mg, 6.83 mmol) was added to a mixture of 2-bromo-3,3-dimethylcyclohexane-1-one (1400.0 mg, 6.83 mmol) in EtOH (36 mL) at 0 °C. The resulting mixture was then stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol. The residue was purified again by preparative TLC (50% ethyl acetate in petroleum ether solution) and preparative HPLC (water (FA)-ACN, 55% to 85%) to give the title compound (35 mg, 2% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ4.46 (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] + .

[1077] Step 4: Preparation of (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[1078]

[1079] NaBH4 (48.05 mg, 1.27 mmol) was slowly added to a solution of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-carboxylate (38.0 mg, 0.16 mmol) in 1.5 mL of methanol (MeOH). The mixture was stirred at 0 °C for 0.5 h. The mixture was then stirred at 25 °C for 2 h. The reaction mixture was diluted with water (0.5 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by reversed-phase chromatography (50% to 100% ethyl acetate in petroleum ether) to give (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)methanol (20 mg, 63.8% yield) as a white solid. 1 H 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] + .

[1080] Step 5: Preparation of methyl 1H-imidazolium-1-carboxylic acid (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl) ester

[1081]

[1082] CDI (24.66 mg, 0.15 mmol) was added 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) at 25 °C, and the solution was stirred at 25 °C for 0.5 h. The crude product was used directly for the next step. LCMS (ESI): m / z 292.0 [M + H] + .

[1083] Step 6: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester hydrochloride

[1084]

[1085] DBU (0.03 mL, 0.2 mmol) and TEA (0.03 mL, 0.2 mmol) and 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindoline-2-yl]piperidin-2,6-dione hydrochloride (52.19 mg, 0.16 mmol) were added to a solution of methyl 1H-imidazolium-1-carboxylic acid (7,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl]piperidin-2,6-dione in DMF (1.5 mL). The mixture was stirred at 25 °C for 16 h. The residue was then purified by preparative HPLC (water (HCl)-ACN, 38% to 68%) to give the title compound as a white solid (2 mg, 3.8% yield). 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 / z515.1 [M + H] + .

[1086] Example 53

[1087] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester (compound 86)

[1088]

[1089] Step 1: Preparation of 2-chloro-3-(trifluoromethyl)cyclohexane-1-one

[1090]

[1091] Add cyclohexyl-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) to a dried borosilicate vial equipped with a magnetic stirrer. After covering with nitrogen, add 1,2-dichloroethane (100 mL) and CF₃SO₂Cl (7.01 g, 41.61 mmol, 2.00 eq) sequentially. Stir the reaction mixture overnight at room temperature while irradiating it with a fluorescent bulb (Daylight GE Energy Smart, 26 W, 1600 lumens) mounted directly above the flask, and then remove the solution by rotary evaporation. The residue was purified by column chromatography on silica gel (0% to 5% petroleum ether solution of ethyl acetate) to give the title compound as a yellow solid (2.60 g, 62% yield). 1 H NMR (400 MHz, CDCl3)4.41 - 4.40 (m, 1H), 3.09 - 2.67 (m, 2H), 2.44 - 1.63 (m, 6H).

[1092] Step 2: Preparation of ethyl 7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylate

[1093]

[1094] Ethyl 2-amino-2-thioethyl (2.66 g, 19.94 mmol, 2.00 eq) was added to a mixture of 2-chloro-3-(trifluoromethyl)cyclohexane-1-one (2.00 g, 9.97 mmol, 1.00 eq) in ethanol (40 mL) at 25 °C. The resulting mixture was then stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum to remove ethanol. The residue was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic layer was washed with brine (20 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 5%) to give the title compound (100 mg, 4% yield) as a yellow solid. LCMS (ESI): m / z 280.0 (M+H) + .

[1095] Step 3: Preparation of (7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazolyl)methanol

[1096]

[1097] NaBH4 (68 mg, 1.79 mmol, 5.00 eq) was slowly added to a solution of ethyl 7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-carboxylate (100 mg, 0.36 mmol, 1.00 eq) in methanol (5 mL) at 0 °C. The mixture was stirred at 0 °C for 5 min. Then, stirring was continued at 25 °C for 3 h. The solution was quenched with NH4Cl solution (5 mL) and concentrated under vacuum. The residue was passed by preparative TLC (25% ethyl acetate in petroleum ether solution, R...). f = 0.3) Purification to give the title compound as a white solid (30 mg, 35% yield). LCMS (ESI): m / z 238.0 (M+H) + .

[1098] Step 4: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methyl ester

[1099]

[1100] CDI (41 mg, 0.25 mmol, 2.00 eq) was added to a solution of (7-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)methanol (30 mg, 0.13 mmol, 1.00 eq) in THF (2 mL). The solution was stirred at 25 °C for 2 h. The resulting solution was added to a mixture of 3-(6-(aminomethyl)-7-fluoro-1-oxoisoindol-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 25 °C for 12 h. The solution was purified by preparative HPLC (C18 150*30 mm, water (HCl)-ACN, 50% to 80%) to give the title compound as a white solid (2 mg, 3% yield). 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).

[1101] Example 54

[1102] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methyl ester (compound 87)

[1103] For this example, the same sequence of steps as compound 88 is followed, except that 3,3-dimethylpyrrolidine-2-carboxylate is used instead of 3-methylpyrrolidine-2-carboxylate in the first step.

[1104]

[1105] Step 1: Preparation of 3,3-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid

[1106]

[1107] The reaction was carried out at a scale of 1.00 mmol with 3,3-dimethylpyrrolidine-2-carboxylic acid salt to give 130.8 mg (76% yield) of (3,3-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid) as a white solid, which could be used without further purification. LCMS (ESI): m / z 173.050 (M+H) + .

[1108] Step 2: Preparation of 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazole-7-onthium-3-ol salt

[1109]

[1110] The reaction was carried out with (3,3-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid) at a scale of 0.76 mmol. The reaction was purified by silica gel column chromatography (0% to 80% iPrOAc in heptane) to give 115.1 mg (98% yield) of 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazole-7-onthium-3-olate as a white solid. LCMS (ESI): m / z 155.100 (M+H) + .

[1111] Step 3: Preparation of ethyl 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate

[1112]

[1113] The reaction was carried out at a scale of 0.75 mmol using 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazole-7-onthium-3-ol. The reaction was purified by silica gel column chromatography (0% to 50% iPrOAc in heptane) to give 43.2 mg (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) + .

[1114] Step 4: Preparation of (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol

[1115]

[1116] The reaction was carried out with ethyl 4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate at a scale of 0.207 mmol. 35.6 mg (103% yield) of a clear oil of (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-yl)methanol was obtained, which could be used without further purification. LCMS (ESI): m / z 167.100 (M+H) + .

[1117] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methyl ester

[1118]

[1119] The reaction was carried out with 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindoline-2-yl]piperidine-2,6-dione hydrochloride at a scale of 0.104 mmol. After a first preparative HPLC (Gemini-NX C18, column size 50 x 30 mm, 5 µm, 0.1% formic acid aqueous solution / ACN), followed by an achiral SFC (2-ethylpyridine column, column size 150 x 21.2 mm, 5 µm, carbon dioxide / pure MeOH), 13.59 mg of ((2-(2,6-dioxopiperidine-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methyl ester as a white solid (27% yield). LCMS (ESI): m / z 484.20 (M+H) + . 1 H 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 = 7.7Hz, 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).

[1120] Example 55

[1121] Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methyl ester (compound 88)

[1122]

[1123] Step 1: Preparation of 3-methyl-1-nitrosopyrrolidine-2-carboxylic acid

[1124]

[1125] Sodium nitrite (3.00 mmol, 207 mg, 3.0 equiv.) was added to a solution of 3-methylpyrrolidine-2-carboxylate (174 mg, 1.00 mmol, 1.0 equiv.) in H₂O (1.25 mL) at 0 °C, followed by the addition of a solution of HCl (12.18 mol / L) in H₂O (1.20 mmol, 0.0985 mL, 1.2 equiv.). The mixture was then gradually warmed to room temperature while stirring overnight. After the reaction was complete, the H₂O was further diluted and extracted with iPrOAc. The aqueous layer was then extracted twice more 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-nitrosopyrrolidine-2-carboxylic acid (134.0 mg, 84.7% yield) as a grayish-white semi-solid. The crude product was then used directly without further purification. LCMS (ESI): m / z 159.050 (M+H) + .

[1126] Step 2: Preparation of 4-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazole-7-onthium-3-ol salt

[1127]

[1128] Trifluoroacetic anhydride (1.27 mmol, 0.18 mL, 1.5 equiv.) was added dropwise to a solution of crude 3-methyl-1-nitrosopyrrolidine-2-carboxylic acid (0.85 mmol, 134.0 mg, 1.0 equiv.) in toluene (1.7 mL). The resulting solution was gradually heated to room temperature. The reaction was considered complete by LCMS analysis to determine the end of the reaction. The reaction was then concentrated under reduced pressure and purified by silica gel column chromatography (0% to 80% iPrOAc in heptane) to give the desired product, 4-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazole-7-onthium-3-ol (104.9 mg, 88% yield), as a red oil. LCMS (ESI): m / z 141.100 (M+H) + .

[1129] Step 3: Preparation of ethyl 4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate

[1130]

[1131] Ethyl propionate (1.50 mmol, 146.9 mg, 0.15 mL, 2.0 equiv.) was added to a 20 mL microwave-safe vial containing 4-methyl-5,6-dihydro-4H-pyrrolo[1,2-c]oxadiazole-7-onthium-3-ol (104.9 mg, 1.0 equiv.), followed by xylene (2.5 mL). The reaction was capped and stirred overnight at 120 °C. The 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% to 50% iPrOAc in heptane). Note that the desired product and regioisomers are formed by cyclization but can 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) + .

[1132] Step 4: Preparation of (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol

[1133]

[1134] A solution of 2-methyltetrahydrofuran (0.72 mmol, 0.30 mL, 3.0 equiv.) containing lithium aluminum hydride (2.3 mol / L) in 1.5 mL anhydrous THF was added dropwise to a 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.). The reaction was allowed to proceed gradually to room temperature after 30 minutes. After completion, the reaction was quenched by partial addition of sodium sulfate dodecahydrate until no further gas evolution was observed. The suspension was then filtered through diatomaceous earth, washed with additional DCM, and concentrated to obtain a clear, oily substance of (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (38 mg, 105% yield), which could be used directly without further purification. LCMS (ESI): m / z 153.100 (M+H) + .

[1135] Step 5: Preparation of ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methyl ester

[1136]

[1137] 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). Then triethylamine (0.47 mmol, 0.07 mL, 4 equiv.) was added, and the reaction was stirred at room temperature for 30 minutes.

[1138] To a separate vial containing 3-[6-(aminomethyl)-7-fluoro-1-oxo-isoindolin-2-yl]piperidin-2,6-dione; hydrochloride (39 mg, 0.12 mmol, 1.0 equiv.), add 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.). Then, an activated alcohol solution is added to the reaction in one step, and the vial is rinsed with excess THF (0.22 mL) to ensure complete transfer. The reaction is stirred at room temperature until complete. The reaction is then quenched by adding saturated aqueous NH4Cl solution and extracted with DCM (3x). The combined organic layers are dried over anhydrous Na2SO4, filtered, and concentrated. The residue was first purified by preparative HPLC (Gemini-NX C18, column size 50 x 30 mm, 5 µm, 0.1% formic acid aqueous solution / ACN), followed by purification by achiral SFC (2-ethylpyridine column, column size 150 x 21.2 mm, 5 µm, carbon dioxide / pure MeOH) to give the title compound as a white solid (10.29 mg, 18.6% yield). LCMS (ESI): m / z 470.18 (M+H) + . 1HNMR (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, 5.1Hz, 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).

[1139] Example 56

[1140] Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (8-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methyl ester (compound 89)

[1141]

[1142] Step 1: Preparation of methyl 2-(3-methyl-2-oxocyclohexyl)acetate

[1143]

[1144] Add 2 M LDA in THF solution (22 mL, 44.58 mmol, 1.00 eq) to a solution of 2-methylcyclohexane-1-one (5.00 g, 44.58 mmol, 1.00 eq) in THF (100 mL) at -78 °C under N2. The mixture was stirred at -78°C for 20 min, and then methyl 2-bromoacetate (10.23 g, 66.86 mmol, 1.50 eq) and HMPA (9.59 g, 53.49 mmol, 1.20 eq) were added at -78°C. The mixture was stirred at -78°C for 3 h. The solution was quenched with NH4Cl solution and extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (0% to 5% ethyl acetate in petroleum ether solution) to give the title compound as a white solid (8.00 g, 98% yield, cis:trans mixture, 1.6:1). 1 H 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).

[1145] Step 2: Preparation of 8-methyl-4,4a,5,6,7,8-hexahydrocinnamyl-3(2H)-one

[1146]

[1147] Add 85% N2H4 to a solution of methyl 2-(3-methyl-2-oxocyclohexyl)acetate (8.00 g, 43.42 mmol, 1.00 eq) in ethanol (100 mL). . H₂O (5.11 g, 86.85 mmol, 2.00 eq) was added, and the solution was stirred at 80 °C for 2 h. The solution was then concentrated under vacuum to give the title compound as a yellow solid (7.00 g, 97% yield). LCMS (ESI): m / z 167.1 (M+H) + .

[1148] Step 3: Preparation of 8-methyl-5,6,7,8-tetrahydrocinnamyl-3(2H)-one

[1149]

[1150] CuCl₂ (11.32 g, 84.23 mmol, 2.00 eq) was added to a solution of 8-methyl-4,4a,5,6,7,8-hexahydrocinnamyl-3(2H)-one (7.00 g, 42.11 mmol, 1.00 eq) in acetonitrile (100 mL). The solution was stirred at 84 °C for 1 h. The solution was filtered and washed with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic layer was concentrated under vacuum and purified by column chromatography (0% to 50% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (2.40 g, 35% yield). LCMS (ESI): m / z 165.1 (M+H) + .

[1151] Step 4: Preparation of 3-chloro-8-methyl-5,6,7,8-tetrahydrocinnamyl alcohol

[1152]

[1153] POCl3 (8.96 g, 263.09 mmol, 8.00 eq) was added to a flask and purged with N2 until the temperature was cooled to 0°C. 8-Methyl-5,6,7,8-tetrahydrocinnamyl-3(2H)-one (1.20 g, 7.31 mmol, 1.00 eq) was added, and the solution was stirred at 100°C for 30 min under N2. The solution was slowly poured into water (30 mL), and extracted with ethyl acetate (20 mL × 3). The organic layer was concentrated under vacuum and purified by column chromatography (0% to 10% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (700 mg, 52% yield). LCMS (ESI): m / z 182.8 (M+H) + .

[1154] Step 5: Preparation of methyl 8-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate

[1155]

[1156] K₂CO₃ (690 mg, 4.93 mmol, 1.50 eq) and Pd₂(dba)₃ (36 mg, 0.16 mmol, 0.10 eq) were added to a solution of 3-chloro-3-chloro-8-methyl-5,6,7,8-tetrahydrocinnamyl alcohol (600 mg, 3.28 mmol, 1.00 eq) in DMSO (10 mL) at 25 °C under N₂. The suspension was degassed under vacuum and purged with CO₂. The mixture was stirred at 100 °C for 1.5 h. The solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (0% to 10% ethyl acetate in petroleum ether) to give the title compound as a white solid (330 mg, 49% yield). LCMS (ESI): m / z 207.1 (M+H) + .

[1157] Step 6: Preparation of (8-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methanol

[1158]

[1159] At 0 °C, CaCl₂ (430 mg, 3.88 mmol, 4.00 eq) was added to a solution of methyl 8-methyl-5,6,7,8-tetrahydrocinnamyl-3-carboxylate (200 mg, 0.97 mmol, 1.00 eq) in methanol (4 mL) and THF (2 mL), followed by slow addition of NaBH₄ (73 mg, 1.94 mmol, 2.00 eq). The mixture was stirred at 0 °C for 5 min. The mixture was then stirred at 25 °C for 2 h. The solution was quenched with NH₄Cl solution (3 mL) and concentrated under vacuum. The residue was purified by column chromatography (0% to 80% EE (ethanol / ethyl acetate 1 / 3) in petroleum ether) to give the title compound (130 mg, 75% yield) as a colorless oil. LCMS (ESI): m / z 179.1 (M+H) + .

[1160] Step 7: Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (8-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methyl ester

[1161]

[1162] CDI (55 mg, 0.34 mmol, 2.00 eq) was added to a solution of (8-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methanol (30 mg, 0.17 mmol, 1.00 eq) in THF (2 mL). The solution was stirred at 25 °C for 2 h, and the resulting solution was added to a mixture of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindoline-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 °C for 12 h. The solution was purified by preparative HPLC (C18 150*40 mm, water (HCl)-ACN, 25% to 55%) to give the title compound as a white solid (12 mg, 12.5% ​​yield). LCMS (ESI): m / z 530.1 (M+H) + . 1 HNMR (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).

[1163] Example 57

[1164] Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl ester (compound 90)

[1165]

[1166] Step 1: Preparation of (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol

[1167]

[1168] Formaldehyde (0.02 mL, 0.65 mmol, 1.00 eq) was added 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 methanol (2 mL) and acetic acid (0.2 mL) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborate (82 mg, 1.31 mmol, 2.00 eq) was added, and the mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 × 4 mL), and the combined organic layers were washed with brine (2 × 6 mL). The organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (dichloromethane / methanol = 20 / 1 to 10 / 1) to give the title compound (50 mg, 45% yield) as a colorless oil. 1 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)

[1169] Step 2: Preparation of methyl 1H-imidazolium-1-carboxylic acid (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)

[1170]

[1171] (5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (50 mg, 0.3 mmol, 1.00 eq) was added to a mixture of CDI (48 mg, 0.3 mmol, 1.00 eq) in THF (1 mL) at 25 °C. The resulting mixture was then stirred at 25 °C for 0.5 h. The reaction mixture, which was a colorless oil, containing the title compound (78 mg, 99% yield), was used directly in the next step without purification. LCMS (ESI): m / z 284.1 (M+Na) + .

[1172] Step 3: Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl ester

[1173]

[1174] A solution of 1H-imidazolium-1-carboxylic acid (5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl) methyl ester (78 mg, 0.3 mmol, 1.00 eq), 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindol-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 25 °C for 12 h. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (Xtimate C18 150 * 40 mm * 10 μm, water (FA)-ACN, 10% to 40%) to give the title compound as a white solid (11.99 mg, 7% yield). 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 = 5.6Hz, 2H), 2.63 - 2.56 (m, 1H), 2.47 - 2.40 (m, 1H), 2.36 (s, 3H), 2.07 - 1.96 (m, 1H).

[1175] Example 58

[1176] Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (5-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methyl ester (compound 91)

[1177]

[1178] Step 1: Preparation of Trimethyl((3-methylcyclohexyl-1-en-1-yl)oxy)silane

[1179]

[1180] Copper(I) iodide (1.39 g, 7.28 mmol, 0.1 eq) was added to 3M methylmagnesium bromide (26.7 mL, 80.1 mmol, 1.1 eq) at 20 °C. The resulting solution was cooled to -30 °C, and a solution of cyclohexyl-2-en-1-one (7.05 mL, 72.82 mmol, 1 eq) in THF (100 mL) was added dropwise. The reaction mixture was then cooled to -50 °C and stirred at this temperature for 30 min. The mixture was cooled to -60 °C, and triethylamine (20.3 mL, 145.64 mmol, 2 eq.) and trichlorotrimethylsilane (13.85 mL, 109.23 mmol, 1.5 eq.) were added sequentially to the cooled solution. The resulting mixture was further cooled to -78 °C and stirred at this temperature for 1 h. The product mixture was heated to 20°C for 10 minutes and stirred at 20°C for 10 minutes. 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 under vacuum. The residue was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 1%) to give the title compound (4.8 g, 35% yield) as a colorless oil. 1 H 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).

[1181] Step 2: Preparation of methyl 2-(2-methyl-6-oxocyclohexyl)acetate

[1182]

[1183] TBAF (26.0 mL, 26.04 mmol, 1 eq) was added to methyl 2-bromoacetate (2.46 mL, 26.04 mmol, 1 eq) and trimethyl((3-methylcyclohexyl-1-en-1-yl)oxy)silane (4.8 g, 26.04 mmol, 1 eq) in THF (30 mL). The reaction mixture was stirred at 20 °C for 2 h under nitrogen. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0% to 10% ethyl acetate in petroleum ether solution) to give the title compound (900 mg, 18% yield) as a yellow oil.

[1184] Step 3: Preparation of 5-methyl-4,4a,5,6,7,8-hexahydrocinnamyl-3(2H)-one

[1185]

[1186] Hydrazine hydrate (0.5 mL, 10.19 mmol, 2 eq) was added to a mixture of methyl 2-(2-methyl-6-oxocyclohexyl)acetate (900 mg, 4.89 mmol, 1 eq) in ethanol (10 mL). The reaction mixture was stirred at 80 °C for 1 h under nitrogen, and the mixture was concentrated under vacuum to give the title compound as a yellow solid (812 mg, 100% yield). LCMS (ESI): m / z 166.8 (M+H) + .

[1187] Step 4: Preparation of 5-methyl-5,6,7,8-tetrahydrocinnamyl-3(2H)-one

[1188]

[1189] Copper(II) chloride (1.22 g, 9.04 mmol, 1.8 eq) was added to a solution of 5-methyl-4,4a,5,6,7,8-hexahydrocinnamyl-3(2H)-one (810 mg, 4.87 mmol, 1 eq) in acetonitrile (20 mL), and the solution was stirred at 84 °C for 1 h. The reaction mixture was quenched with 30 mL of saturated NH4Cl aqueous solution. The resulting solution was extracted with ethyl acetate (30 mL × 3), the organic layers were combined, and the organic phase was dried to give the title compound (800 mg, 99% yield) as a yellow solid. LCMS (ESI): m / z 164.8 (M+H) + .

[1190] Step 5: Preparation of 3-chloro-5-methyl-5,6,7,8-tetrahydrocinnamyl alcohol

[1191]

[1192] 5-Methyl-5,6,7,8-tetrahydrocinnamyl-3(2H)-one (800.0 mg, 4.87 mmol, 1 eq) was added to phosphoryl trichloride (3.0 mL, 32.61 mmol, 6.7 eq) at 0°C, and the solution was stirred at 100°C for 1 h. The reaction mixture was quenched with 20 mL of water. The residue was alkalized with aqueous NaHCO3 solution to pH = 8. The resulting solution was extracted with ethyl acetate (30 mL × 3), the organic phase was dried and filtered to give a crude product, which was purified by column chromatography (0% to 15% ethyl acetate in petroleum ether) to give the title compound (550 mg, 61% yield) as a colorless oil. LCMS (ESI): m / z 182.8 (M+H) +

[1193] Step 6: Preparation of methyl 5-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate

[1194]

[1195] Methanol (1.83 mL, 45.17 mmol, 15 eq), K₂CO₃ (633.35 mg, 4.52 mmol, 1.5 eq), 1,3-bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) (184.37 mg, 0.3 mmol, 0.1 eq), and palladium(ii) acetate (33.8 mg, 0.15 mmol, 0.05 eq) were added to a solution of 3-chloro-5-methyl-5,6,7,8-tetrahydrocinnamyl alcohol (550.0 mg, 3.01 mmol, 1 eq) in dimethyl sulfoxide (8 mL) at 25°C under N₂. The suspension was degassed under vacuum and purged with CO (15 psi), and the mixture was stirred at 100°C for 1.5 h. The reaction mixture was quenched with 20 mL of water, and the residue was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (50 mL × 3), dried, and filtered to give a crude product. The crude product was purified by column chromatography (0% to 40% ethyl acetate in petroleum ether) to give the title compound as a colorless oil (350 mg, 56% yield). LCMS (ESI): m / z 207.1 (M+H) + .

[1196] Step 7: Preparation of (5-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methanol

[1197]

[1198] Calcium chloride (753.3 mg, 6.79 mmol, 4 eq) and NaBH4 (130.0 mg, 3.44 mmol, 2 eq) were slowly added to a solution of methyl 5-methyl-5,6,7,8-tetrahydrocinnamyl-3-carboxylate (350.0 mg, 1.7 mmol, 1 eq) in methanol (4 mL) and THF (2 mL) at 0°C. The mixture was stirred at 0°C for 5 min. The mixture was stirred at 25°C for 2 h. The solution was quenched with NH4Cl solution (3 mL) and concentrated under vacuum. The residue was purified by column chromatography (0% to 30% in petroleum ether [(3:1) ethyl acetate / ethanol]) to give the title compound (250 mg, 82% yield) as a colorless oil. LCMS (ESI): m / z 178.9 (M+H) + .

[1199] Step 8: Preparation of methyl 1H-imidazolium-1-carboxylic acid (5-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl) ester

[1200]

[1201] CDI (48.04 mg, 0.3 mmol, 1 eq) was added to a solution of (5-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methanol (60.0 mg, 0.27 mmol, 1 eq) in THF (2 mL). The solution was stirred at 25°C for 2 h. The reactants were used directly in the next step.

[1202] Step 9: Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-yl)methyl)carbamate (5-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methyl ester

[1203]

[1204] A solution of 1H-imidazolium-1-carboxylic acid (5-methyl-5,6,7,8-tetrahydrocinnamyl-3-yl)methyl methyl 1H-imidazolium-1-carboxylic acid (70.0 mg, 0.26 mmol, 1 eq) in THF (2 mL) was added to a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride (101.82 mg, 0.28 mmol, 1.1 eq), DBU (38.44 μL, 0.26 mmol, 1 eq), and triethylamine (71.66 μL, 0.51 mmol, 2 eq) in DMF (2 mL). The mixture was stirred at 25°C for 12 h. The residue was purified by preparative HPLC (water (FA)-ACN, 23%–53%) to give the title compound as a white solid (30.7 mg, 22% yield). LCMS (ESI): m / z 530.1 (M+H) + , 1 H 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).

[1205] Example 59

[1206] Preparation of ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindol-5-yl)methyl)carbamate (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methyl ester (compound 93)

[1207]

[1208] Step 1: Preparation of 1-nitrosoperpiperidine-2-carboxylic acid

[1209]

[1210] A solution of sodium nitrite (117 mg, 1.70 mmol, 1.1 eq) in water (5 mL) was added to a solution of piperidine-2-carboxylic acid (200 mg, 1.55 mmol, 1.00 eq) and hydrogen chloride (0.14 mL, 1.63 mmol, 1.05 eq) in water (10 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 4 h. 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 a colorless oil. The crude product was used for the next step without purification.

[1211] Step 2: Preparation of 4,5,6,7-tetrahydro-[1,2,3]oxadiazolo[3,4-a]pyridine-8-on-3-ol salt

[1212]

[1213] Under a nitrogen atmosphere at 0 °C, trifluoroacetic anhydride (2.4 mL, 16.97 mmol, 1.10 eq) was added to a solution of 1-nitrosopiperidin-2-carboxylic acid (2440 mg, 15.43 mmol, 1.00 eq) in THF (50 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to dryness under reduced pressure to give the title compound (2100 mg, 97% yield) as a colorless oil. The crude product was used directly in the next s...

Claims

1. A compound of formula (I) ， in: (1) Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Haloalkyl, C 1-6 Alkoxy, OC 1-6 Halogenated alkyl groups and -N(R) a (R) b ); (2) p is an integer selected from 0, 1, 2 and 3; (3) Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted OC 3-6 cycloalkyl; (4) q is an integer selected from 0, 1, 2 and 3; (5)R 3 It is hydrogen or C 1-4 alkyl; (6) Each R 4 C independently selected from hydrogen, optionally substituted 1-6 Alkyl groups, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 3- to 6-membered heterocyclic alkyl and optionally substituted 5- to 6-membered heteroaryl; (7) m is 1 or 2; (8) A is selected from (i) 5-membered monocyclic heteroaryl, and (ii) 6- to 10-member fused bicyclic heteroaryl groups; and (9) Each R a and R b Independently selected from H and optionally substituted C 1-6 Alkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form optionally substituted 3- to 8-membered heterocyclic alkyl groups; Or its pharmaceutically acceptable salt.

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

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

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

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

6. The compound according to any one of claims 1 to 4, wherein each R 1 It is a halogen.

7. The compound according to claim 6, wherein each R 1 Selected from -F and -Cl.

8. The compound according to any one of claims 1 to 4, wherein each R 1 C 1-6 alkyl.

9. The compound according to any one of claims 1 to 8, wherein each R 2 Independently selected from halogens, haloalkyl groups, and optionally substituted C-type compounds. 1-4 Alkyl, C 3-6 cycloalkyl and C 5-6 Aryl.

10. The compound according to any one of claims 1 to 8, wherein each R 2 It is independently selected from fluorine, chlorine, methyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, cyclohexyl and phenyl.

11. The compound according to any one of claims 1 to 10, wherein R 3 It is hydrogen.

12. The compound according to any one of claims 1 to 10, wherein R 3 It is a methyl group.

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

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

15. The compound according to any one of claims 1 to 12 and 14, wherein m is 2 and R 4 At least one of them is hydrogen.

16. The compound according to any one of claims 1 to 15, wherein each R 4 It is hydrogen.

17. The compound according to any one of claims 1 to 14, wherein each R 4 C is arbitrarily substituted 6-10 Aryl.

18. The compound according to any one of claims 1 to 14, wherein each R 4 The phenyl group is optionally substituted.

19. The compound according to claim 1, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

20. The compound according to any one of claims 1 to 19, characterized in that... When measured by HiBiT, CDK2 D max It must be at least 50%, at least 60%, or at least 70%.

21. The compound according to any one of claims 1 to 20, characterized in that... When measured by HiBiT, CDK2 DC 50 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.

22. The compound of claim 20 or claim 21, wherein the HiBiT assay is performed in HEK293 cells.

23. A compound of formula (II) ， in: (1) Y is an optionally substituted monocyclic C 3-6 Cycloalkyl or optionally substituted monocyclic 3- to 5-membered heterocyclic alkyl groups; (2) Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Halogenated alkyl groups; (3) p is an integer selected from 0, 1, 2 and 3; (4) Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, OC 3-6 cycloalkyl and -NR 2a R 2b ; (5) q is an integer selected from 0, 1, 2 and 3; (6) Each R 2a and R 2b Independently selected from H and optionally substituted C 1-6 Alkyl, or R 2a and R 2b Together with the nitrogen atoms to which they are attached, they form optionally substituted 3- to 8-membered heterocyclic alkyl groups; (7)R 3 It is hydrogen or C 1-4 alkyl; (8)L 3 For keys or connectors, the connectors being selected from optionally substituted -C 1-4 Alkylene-, optionally substituted -OC 1-4 Alkylene-, optionally substituted -C(O)OC 1-4 alkylene- and -C(O)-; and (9)B is selected from (i)C 6-10 Aryl, (ii) 5 to 10 yuan of heteroaryl and (iii) 5- to 10-membered fused bicyclic heterocyclic alkyl groups, Or its pharmaceutically acceptable salt. The condition is when (i) L 3 When (ii) B is a phenyl bond, q is 1, 2, or 3.

24. The compound according to claim 23, wherein Y is a monocyclic C 3-6 Cycloalkyl.

25. The compound according to claim 24, wherein Y is cyclobutyl.

26. The compound according to claim 24, wherein Y is cyclopentyl.

27. The compound according to claim 23, wherein Y is a monocyclic 3- to 5-membered heterocyclic alkyl group.

28. The compound according to claim 27, wherein Y is a nitrogen-containing cyclobutane.

29. The compound according to any one of claims 23 to 28, wherein Y is substituted with a hydroxyl group or a halogen.

30. The compound according to any one of claims 23 to 29, wherein B is selected from:

31. The compound according to any one of claims 23 to 30, wherein each R 1 It can be independently selected from: -CH3, -F, -Cl and –OH.

32. The compound according to any one of claims 23 to 30, wherein each R 1 It is a halogen.

33. The compound according to claim 32, wherein each R 1 Selected from -F and -Cl.

34. The compound according to any one of claims 23 to 30, wherein each R 1 C 1-6 alkyl.

35. The compound according to any one of claims 23 to 34, wherein each R 2 Independently selected from halogens, haloalkyl groups, and OCs 1-6 Halogenated alkyl groups, optionally substituted C 1-4 Alkyl, C 3-6 cycloalkyl, oxo, C 1-4 Alkoxy and N(C) 1-6 Alkyl)2.

36. The compound of claim 35, wherein each R 2 It is independently selected from fluorine, chlorine, trifluoromethyl, cyclopropyl and methoxy.

37. The compound according to any one of claims 23 to 36, wherein L 3 For key.

38. The compound according to any one of claims 23 to 36, wherein L 3 C 1-4 Alkylene.

39. The compound according to claim 38, wherein L 3 It is a methylene group.

40. The compound according to any one of claims 23 to 36, wherein L 3 -OC 1-4 Alkylene-.

41. The compound according to claim 40, wherein L 3 It is -OCH2-.

42. The compound according to any one of claims 23 to 36, wherein L 3 -C(O)OC 1-4 Alkylene-.

43. The compound according to claim 42, wherein L 3 It is -C(O)OCH2-.

44. The compound according to any one of claims 23 to 36, wherein L 3 It is -C(O)-.

45. The compound according to claim 23, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

46. ​​The compound according to any one of claims 23 to 45, characterized in that... When measured by HiBiT, CDK2 D max It must be at least 50%, at least 60%, or at least 70%.

47. The compound according to any one of claims 23 to 46, characterized in that... When measured by HiBiT, CDK2 DC 50 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.

48. The compound of claim 46 or claim 47, wherein the HiBiT assay is performed in HEK293 cells.

49. A pharmaceutical composition comprising: a compound according to 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 for degrading CDK2 in a subject, the method comprising administering to the subject: (i) a compound of any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof; or (ii) a pharmaceutical composition of claim 49 or claim 50.

52. A method of treating cancer in a subject with such need, the method comprising administering to the subject: (i) an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 48; or (ii) a pharmaceutical composition according to claim 49 or claim 50.

53. The method according to claim 52, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, prostate cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, upper respiratory and digestive tract cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, neck cancer, thyroid cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, uterine cancer, neuroblastoma, meningioma, hemangiopericytoma, leiomyoma, leukemia, lymphoma, and myeloma.

54. The method according to 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 who requires such treatment, the method comprising administering to the subject: (i) an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 48; or (ii) a pharmaceutical composition according to claim 49 or claim 50.

56. A method of treating a subject with a liquid tumor, the method comprising administering to the subject: (i) an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 48; or (ii) a pharmaceutical composition according to claim 49 or claim 50.

57. A compound of formula (III) ， in: (1) Y is an optionally substituted monocyclic C 3-6 Cycloalkyl or optionally substituted monocyclic 3- to 5-membered heterocyclic alkyl groups; (2) Each R 1 Independently selected from halogen, cyano, C 1-6 Alkyl, hydroxyl and C 1-6 Halogenated alkyl groups; (3) p is an integer selected from 0, 1, 2 and 3; (4) Each R 2 C groups independently selected from halogen, cyano, oxo, or optionally substituted C groups 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 1-6 Halogenated alkyl, OC 1-6 Halogenated alkyl groups, optionally substituted C 3-8 Cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5- to 6-membered heteroaryl, OC 3-6 cycloalkyl; (5) q is an integer selected from 0, 1, 2 and 3; (6)R 3 It is hydrogen or C 1-4 alkyl; (7)L 3 For keys or connectors, the connectors being selected from optionally substituted -C 1-4 Alkylene-, optionally substituted -OC 1-4 Alkylene-, optionally substituted -C(O)OC 1-4 alkylene- and -C(O)-; and (8) C is connected to L 3 The nitrogen-containing heterocyclic alkyl group consisting of 3 to 6 members. Or its pharmaceutically acceptable salt.

58. The compound according to claim 57, wherein Y is a monocyclic C 3-6 Cycloalkyl.

59. The compound according to claim 58, wherein Y is cyclobutyl.

60. The compound according to any one of claims 57 to 59, wherein L 3 Selected from the bond and -C(O)-.

61. The compound according to any one of claims 57 to 60, wherein C is selected from: as well as .

62. The compound according to any one of claims 57 to 61, wherein each R 2 Independently selected from halogens, oxidants, and C 1-6 Halogenated alkyl groups.

63. The compound according to claim 57, wherein the compound is selected from:

64. The compound according to any one of claims 57 to 63, characterized in that... When measured by HiBiT, CDK2 D max It must be at least 50%, at least 60%, or at least 70%.

65. The compound according to any one of claims 57 to 64, characterized in that... When measured by HiBiT, CDK2 DC 50 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.

66. The compound of claim 64 or claim 65, wherein the HiBiT assay is performed in HEK293 cells.

67. A pharmaceutical composition comprising: a compound according to 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 for degrading CDK2 in a subject, the method comprising administering to the subject: (i) a compound of any one of claims 57 to 66 or a pharmaceutically acceptable salt thereof; or (ii) a pharmaceutical composition of claim 67 or claim 68.

70. A method of treating cancer in a subject with this need, the method comprising administering to the subject: (i) an effective amount of a compound according to any one of claims 57 to 66 or a pharmaceutically acceptable salt thereof; or (ii) a pharmaceutical composition according to claim 67 or claim 68.

71. The method according to claim 70, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, prostate cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, upper respiratory and digestive tract cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, neck cancer, thyroid cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, uterine cancer, neuroblastoma, meningioma, hemangiopericytoma, leiomyoma, leukemia, lymphoma, and myeloma.

72. The method according to 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 subject with a solid tumor, the method comprising administering to the subject: (i) an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 57 to 66; or (ii) a pharmaceutical composition according to claim 67 or claim 68.

74. A method of treating a subject with a fibroma, the method comprising administering to the subject: (i) an effective amount of the compound according to any one of claims 57 to 66 or a pharmaceutically acceptable salt thereof; or (ii) The pharmaceutical composition according to claim 67 or claim 68.

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