Compounds that mediate protein degradation and methods of use thereof

Abstract

Described herein, in part, are compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2), which are useful in the treatment of various disorders, such as cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 63 / 419,575, filed October 26, 2022, the contents of which are incorporated herein by reference. [Background technology]

[0002] The ubiquitin-proteasome system can be manipulated with various small molecules to induce targeted degradation of specific proteins of interest. Using small-molecule degraders to promote targeted degradation of pathogenic proteins is emerging as a novel modality for disease treatment. One such modality relies on redirecting the activity of E3 ligases, such as cereblon, using low-molecular-weight compounds called molecular glues (a phenomenon known as E3 reprogramming) to promote the polyubiquitination and eventual proteasomal degradation of novel protein substrates involved in disease pathogenesis. By binding to both the E3 ligase and the target protein, the molecular glue mediates changes to the ligase surface, allowing it to interact with the target protein.

[0003] There is a need for therapeutic agents that effectively mediate the degradation of certain proteins for the treatment of disease. Summary of the Invention

[0004] Described herein, in part, are compounds contemplated as modulators of cereblon, which mediate protein degradation, and are useful in the treatment of disorders such as cancer. In some embodiments, the compounds of the present disclosure mediate targeted degradation of the protein cyclin-dependent kinase 2 (CDK2).

[0005] In some embodiments, provided herein are compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X is selected from H and deuterium; 1 teeth, [ka] and 5-6 membered heteroaryl; L 2 is a bond and [ka] Selected from;R 1 , R 2 , R 3 , and R 4 each independently represents hydrogen, halogen, C 1~6 Alkoxy, cyano, hydroxy, C 3~6 Cycloalkyl, and C 1~6 alkyl; Ring A is selected from the group consisting of C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl, wherein C 3~6 Each of cycloalkyl and 3- to 6-membered heterocyclyl is one or more R 5 and each R 5 are independently hydrogen, C 1~6 is selected from the group consisting of alkyl, hydroxy, and oxo, wherein C 1~6 The alkyl is optionally substituted with one or more halogens; and ring B is C 3~12 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and heteroaryl, wherein C 3~12 Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and heteroaryl may be one or more R 6 and each R 6 are independently halogen, cyano, C 1~6 Alkoxy, C 1~6 Alkyl, -C(O)R 7 , -C(O)NR 7 R 8 , -S(O)2R 7 , pyridine, [ka] wherein each C 1~6 Alkyl, C 1~6 Alkoxy and pyridine are C 1~6 optionally substituted with one or more substituents selected from alkyl and halogen; 7 independently, C 1~6 Alkyl, phenyl, cyclopropane, N-bonded C 3~9 heterocycloalkyl, N-linked heteroaryl, [ka] wherein R 7 But C 1~6 Alkyl, halogen, cyano, trifluoro(methoxy)methane, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of alkoxy (e.g., methoxy); R 8 , R 9 , and R 10 each independently represents hydrogen, deuterium, C 1~6 Alkyl and deuterated C 1~6 alkyl (e.g., -CD3); and n is an integer selected from the group consisting of 0, 1, 2, and 3.

[0006] In certain aspects, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In certain aspects, provided herein is a method for degrading CDK2 in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0008] In certain aspects, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0009] In certain aspects, provided herein is a method of treating a solid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0010] In certain aspects, provided herein is a method of treating a liquid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] The features and other details of the present disclosure will now be described more specifically. Specific terms used in the specification, examples, and appended claims are summarized here. These definitions should be interpreted as understood by those skilled in the art in light of the rest of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0012] compound In one aspect, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X is selected from H and deuterium; 1 teeth, [ka] and 5-6 membered heteroaryl; L 2 is a bond and [ka] Selected from;R 1 , R 2 , R 3 , and R 4 each independently represents hydrogen, halogen, C 1~6 Alkoxy, cyano, hydroxy, C 3~6 Cycloalkyl, and C 1~6 alkyl; Ring A is selected from the group consisting of C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl, wherein C 3~6 Each of cycloalkyl and 3- to 6-membered heterocyclyl is one or more R 5 and each R 5 are independently hydrogen, C 1~6 is selected from the group consisting of alkyl, hydroxy, and oxo, wherein C 1~6 The alkyl is optionally substituted with one or more halogens; and ring B is C 3~12 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and heteroaryl, wherein C 3~12 Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and heteroaryl may be one or more R 6 and each R 6 are independently halogen, cyano, C 1~6 Alkoxy, C 1~6 Alkyl, -C(O)R 7 , -C(O)NR 7 R 8 , -S(O)2R 7 , pyridine, [ka] wherein each C 1~6 Alkyl, C 1~6 Alkoxy and pyridine are C 1~6optionally substituted with one or more substituents selected from alkyl and halogen; 7 independently, C 1~6 Alkyl, phenyl, cyclopropane, N-bonded C 3~9 heterocycloalkyl, N-linked heteroaryl, [ka] wherein R 7 But C 1~6 Alkyl, halogen, cyano, trifluoro(methoxy)methane, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of alkoxy (e.g., methoxy); R 8 , R 9 , and R 10 each independently represents hydrogen, deuterium, C 1~6 Alkyl and deuterated C 1~6 alkyl (e.g., -CD3); and n is an integer selected from the group consisting of 0, 1, 2, and 3.

[0013] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0014] In some embodiments, ring B is C 3~12 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and aryl, wherein C 3~12 Each of cycloalkyl, 3- to 10-membered heterocyclyl, and aryl may be one or more R 6 is replaced by .

[0015] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0016] In some embodiments, ring B is [ka] is.

[0017] In some embodiments, ring B is [ka] is.

[0018] In some embodiments, ring B is [ka] is.

[0019] In some embodiments, R 6 is selected from the group consisting of Cl, F, —CN, —CH, —CF, —CH(CH), —OCH, —OC(CH), —OCF, and —O—Si(CH)C(CH).

[0020] In some embodiments, R 6 is -C(O)R 7 where R 7 is phenyl, [ka] is selected from the group consisting of:

[0021] In some embodiments, R 6 is -C(O)NR 7 R 8 where R 7 is methyl, phenyl, [ka] and R 8 is CH3 or CD3.

[0022] In some embodiments, R 6 is -S(O)2R 7 where R 7 teeth [ka] is.

[0023] In some embodiments, L 1 teeth, [ka] is selected from the group consisting of:

[0024] In some embodiments, L 1 teeth [ka] is.

[0025] In some embodiments, the compound is a compound of formula (IA) [ka] is.

[0026] In some embodiments, the compound is a compound of formula (IB) [ka] is.

[0027] In some embodiments, the compound is a compound of formula (IC) [ka] is.

[0028] In some embodiments, the compound is a compound of formula (ID) [ka] is.

[0029] In some embodiments, the compound is a compound of formula (IE) [ka] is.

[0030] In some embodiments, the compound is a compound of formula (IF) [ka] is.

[0031] In some embodiments, the compound is a compound of formula (IG) [ka] is.

[0032] In some embodiments, the compound is a compound of formula (IH) [ka] is.

[0033] In some embodiments, the compound is a compound of formula (II) [ka] is.

[0034] In some embodiments, the compound is a compound of formula (II-0) [ka] is.

[0035] In some embodiments, the compound is a compound of formula (II-1-1) [ka] is.

[0036] In some embodiments, the compound is a compound of formula (II-1-2) [ka] is.

[0037] In some embodiments, the compound is a compound of formula (II-2) [ka] is.

[0038] In some embodiments, the compound is a compound of formula (II-2-1) [ka] is.

[0039] In some embodiments, the compound is a compound of formula (II-2-2) [ka] is.

[0040] In some embodiments, the compound is a compound of formula (II-3) [ka] is.

[0041] In some embodiments, the compound is a compound of formula (II-3-1) [ka] is.

[0042] In some embodiments, the compound is a compound of formula (II-3-2) [ka] is.

[0043] In some embodiments, the compound is a compound of formula (II-4) [ka] is.

[0044] In some embodiments, the compound is a compound of formula (II-4-1) [ka] is.

[0045] In some embodiments, the compound is a compound of formula (II-4-2) [ka] is.

[0046] In some embodiments, the compound is a compound of formula (II-5) [ka] is.

[0047] In some embodiments, the compound is a compound of formula (II-5-1) [ka] is.

[0048] In some embodiments, the compound is a compound of formula (II-5-2) [ka] is.

[0049] In some embodiments, the compound is a compound of formula (IJ) [ka] is.

[0050] In some embodiments, the compound is a compound of formula (IK) [ka] is.

[0051] In some embodiments, the compound is a compound of formula (IL) [ka] is.

[0052] In some embodiments, the compound is a compound of formula (Ii) [ka] is.

[0053] In some embodiments, the compound is a compound of formula (I-ii) [ka] is.

[0054] In some embodiments, the compound is a compound of formula (I-iii) [ka] is.

[0055] In some embodiments, the compound is a compound of formula (I-iv) [ka] is.

[0056] In some embodiments, the compound is a compound of formula (Iv) [ka] is.

[0057] In some embodiments, the compound is a compound of formula (I-vi) [ka] is.

[0058] In some embodiments, the compound is a compound of formula (I-vii) [ka] is.

[0059] In some embodiments, the compound is a compound of formula (I-viii) [ka] is.

[0060] In some embodiments, the compound is a compound of formula (I-ix) [ka] is.

[0061] In some embodiments, the compound is a compound of formula (Ix) [ka] is.

[0062] In some embodiments, the compound is a compound of formula (I-xi) [ka] is.

[0063] In some embodiments, the compound is a compound of formula (I-xii) [ka] is.

[0064] In some embodiments, the compound is a compound of formula (I-xiii) [ka] is.

[0065] In some embodiments, the compound is a compound of formula (I-xix) [ka] is.

[0066] In some embodiments, the compound is a compound of formula (I-xx) [ka] is.

[0067] In some embodiments, the compound is a compound of formula (I-xxi) [ka] is.

[0068] In some embodiments, the compound is a compound of formula (I-xxii) [ka] is.

[0069] In some embodiments, the compound is a compound of formula (I-xxiii) [ka] is.

[0070] In some embodiments, the compound is a compound of formula (I-xxiv) [ka] is.

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

[0072] In some embodiments, X is H.

[0073] In some embodiments, L 2 is a bond.

[0074] In some embodiments, L 2 teeth, [ka] is.

[0075] In some embodiments, R 1 , R 2 , R 3 , and R 4 is H.

[0076] In some embodiments, R 1 is fluoro and R 2 is fluoro and R 3 is H and R 4 is H.

[0077] In some embodiments, R 9 and R 10 is H.

[0078] In some embodiments, n is 3.

[0079] In some embodiments, n is 2.

[0080] In some embodiments, n is 1.

[0081] In some embodiments, n is 0.

[0082] In some embodiments, R 7 is methyl, benzene, cyclopropane, [ka] is selected from the group consisting of [ka] Each of is optionally substituted with one or two selected from the group consisting of methyl, fluorine, chlorine, cyano, and methoxy.

[0083] In some embodiments, R 7 is methyl, phenyl, [ka] is selected from the group consisting of:

[0084] In some embodiments, R 7 is C 1~6 Alkyl (e.g., methyl), halogen, cyano, trifluoro(methoxy)methane, and C 1~6 Phenyl optionally substituted with alkoxy (eg, methoxy).

[0085] In some embodiments, R 8 , R 9 , and R 10 Each of R is independently hydrogen or methyl. 8 is methyl. In some embodiments, R 8 is -CD3.

[0086] In some embodiments, R 8 , R 9 , and R 10 each independently represents a deuterated C 1~6 In some embodiments, R 8 , R 9 , and R 10 Each of is independently -CD3.

[0087] In some embodiments, the compound is a compound set forth in Table 1 below, which also includes the compound number for each compound according to the present disclosure. [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44

[0088] Medical ingredients In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0089] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0090] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are provided in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as single doses for human subjects and other mammals, each containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually a minor component, with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0091] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle, such as buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a flow agent such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0092] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable vehicles known in the art. As mentioned above, the active compound in such compositions is typically a minor component, with the remainder being the injectable vehicle, etc.

[0093] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically mixed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients to enhance the transdermal penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are within the scope of the present disclosure provided herein.

[0094] The compounds provided herein can also be administered by a transdermal device. Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0095] The above ingredients for oral, injectable, or topical compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0096] Treatment and Use Furthermore, it is contemplated that the compounds and pharmaceutical compositions described herein are useful for treating or preventing a disorder in a subject in need thereof. In one embodiment, the compounds described herein are used to degrade CDK2 for the treatment or prevention of a disorder.

[0097] Cyclin-dependent kinase (CDK) is a family of closely related kinases that control the progression of cell cycle.CDK activity is further regulated by the level of certain cyclin, for example, cyclin E1 activates cyclin-dependent kinase 2 (CDK2).To treat patients with tumors that have activated CDK2, removal of CDK2 is intended.The mechanism of activating CDK2 in tumors includes but is not limited to the amplification or high expression of cyclin E1 or cyclin E2.

[0098] Thus, in one embodiment of the present disclosure, a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered to a subject to degrade CDK2 in the subject.

[0099] In one aspect of the disclosure, described herein is a method of treating or preventing a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0100] In another aspect, described herein are methods for degrading CDK2 in a subject suffering from a disorder, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the compound binds to cereblon and CDK2 protein, thereby inducing ubiquitination and subsequent proteasomal degradation of CDK2.

[0101] Exemplary disorders that may be treated or prevented by the methods of the present disclosure include, but are not limited to, cancer of the bladder, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph node, lung, upper aerodigestive tract (including the nasal cavity and paranasal sinuses, nasopharynx or nasopharynx, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), cervix, ovary, pancreas, prostate, rectum, skin, stomach, testicles, throat, or uterus. Other exemplary disorders include, but are not limited to, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple metastatic brain tumors, glioblastoma multiforme, glioblastoma, brain stem glioma, malignant brain tumors with poor prognosis, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, e.g., neuroendocrine prostate cancer, such as castration-resistant neuroendocrine prostate cancer (NEPC), and pulmonary neuroendocrine tumors (Lu-NET), rectal adenocarcinoma, colorectal cancer (including stage 3 and stage 4 colorectal cancer), unresectable colorectal cancer, 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, fibrodysplasia ossificans progressiva, hormone-resistant prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma;and blood-borne (liquid) or hematological cancers, including but not limited to leukemia, lymphoma, and myeloma, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocytocyte-rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, These include splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, low-grade lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndromes (MDS), human lymphotropic virus type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma (MM);

[0102] In some embodiments, the disorder is breast cancer or ovarian cancer. In some embodiments, the breast cancer is estrogen receptor positive breast cancer or triple negative breast cancer.

[0103] In another aspect of the disclosure, described herein is a method of treating cancer (e.g., a cancer described herein) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0104] In another aspect, described herein is a method of degrading CDK2 in a subject suffering from cancer (e.g., a cancer described herein), the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0105] In another aspect, described herein is a method of treating a solid tumor (e.g., a solid tumor described herein) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0106] In another aspect, described herein is a method of treating a liquid tumor (e.g., a solid tumor described herein) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the liquid tumor is a hematological cancer (e.g., a hematological cancer described herein).

[0107] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS Periodic Table of the Elements, located on the inside cover of Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0108] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0109] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0110] The term "alkenyl," as used herein, refers to the radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., as in 2-butenyl) or terminal (e.g., as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0111] The term "alkynyl," as used herein, refers to the radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). Examples of C2-4 alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0112] The term "cycloalkyl," as used herein, refers to the radical of a saturated or partially unsaturated cyclic hydrocarbon group having 3 to 12 ring carbon atoms ("C3-12 cycloalkyl") and zero heteroatoms in the ring system. In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl"). Exemplary C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), bicyclo[1.1.1]pentyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C3-8 cycloalkyl groups include, but are not limited to, the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C3-10 cycloalkyl groups include, but are not limited to, the aforementioned C3-8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), etc. As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or is a fused, bridged, or spiro ring system, e.g., a bicyclic system ("bicyclic cycloalkyl")."Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring or on one or more of the aryl or heteroaryl groups, and in such cases the carbon number continues to refer to the number of carbons within the cycloalkyl ring system.

[0113] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to the radical of a saturated or partially unsaturated 3- to 10-membered ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting. A heterocyclyl group may be monocyclic (a "monocyclic heterocyclyl"), or a fused, bridged, or spirocyclic ring system, e.g., a bicyclic system (a "bicyclic heterocyclyl"). A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, where the point of attachment is on either the cycloalkyl or the heterocyclyl ring, and includes ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring or on one or more aryl or heteroaryl groups, in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system.

[0114] In some embodiments, a heterocyclyl group is a 5- to 10-membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocycloalkyl group is a 5- to 10-membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0115] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0116] The term "aryl," as used herein, refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and no heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "aryl"; e.g., anthracyl). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0117] As used herein, the term "heteroaryl" refers to a radical of a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at either a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0118] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are monocyclic 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group is a monocyclic 5-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5-membered heteroaryl"). In some embodiments, a heteroaryl group is a monocyclic 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "6-membered heteroaryl").

[0119] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0120] As used herein, the term "alkoxy" refers to an -OR 100 refers to the group, where R 100is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Other exemplary alkoxy groups are lower alkoxy, i.e., alkoxy having 1 to 6 carbon atoms. In other examples, alkoxy groups have 1 to 4 carbon atoms.

[0121] As used herein, the term "thioalkoxy" refers to a group selected from the group consisting of -SR 101 refers to the group, where R 101 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Other exemplary alkoxy groups are lower alkoxy, i.e., alkoxy having 1 to 6 carbon atoms. In other examples, alkoxy groups have 1 to 4 carbon atoms.

[0122] As used herein, the term "cyano" refers to the radical --CN.

[0123] The term "halogen" as used herein refers to F, Cl, Br, or I.

[0124] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without causing undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0125] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0126] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0127] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is suffering from a particular disease, disorder, or condition, or that reduce the severity of the disease, disorder, or condition, or slow or delay the progression of the disease, disorder, or condition. In an alternative embodiment, the present disclosure contemplates administering the compounds described herein as prophylactics, before a subject begins to suffer from a particular disease, disorder, or condition.

[0128] Generally, the "effective amount" of a compound used herein refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0129] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0130] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers." Stereoisomers that are not mirror images of one another are referred to as "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+) or (-) form, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0131] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and chiral salt formation, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0132] The compounds provided herein may be administered as the sole active agent or in combination with other active agents. In some embodiments, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. Coadministration may proceed by any technique apparent to one skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0133] In alternative embodiments, the present disclosure also encompasses isotopically labeled compounds that are identical to the compounds recited herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium. [Example]

[0134] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0135] Abbreviations: eq: equivalent weight; ESI: electrospray ionization; h: time; HPLC: high-performance liquid chromatography; MS: mass spectrometry; NMR: nuclear magnetic resonance; AcOH or HOAc: acetic acid; Boc: tert-butyloxycarbonyl; BOP: basic oxygen method; BrettPhos: dialkylbiarylphosphine ligand; CDI: carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EDCI: ethylene dichloride; HOBt: hydroxybenzotriazole; LAH: lithium aluminum hydride; MeCN: acetonitrile; MeOH: methanol; Pd PEPPSI-IHetp Cl: dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Pd(PPh)4: palladium-tetrakis(triphenylphosphine); Py: pyridine; t-BuONa: sodium tert-butoxide; TBuONO: tert-butyl nitrite; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; triphosgene: bis(trichloromethyl)carbonate; ZnEt2: diethylzinc.

[0136] Example 1. Synthesis of Compound 1 [ka] Step 1. Procedure for compound 1 spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of spiro[3.3]heptan-2-ylmethanol (5.98 mg, 47.4 µmol, 1.00 equiv) in tetrahydrofuran (0.200 mL) was added di(1H-imidazol-1-yl)methanone (15.4 mg, 94.8 µmol, 2.00 equiv) at 0° C. The mixture was stirred at 0° C. for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (20.0 mg, 47.4 μmol, 70% purity, 1.00 equiv.), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (7.22 mg, 47.4 μmol, 7.15 μL, 1.00 equiv.), and N,N-diisopropylethylamine (6.13 mg, 47.4 μmol, 8.26 μL, 1.00 equiv.) in tetrahydrofuran (0.200 mL) and dimethylformamide (0.200 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 46% to 76%, 9 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (3.93 mg, 8.69 umol, 18% yield, 99% purity) as an off-white solid.

[0137] Example 2. Synthesis of Compound 2 [ka] Step 1. Procedure for compound 2 tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)-3-methylazetidin-3-yl)carbamate. To a solution of 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione (100 mg, 316 μmol, 1.00 equiv.), tert-butyl (3-methylazetidin-3-yl)carbamate (70.5 mg, 316 μmol, 1.0 equiv., hydrochloric acid) in dioxane (2.00 mL), cesium carbonate (309 mg, 949 μmol, 3.00 equiv.), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; and dichloropalladium (30.8 mg, 31.6 μmol, 0.100 equiv.) were added. The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give tert-butyl N-[1-[4-(2,6-dioxo-3-piperidyl)-3-fluoro-2-methoxy-phenyl]-3-methyl-azetidin-3-yl]carbamate (56.0 mg, 133 umol, 42% yield) as a white solid.

[0138] 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 7.42 - 7.28 (m, 1H), 6.79 (t, J = 8.1 Hz, 1H), 6.21 (d, J = 8.1 Hz, 1H), 3.93 - 3.83 (m, 3H), 3.73 (d, J = 7.9 Hz, 2H), 3.67 (s, 3H), 2.76 - 2.67 (m, 1H), 2.58 - 2.53 (m, 1H), 2.17 - 2.06 (m, 1H), 1.98 - 1.89 (m, 1H), 1.51 (s, 3H), 1.38 (s, 9H).

[0139] Step 2. Procedure for compound 3 3-(4-(3-amino-3-methylazetidin-1-yl)-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)-3-methylazetidin-3-yl)carbamate (48.0 mg, 114 μmol, 1.00 equiv.) in dichloromethane (2.00 mL) was added methanesulfonic acid (32.8 mg, 341 μmol, 24.3 μL, 3.00 equiv.). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give 3-[4-(3-amino-3-methyl-azetidin-1-yl)-2-fluoro-3-methoxy-phenyl]piperidine-2,6-dione (40.0 mg, crude) as a yellow oil. MS (ESI) m / z. 322.1 [M+H] +

[0140] Step 3. Procedure for compound 3A spiro[3.3]heptan-2-ylmethyl carbonochloridate. To a solution of spiro[3.3]heptan-2-ylmethanol (30.0 mg, 238 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added N,N-diisopropylethylamine (61.5 mg, 475 μmol, 82.8 μL, 2.00 equiv) and triphosgene (106 mg, 357 μmol, 1.5 equiv) at 0° C. The mixture was stirred at 20° C. for 1 hour. The mixture was concentrated under reduced pressure to give spiro[3.3]heptan-2-ylmethyl carbonochloridate (45 mg, crude) as a white solid.

[0141] Step 4. Procedure for spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)-3-methylazetidin-3-yl)carbamate. To a solution of 3-[4-(3-amino-3-methyl-azetidin-1-yl)-2-fluoro-3-methoxy-phenyl]piperidine-2,6-dione (40.0 mg, 124 μmol, 1.00 equiv.) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (16.1 mg, 124 μmol, 21.7 μL, 1.00 equiv.) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (45.0 mg, 238.54 μmol, 1.92 equiv.). The reaction mixture was stirred at 20° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (C18, 120 g; conditions: water / acetonitrile = 100:0 to 60:40, 0.1% formic acid) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)-3-methylazetidin-3-yl)carbamate (10.44 mg, 21.8 μmol, 17% yield, 99% purity) as a white solid.

[0142] 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (br s, 1H), 7.76 - 7.50 (m, 1H), 6.79 (t, J = 8.1 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 3.88 (br d, J = 6.8 Hz, 5H), 3.75 (d, J = 7.8 Hz, 2H), 3.67 (s, 3H), 2.75 - 2.66 (m, 1H), 2.54 - 2.51 (m, 1H), 2.34 (td, J = 7.5, 14.8 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.04 - 1.93 (m, 5H), 1.89 - 1.84 (m, 2H), 1.79 - 1.67 (m, 4H), 1.51 (s, 3H). MS (ESI) m / z. 474.3 [M+H] +

[0143] Example 3. Synthesis of Compound 3 [ka] Step 1. Procedure for the preparation of compound 2 (1R,2R,4S)-bicyclo[2.2.1]heptane-2-carboxylic acid. Palladium on carbon (50.0 mg, 10% purity) was added to a solution of (1S,2R,4S)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (50.0 mg, 362 μmol, 1.00 equiv) in methanol (1.00 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 20°C under a hydrogen atmosphere (15 psi) for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (1R,2R,4S)-bicyclo[2.2.1]heptane-2-carboxylic acid (50.0 mg, 357 μmol, 99% yield) as a colorless oil.

[0144] 1 H NMR (400 MHz, CHCl3-d) δ = 2.58 (br s, 1H), 2.39 (br dd, J = 5.4, 8.6 Hz, 1H), 2.33 (br s, 1H), 1.92 - 1.81 (m, 1H), 1.66 - 1.54 (m, 2H), 1.54 - 1.47 (m, 2H), 1.32 - 1.26 (m, 1H), 1.21 (br d, J = 8.8 Hz, 2H).

[0145] Step 2. Procedure for the preparation of compound 3 (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethanol. To a solution of (1R,2R,4S)-bicyclo[2.2.1]heptane-2-carboxylic acid (50.0 mg, 357 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added borane dimethyl sulfide complex (10.0 M, 71.3 μL, 2.00 equiv) at 0°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethanol (45.0 mg, 357 μmol, 99% yield) as a colorless oil.

[0146] 1H NMR (400 MHz, CHCl3-d) δ = 3.42 - 3.29 (m, 2H), 2.22 (br s, 1H), 2.17 (br s, 1H), 1.69 - 1.65 (m, 1H), 1.55 - 1.49 (m, 2H), 1.40 - 1.35 (m, 1H), 1.28 - 1.10 (m, 4H), 1.00 (ddd, J = 4.6, 7.2, 12.0 Hz, 1H).

[0147] Step 3. Procedure for the preparation of compound 4 (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl carbonochloridate. To a solution of (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethanol (45.0 mg, 357 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added bis(trichloromethyl)carbonate (106 mg, 357 μmol, 1.00 equiv) and N,N-diisopropylethylamine (184 mg, 1.43 mmol, 248 μL, 4.00 equiv) at 0° C. The reaction was then stirred at 20° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl carbonochloridate (65 mg, crude) as a yellow solid.

[0148] Step 4. Procedure for the preparation of (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (111 mg, 284 μmol, 1.00 equiv, mesylate salt) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (134 mg, 1.03 mmol, 180 μL, 3.00 equiv) and (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl carbonochloridate (65.0 mg, crude). The reaction was then stirred at 0° C. for 0.15 hours. The reaction mixture was diluted with N,N-dimethylformamide (1.00 mL) and filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give (1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (50.00 mg, 110.62 μmol, 32.11% yield, 99% purity) as a white solid.

[0149] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.83 (br d, J = 7.1 Hz, 1H), 6.14 (d, J = 11.1 Hz, 2H), 4.50 - 4.30 (m, 1H), 4.08 (br t, J = 7.7 Hz, 2H), 4.03 (br dd, J = 5.1, 12.8 Hz, 1H), 3.77 - 3.66 (m, 2H), 3.63 (br t, J = 6.8 Hz, 2H), 2.85 - 2.70 (m, 1H), 2.48 (br s, 1H), 2.18 (br s, 1H), 2.12 - 2.02 (m, 2H), 1.99 - 1.89 (m, 1H), 1.76 - 1.64 (m, 1H), 1.53 - 1.40 (m, 2H), 1.36 - 1.25 (m, 2H), 1.19 - 0.96 (m, 4H). MS (ESI) m / z 448.2 [M+H] +

[0150] Example 4. Synthesis of Compound 4 [ka] Step 1. Procedure for the preparation of compound 2, 3-hydroxy-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide. To a solution of 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 780 μmol, 1.00 equiv.) in dimethylformamide (1.00 mL), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (356.12 mg, 936.58 μmol, 1.2 equiv.) and N,N-diisopropylethylamine (403 mg, 3.12 mmol, 544 μL, 4.00 equiv.) were added at 25°C to obtain mixture A. To a solution of N,O-dimethylhydroxylamine (91.4 mg, 937 μmol, 1.20 equiv., hydrochloride salt) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (202 mg, 1.56 mmol, 272 μL, 2.00 equiv.) to obtain mixture B. Mixture B was added to mixture A at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain 3-hydroxy-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (50.0 mg, 292 μmol, 37.42% yield) as a colorless oil.

[0151] 1 H NMR (400 MHz, CDCl3-d) δ = 3.67 (s, 3H), 3.20 (s, 3H), 2.30 - 2.23 (m, 6H).

[0152] Step 2. Procedure for the preparation of compound 3 (3-hydroxybicyclo[1.1.1]pentan-1-yl)(phenyl)methanone. A solution of 3-hydroxy-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (210 mg, 1.23 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) was degassed and purged with nitrogen. The resulting clear solution was cooled to 0 °C. Phenylmagnesium bromide solution (3 M, 1.23 mL, 3.00 equiv) was then added dropwise to the mixture via syringe. After 20 min, the mixture was warmed to 25 °C for 6 h. The reaction mixture was quenched with ammonium chloride (10.0 mL) at 0 °C and extracted with 20 mL of ethyl acetate (10 mL * 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1) to give (3-hydroxybicyclo[1.1.1]pentan-1-yl)(phenyl)methanone (160 mg, 850 umol, yield 69.0%) as a pale yellow oil.

[0153] 1 H NMR (400 MHz, CDCl3-d) δ = 7.88 (d, J = 7.6 Hz, 2H), 7.51 - 7.46 (m, 1H), 7.42 - 7.35 (m, 2H), 2.38 (s, 6H)

[0154] Step 3. Procedure for the preparation of compound 4, 3-benzoylbicyclo[1.1.1]pentan-1-yl carbonochloridate. To a solution of (3-hydroxybicyclo[1.1.1]pentan-1-yl)(phenyl)methanone (60.0 mg, 319 μmol, 1.00 equiv) in dichloromethane (2.00 mL) was added triphosgene (151 mg, 510 μmol, 1.60 equiv) and N,N-diisopropylethylamine (82.4 mg, 638 μmol, 111 μL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give 3-benzoylbicyclo[1.1.1]pentan-1-ylcarbonochloridate (70.0 mg, 279 μmol, 88% yield) as a yellow solid.

[0155] Step 4. Procedure for the preparation of compound 4 1-(methyl(p-tolyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 256 μmol, 1.00 equiv, methanesulfonic acid) in dichloromethane (3.00 mL) was added N,N-diisopropylethylamine (33.0 mg, 256 μmol, 44.5 μL, 1.00 equiv) and 3-benzoylbicyclo[1.1.1]pentan-1-ylcarbonochloridate (70 mg, 279 μmol, 1.09 equiv). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give 1-(methyl(p-tolyl)carbamoyl)azetidin-3-yl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (11.29 mg, 21.72 μmol, yield 8.50%, purity 98%) as a white solid.

[0156] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 7.4 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.58 - 7.51 (m, 2H), 6.16 (d, J = 11.0 Hz, 2H), 4.50 - 4.36 (m, 1H), 4.11 (t, J = 7.7 Hz, 2H), 4.04 (br dd, J = 5.2, 12.8 Hz, 1H), 3.70 - 3.60 (m, 2H), 2.84 - 2.73 (m, 1H), 2.59 (s, 6H), 2.55 - 2.54 (m, 1H), 2.15 - 2.03 (m, 1H), 2.01 - 1.90 (m, 1H). MS (ESI) m / z 510.3 [M+H] +

[0157] Example 5. Synthesis of Compound 5 [ka] Step 1. Preparation of compound 2, isoindoline-2-carbonyl chloride. To a solution of isoindoline (950 mg, 7.97 mmol, 904 uL, 1.00 equiv) in dichloromethane (10.0 mL) was added triphosgene (2.84 g, 9.57 mmol, 1.20 equiv) and N,N-diisopropylethylamine (1.55 g, 11.9 mmol, 2.08 mL, 1.50 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give isoindoline-2-carbonyl chloride (1.50 g, crude) as a yellow solid.

[0158] Step 2. Procedure for the preparation of compound 3 (3-hydroxyazetidin-1-yl)(isoindolin-2-yl)methanone. To a solution of isoindoline-2-carbonyl chloride (1.45 g, 7.98 mmol, 1.00 equiv.) in dimethylformamide (10.0 mL) were added potassium carbonate (8.83 g, 64.0 mmol, 8.00 equiv.) and azetidin-3-ol (1.75 g, 15.97 mmol, 2.00 equiv., hydrochloride salt). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 3 to 0 / 1) to give (3-hydroxyazetidin-1-yl)(isoindolin-2-yl)methanone (700 mg, 3.21 mmol, 40% yield) as an off-white solid.

[0159] 1 H NMR (400MHz, DMSO-d6) δ = 7.33 - 7.26 (m, 4H), 4.61 (s, 4H), 4.45 - 4.39 (m, 1H), 4.15 (d, J = 7.9 Hz, 2H), 3.74 (dd, J = 4.9, 8.8 Hz, 2H), 3.60 (dt, J = 3.8, 6.4Hz, 1H)

[0160] Step 3. Procedure for the preparation of 1-(isoindoline-2-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (3-hydroxyazetidin-1-yl)(isoindolin-2-yl)methanone (100 mg, 275 μmol, 60% purity, 1.00 equiv.) in tetrahydrofuran (2.00 mL) was added 1,1'-carbonyldiimidazole (66.9 mg, 412 μmol, 1.50 equiv.). The mixture was stirred at 25°C for 1 hour to obtain a solution. To the resulting solution was added a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (107 mg, 273 μmol, 1.00 equiv., mesylate salt) and N,N-diisopropylethylamine (53.0 mg, 410 μmol, 71.4 μL, 1.50 equiv.) in dimethylformamide (1.00 mL). The mixture was stirred at 25°C for 12 hours. The mixture was purified by preparative HPLC (Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 31% to 61%, 9 min) and lyophilized to give 1-(isoindoline-2-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (17.53 mg, 32.17 umol, 11% yield, 99% purity) as a white solid.

[0161] 1H NMR (400 MHz, DMSO-d6) δ =10.87 - 10.81 (m, 1H), 8.13 (br d, J = 7.1 Hz, 1H), 7.34 - 7.23 (m, 4H), 6.16 (br d, J = 11.1 Hz, 2H), 5.09 - 5.00 (m, 1H), 4.62 (s, 4H), 4.49 - 4.39 (m, 1H), 4.29 (dd, J = 6.9, 9.3 Hz, 2H), 4.11 (br t, J = 7.6 Hz, 2H), 4.03 (br dd, J = 4.9, 12.4 Hz, 1H), 3.89 (br dd, J = 3.8, 9.3 Hz, 2H), 3.66 (br t, J = 6.6 Hz, 2H), 2.83 - 2.71 (m, 1H), 2.47 - 2.41 (m, 1H), 2.13 - 2.03 (m, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 539.9 [M+H] +

[0162] Example 6. Synthesis of Compound 6 [ka] Step 1. Procedure for the preparation of compound 2, 1-(4-methylpyridin-2-yl)azetidin-3-ol. To a solution of 2-fluoro-4-methylpyridine (500 mg, 4.50 mmol, 1.00 equiv) in dimethyl sulfoxide (5.00 mL) was added azetidin-3-ol (592 mg, 5.40 mmol, 1.20 equiv, hydrochloride salt) and cesium carbonate (2.93 g, 9.00 mmol, 2.00 equiv). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give 1-(4-methylpyridin-2-yl)azetidin-3-ol (730 mg, 4.45 mmol, 98% yield) as a colorless oil.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.89 (d, J = 5.1 Hz, 1H), 6.45 (d, J = 4.9 Hz, 1H), 6.19 (s, 1H), 4.58 - 4.51 (m, 1H), 4.10 (s, 2H), 3.63 - 3.60 (m, 2H), 2.19 (s, 3H). MS (ESI) m / z 165.4 [M+H] +

[0164] Step 2. Procedure for the preparation of 1-(4-methylpyridin-2-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(4-methylpyridin-2-yl)azetidin-3-ol (300 mg, 1.83 mmol, 1.00 equiv) in tetrahydrofuran (4.00 mL) was added 1,1'-carbonyldiimidazole (311 mg, 1.92 mmol, 1.05 equiv), and the mixture was stirred at 25°C for 0.5 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (474 ​​mg, 1.21 mmol, 1.00 equiv., methanesulfonic acid), triethylamine (123 mg, 1.21 mmol, 168 μL, 1.00 equiv.), and 1,8-diazabicyclo[5.4.0]undec-7-ene (184 mg, 1.21 mmol, 182 μL, 1.00 equiv.) in dimethylformamide (2.00 mL). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give the crude product. The crude product was triturated with water (10.0 mL) and filtered. The filter cake was washed with petroleum ether (3 x 5.00 ml) and lyophilized to give 1-(4-methylpyridin-2-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (19.18 mg, 39.1 umol, 3.22% yield, 99.0% purity) as a white solid.

[0165] 1H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 8.23 ​​(br d, J = 7.3 Hz, 1H), 7.90 (d, J = 6.4 Hz, 1H), 6.87 - 6.65 (m, 2H), 6.17 (br d, J = 11.1 Hz, 2H), 5.29 - 5.15 (m, 1H), 4.59 - 4.50 (m, 2H), 4.49 - 4.40 (m, 1H), 4.20 - 4.14 (m, 2H), 4.14 - 4.08 (m, 2H), 4.04 (br dd, J = 4.9, 12.5 Hz, 1H), 3.67 (br t, J = 6.8 Hz, 2H), 2.85 - 2.73 (m, 1H), 2.50 - 2.47 (m, 1H), 2.36 (s, 3H), 2.15 - 2.02 (m, 1H), 2.00 - 1.90 (m, 1H). MS (ESI) m / z 486.4 [M+H] +

[0166] Example 7. Synthesis of Compound 7 [ka] Step 1. Procedure for the preparation of compound 2, 5-(3-(benzyloxy)azetidin-1-yl)-1-methyl-1H-pyrazole. To a solution of 5-bromo-1-methyl-1H-pyrazole (100 mg, 621 μmol, 1.00 equiv) in toluene (4.00 mL), 3-(benzyloxy)azetidine hydrochloride (62.0 mg, 311 μmol, 0.500 equiv, hydrochloric acid), cesium carbonate (809 mg, 2.48 mmol, 4.00 equiv), tris(dibenzylideneacetone)dipalladium(0) (56.9 mg, 62.1 μmol, 0.100 equiv), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (77.4 mg, 124 μmol, 0.200 equiv) were added. The mixture was stirred at 110°C for 16 hours. The reaction mixture was quenched with water (10.0 mL) at 20°C and extracted with ethyl acetate (20.0 mL). The combined organic layers were washed with water (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 5-(3-(benzyloxy)azetidin-1-yl)-1-methyl-1H-pyrazole (90.0 mg, 370 μmol, 60% yield) as a yellow oil.

[0167] 1 H NMR (400 MHz, CDCl3) δ = 7.41 - 7.30 (m, 5H), 7.28 (d, J = 1.9 Hz, 1H), 5.54 (d, J = 2.0 Hz, 1H), 4.51 (s, 2H), 4.49 - 4.41 (m, 1H), 4.08 - 3.99 (m, 2H), 3.76 - 3.69 (m, 2H), 3.63 (s, 3H)

[0168] Step 2. Procedure for the preparation of compound 3, 1-(1-methyl-1H-pyrazol-5-yl)azetidin-3-ol. To a solution of 5-(3-(benzyloxy)azetidin-1-yl)-1-methyl-1H-pyrazole (50.0 mg, 206 μmol, 1.00 equiv.) in dioxane (1.00 mL) was added palladium on activated carbon (50.0 mg, 60% purity, 1.00 equiv.). The mixture was stirred under a hydrogen atmosphere at 40° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give 1-(1-methyl-1H-pyrazol-5-yl)azetidin-3-ol (100 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0169] Step 3. Procedure for the preparation of 1-(1-methyl-1H-pyrazol-5-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(1-methyl-1H-pyrazol-5-yl)azetidin-3-ol (30 mg, 196 μmol, 1.00 equiv.) in tetrahydrofuran (0.50 mL) was added di(1H-imidazol-1-yl)methanone (38.1 mg, 235 μmol, 1.20 equiv.). The mixture was stirred at 25° C. for 0.5 hours. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (76.7 mg, 196 μmol, 1.00 equiv., methanesulfonic acid) and N,N-diisopropylethylamine (75.9 mg, 588 μmol, 102 μL, 3.00 equiv.) in dimethylformamide (1.00 mL). The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography (C18, 40 g, conditions: water / acetonitrile = 100:0 to 0:1, 0.1% formic acid) and lyophilized to give 1-(1-methyl-1H-pyrazol-5-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (10.29 mg, 21.69 μmol, yield 11.07%) as a white solid.

[0170] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.13 (br d, J = 7.1 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 6.15 (d, J = 11.1 Hz, 2H), 5.59 (d, J = 1.3 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.43 (br d, J = 7.3 Hz, 1H), 4.18 - 4.07 (m, 4H), 4.03 (br dd, J = 5.1, 12.4 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.65 (br t, J = 6.9 Hz, 2H), 3.52 (s, 3H), 2.83 - 2.72 (m, 1H), 2.62 - 2.57 (m, 1H), 2.13 - 2.01 (m, 1H), 1.99 - 1.88 (m, 1H). MS (ESI) m / z.475.2 [M+H] +

[0171] Example 8. Synthesis of Compound 8 [ka] Step 1. Procedure for Compound 1A (3-chlorophenyl)(methyl)carbamic acid chloride. To a solution of 3-chloro-N-methylaniline (45.0 mg, 318 μmol, 38.8 μL, 1.00 equiv) in dichloromethane (5.00 mL) was added N,N-diisopropylethylamine (82.2 mg, 636 μmol, 111 μL, 2.00 equiv) and bis(trichloromethyl)carbonate (151 mg, 508 μmol, 1.60 equiv) at 25° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give (3-chlorophenyl)(methyl)carbamic acid chloride (64.0 mg, 314 μmol, 99% yield) as a brown solid.

[0172] Step 2. Procedure for compound 2 azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (100 mg, 202 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 66.8 equiv) at 0° C. The mixture was stirred at 20° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (102 mg, crude, trifluoroacetic acid) as a colorless oil.

[0173] Step 3. Procedure for 1-((3-chlorophenyl)(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (102 mg, 201 μmol, 1.00 equiv., trifluoroacetic acid) in dichloromethane (3.00 mL) was added N,N-diisopropylethylamine (77.8 mg, 602 μmol, 105 μL, 3.00 equiv.) and (3-chlorophenyl)(methyl)carbamic acid chloride (49.1 mg, 241 μmol, 1.20 equiv.). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 32% to 62%, 10 min) and lyophilized to give 1-((3-chlorophenyl)(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (27.53 mg, 51.6 umol, 25.7% yield) as an off-white solid.

[0174] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.06 (br d, J = 7.3 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.26 (br dd, J = 8.3, 15.8 Hz, 2H), 6.13 (br d, J = 11.1 Hz, 2H), 4.89 - 4.82 (m, 1H), 4.43 - 4.31 (m, 1H), 4.11 - 4.01 (m, 3H), 3.87 - 3.79 (m, 2H), 3.60 (br t, J = 6.7 Hz, 2H), 3.43 (br dd, J = 3.3, 9.3 Hz, 2H), 3.14 (s, 3H), 2.82 - 2.72 (m, 1H), 2.56 - 2.53 (m, 1H), 2.10 - 2.01 (m, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 562.4 [M+H] +

[0175] Example 9. Synthesis of Compound 9 [ka] Step 1. Procedure for compound 2 indoline-1-carbonyl chloride. To a solution of indoline (30.0 mg, 252 μmol, 28.3 μL, 1.00 equiv) in dichloromethane (1.00 mL) was added N,N-diisopropylethylamine (48.8 mg, 378 μmol, 65.8 μL, 1.50 equiv) and triphosgene (112 mg, 378 μmol, 1.50 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give indoline-1-carbonyl chloride (45.0 mg, 248 μmol, 98% yield) as a yellow oil.

[0176] Step 2. Procedure for 1-(indoline-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (102 mg, 201 μmol, 1.00 equiv, trifluoroacetic acid) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (51.9 mg, 401 μmol, 69.9 μL, 2.00 equiv) and indoline-1-carbonyl chloride (40.1 mg, 221 μmol, 1.10 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 33% to 63%, 10 min) and lyophilized to give 1-(indoline-1-carbonyl)azetidin-3-yl-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (36.23 mg, 66.48 umol, yield 33%, purity 99%) as a white solid.

[0177] 1H NMR (400 MHz, DMSO-d6) δ =10.86 (s, 1H), 8.14 (br d, J = 7.4 Hz, 1H), 7.62 (br d, J = 7.9 Hz, 1H), 7.17 (br d, J = 7.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.15 (br d, J = 11.3 Hz, 2H), 5.18 - 4.98 (m, 1H), 4.49 - 4.36 (m, 1H), 4.35 - 4.25 (m, 2H), 4.10 (br t, J = 7.6 Hz, 2H), 4.03 (br dd, J = 5.1, 12.4 Hz, 1H), 3.95 - 3.84 (m, 4H), 3.66 (br t, J = 6.6 Hz, 2H), 3.08 (br t, J = 8.4 Hz, 2H), 2.82 - 2.72 (m, 1H), 2.48 - 2.46 (m, 1H), 2.11 - 2.00 (m, 1H), 1.99 - 1.88 (m, 1H). MS (ESI) m / z.540.4 [M+H] +

[0178] Example 10. Synthesis of Compound 10 [ka] Step 1. Procedure for the preparation of compound 2A methyl(m-tolyl)carbamic acid chloride. To a solution of N,3-dimethylaniline (30.0 mg, 247 μmol, 30.9 μL, 1.00 equiv) in dichloromethane (2.00 mL) was added N,N-diisopropylethylamine (96.0 mg, 743 μmol, 129 μL, 3.00 equiv) and bis(trichloromethyl)carbonate (95.5 mg, 321 μmol, 1.30 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give methyl (m-tolyl)carbamic acid chloride (40.0 mg, crude) as a colorless oil.

[0179] Step 2. Procedure for preparation of compound 2, azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (100 mg, 202 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 66.8 equiv). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (70.0 mg, 177 μmol, 87% yield) as a yellow oil.

[0180] Step 3. Procedure for preparation of 1-(methyl(m-tolyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (70.0 mg, 177 μmol, 1.00 equiv.) in dichloromethane (1.00 mL) was added N,N-diisopropylethylamine (45.9 mg, 355 μmol, 61.8 μL, 2.00 equiv.) and methyl (m-tolyl)carbamic acid chloride (39.1 mg, 213 μmol, 1.20 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 35% to 65%, 9 min) to give 1-(methyl(m-tolyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (20.59 mg, 35.9 umol, yield 20.2%, purity 94%) as a yellow solid.

[0181] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.03 (br d, J = 7.5 Hz, 1H), 7.31 - 7.23 (m, 1H), 7.13 - 6.99 (m, 3H), 6.13 (br d, J = 11.1 Hz, 2H), 4.85 - 4.74 (m, 1H), 4.43 - 4.27 (m, 1H), 4.11 - 4.04 (m, 2H), 4.04 - 3.98 (m, 1H), 3.80 - 3.69 (m, 2H), 3.59 (br t, J = 6.7 Hz, 2H), 3.35 (br d, J = 3.5 Hz, 2H), 3.11 (s, 3H), 2.83 - 2.72 (m, 1H), 2.47 (br s, 1H), 2.31 (s, 3H), 2.13 - 2.02 (m, 1H), 1.98 - 1.88 (m, 1H). MS (ESI) m / z 542.1 [M+H] +

[0182] Example 11. Synthesis of Compound 11 [ka] Step 1. Procedure for the preparation of compound 2 tert-butyl 3-((phenoxycarbonyl)amino)-3-(trifluoromethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-amino-3-(trifluoromethyl)azetidine-1-carboxylate (500 mg, 2.08 mmol, 1.00 equiv) in acetonitrile (3.00 mL) was added pyridine (494 mg, 6.24 mmol, 504 μL, 3.00 equiv) and phenyl carbonochloridate (391 mg, 2.50 mmol, 313 μL, 1.20 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (20.0 mL) at 25° C. for 30 minutes to give tert-butyl 3-((phenoxycarbonyl)amino)-3-(trifluoromethyl)azetidine-1-carboxylate (600 mg, crude) as a white solid.

[0183] 1 H NMR (400 MHz, DMSO-d6) δ = 9.09 (br s, 1H), 7.44 - 7.35 (m, 2H), 7.28 - 7.20 (m, 1H), 7.17 (br d, J = 7.9 Hz, 2H), 4.19 (br s, 2H), 4.06 (br d, J = 9.6 Hz, 2H), 1.40 (s, 9H).

[0184] Step 2. Procedure for the preparation of compound 3 tert-butyl 3-((((1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl)oxy)carbonyl)amino)-3-(trifluoromethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-(phenoxycarbonylamino)-3-(trifluoromethyl)azetidine-1-carboxylate (500 mg, 1.39 mmol, 1.00 equiv.) in N,N-dimethylformamide (5.00 mL) was added N-cyclopropyl-3-hydroxy-N-methylazetidine-1-carboxamide (283 mg, 1.67 mmol, 1.20 equiv.) and sodium hydride (111 mg, 2.78 mmol, 60% purity, 2.00 equiv.) at 0° C. The reaction was stirred at 25° C. for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine (10.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (C18, 40 g, conditions: water / acetonitrile = 7 / 3 to 1 / 1, 0.1% formic acid) and lyophilized to give tert-butyl 3-((((1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl)oxy)carbonyl)amino)-3-(trifluoromethyl)azetidine-1-carboxylate (277 mg, 635 μmol, 46% yield) as a white solid.

[0185] 1 H NMR (400 MHz, DMSO-d6) δ = 8.69 (br s, 1H), 5.08 - 4.99 (m, 1H), 4.23 (br dd, J = 6.8, 9.5 Hz, 2H), 4.14 - 4.07 (m, 2H), 4.01 (br d, J = 9.6 Hz, 2H), 3.85 (br dd, J = 3.6, 9.6 Hz, 2H), 2.73 (s, 3H), 2.56 (br dd, J = 3.4, 6.8 Hz, 1H), 1.39 (s, 9H), 0.75 - 0.69 (m, 2H), 0.64 - 0.59 (m, 2H).

[0186] Step 3. Procedure for the preparation of compound 4 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (3-(trifluoromethyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-((((1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl)oxy)carbonyl)amino)-3-(trifluoromethyl)azetidine-1-carboxylate (277 mg, 635 μmol, 1.00 equiv.) in dichloromethane (3.00 mL) was added trifluoroacetic acid (924 mg, 8.10 mmol, 0.600 mL, 12.8 equiv.). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl(3-(trifluoromethyl)azetidin-3-yl)carbamate (213 mg, crude) as a yellow oil, which was used directly in the next step. MS (ESI) m / z. 337.1 [M+H] +

[0187] Step 4. Procedure for the preparation of 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-(trifluoromethyl)azetidin-3-yl)carbamate. To a solution of 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (3-(trifluoromethyl)azetidin-3-yl)carbamate (213 mg, 633 umol, 1.00 equiv.) in dioxane (5.00 mL), 3-(4-bromo-2,6-difluoro-phenyl)piperidine-2,6-dione (289 mg, 950 umol, 1.50 equiv.), cesium carbonate (619 mg, 1.90 mmol, 3.00 equiv.) and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (61.6 mg, 63.3 umol, 0.100 equiv.) were added. The reaction mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) and concentrated under reduced pressure to obtain a yellow solid. The yellow solid was purified by preparative HPLC (column: Phenomenex C18 150*25mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 48% to 78%, 8 min) and lyophilized to obtain the crude product. The crude product was triturated with acetonitrile (10.0 ml) at 25° C. for 1 hour to give 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-(trifluoromethyl)azetidin-3-yl)carbamate (33.53 mg, 59.33 μmol, 9.37% yield, 99% purity) as a white solid.

[0188] 1H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 8.77 (br s, 1H), 6.31 (d, J = 10.9 Hz, 2H), 5.12 - 4.89 (m, 1H), 4.25 - 4.15 (m, 4H), 4.05 (br d, J = 8.6 Hz, 3H), 3.85 (dd, J = 3.9, 9.9 Hz, 2H), 2.82 - 2.76 (m, 1H), 2.72 (s, 3H), 2.58 - 2.53 (m, 2H), 2.10 - 2.03 (m, 1H), 1.98 - 1.90 (m, 1H), 0.75 - 0.68 (m, 2H), 0.64 - 0.57 (m, 2H). MS (ESI) m / z.559.9 [M+H] +

[0189] Example 12. Synthesis of Compound 12 [ka] Step 1. Procedure for the preparation of compound 2, phenyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate. To a solution of 3-(4-(3-amino-3-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (400 mg, 1.29 mmol, 1.00 equiv) in acetonitrile (2.00 mL) was added 4-dimethylaminopyridine (15.8 mg, 129 µmole, 0.100 equiv), triethylamine (393 mg, 3.88 mmol, 540 µL, 3.00 equiv), and phenyl carbonochloridate (243 mg, 1.55 mmol, 194 µL, 1.20 equiv). The mixture was stirred at 20° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give phenyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (62.0 mg, 144 umol, 11% yield) as a white solid.

[0190] 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.39 (s, 1H), 7.37 (br d, J = 7.9 Hz, 2H), 7.26 - 7.18 (m, 2H), 7.13 (br s, 1H), 6.18 (br d, J = 11.1 Hz, 2H), 4.03 (br dd, J = 5.1, 12.9 Hz, 1H), 3.97 (br d, J = 7.9 Hz, 2H), 3.76 (br d, J = 7.6 Hz, 2H), 2.81 - 2.74 (m, 1H), 2.63 - 2.54 (m, 1H), 2.10 - 2.04 (m, 1H), 1.96 - 1.90 (m, 1H), 1.57 (s, 3H)

[0191] Step 2. Procedure for the preparation of 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate. To a solution of N-cyclopropyl-3-hydroxy-N-methylazetidine-1-carboxamide (28.5 mg, 168 μmol, 1.20 equiv.) in dimethylformamide (1.00 mL) was added sodium hydride (67.1 mg, 279 μmol, 60% purity, 2.00 equiv.) at 0° C. The mixture was stirred at 25° C. for 0.5 hours. To the resulting solution was added phenyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (60.0 mg, 140 μmol, 1 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with water (1.00 mL) and concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25% to 55%, 10 min) and lyophilized to give 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (13.65 mg, 24.50 umol, yield 17.54%, purity 96%, formic acid) as a white solid.

[0192] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.52 - 8.43 (m, 1H), 8.17 - 7.81 (m, 1H), 6.14 (d, J = 11.1 Hz, 2H), 5.16 - 4.85 (m, 1H), 4.22 (dd, J = 6.8, 9.6 Hz, 2H), 4.03 (br dd, J = 4.9, 12.2 Hz, 1H), 3.88 (br d, J = 7.5 Hz, 2H), 3.81 (dd, J = 3.9, 9.6 Hz, 2H), 3.71 (br d, J = 7.4 Hz, 2H), 2.83 - 2.74 (m, 1H), 2.72 (s, 3H), 2.60 - 2.55 (m, 1H), 2.55 - 2.53 (m, 1H), 2.13 - 2.01 (m, 1H), 1.97 - 1.85 (m, 1H), 1.50 (s, 3H), 0.78 - 0.66 (m, 2H), 0.65 - 0.55 (m, 2H). MS (ESI) m / z.506.3 [M+H] +

[0193] Example 13. Synthesis of Compound 13 [ka] Step 1. Procedure for compound 2A (4-methoxyphenyl)(methyl)carbamic acid chloride. To a mixture of 4-methoxy-N-methylaniline (45.0 mg, 328 μmol, 1.00 equiv) and N,N-diisopropylethylamine (84.8 mg, 656 μmol, 114 μL, 2.00 equiv) in dichloromethane (2.00 mL) was added triphosgene (195 mg, 656 μmol, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give (4-methoxyphenyl)(methyl)carbamic acid chloride (65.0 mg, crude) as a yellow oil.

[0194] Step 2. Procedure for compound 2 azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. A solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (126 mg, 255 μmol, 1.00 equiv) in trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL) was added at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (100 mg, crude) as a yellow oil. MS (ESI) m / z. 395.2 [M+H]+

[0195] Step 3. Procedure for 3-(2,6-dichloro-4-(3-((5-(spiro[3.3]heptan-2-yl)-1,3,4-oxadiazol-2-yl)amino)azetidin-1-yl)phenyl)piperidine-2,6-dione. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (100 mg, 254 μmol, 1.00 equiv.) in dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (65.5 mg, 507 μmol, 88.3 μL, 2.00 equiv.) and (4-methoxyphenyl)(methyl)carbamic acid chloride (60.7 mg, 304 μmol, 1.20 equiv.) at 25° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 1) to give 1-((4-methoxyphenyl)(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (35.23 mg, 60.0 μmol, 23% yield, 95% purity) as a white solid.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.03 (br d, J = 7.4 Hz, 1H), 7.18 (br d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.13 (br d, J = 11.0 Hz, 2H), 4.85 - 4.72 (m, 1H), 4.43 - 4.25 (m, 1H), 4.08 - 4.03 (m, 2H), 4.01 (br d, J = 5.0 Hz, 1H), 3.76 (s, 3H), 3.72 - 3.65 (m, 2H), 3.59 (br t, J = 6.6 Hz, 2H), 3.31 - 3.29 (m, 2H), 3.07 (s, 3H), 2.81 - 2.72 (m, 1H), 2.40 (br s, 1H), 2.10 - 2.01 (m, 1H), 1.96 - 1.91 (m, 1H)。

[0197] 1 H NMR (400 MHz, DMSO-d6) δ = 7.16 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.11 (br d, J = 11.0 Hz, 2H), 4.79 - 4.72 (m, 1H), 4.39 - 4.29 (m, 1H), 4.04 (br t, J = 8.0 Hz, 2H), 3.99 (br d, J = 4.6 Hz, 1H), 3.74 (s, 3H), 3.71 - 3.66 (m, 2H), 3.58 (br s, 2H), 3.30 (br dd, J = 3.4, 9.7 Hz, 2H), 3.05 (s, 3H), 2.80 - 2.70 (m, 1H), 2.60 - 2.53 (m, 1H), 2.10 - 1.99 (m, 1H), 1.97 - 1.89 (m, 1H)。MS (ESI) m / z.558.4 [M+H] +

[0198] Example 14. Synthesis of Compound 14 [ka] Step 1. Procedure for the preparation of 1-(dimethylcarbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate. To a solution of 3-hydroxy-N,N-dimethylazetidine-1-carboxamide (53.0 mg, 368 μmol, 1.00 equiv.) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (71.5 mg, 441 μmol, 1.20 equiv.), and the mixture was stirred at 25° C. for 1 hour. The resulting solution was added to a solution of 3-(4-(3-amino-3-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (148 mg, 366 μmol, 1.00 equiv, mesylate salt), triethylamine (56.0 mg, 549 μmol, 76.5 μL, 1.50 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (83.6 mg, 549 μmol, 82.8 μL, 1.50 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 1-(dimethylcarbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (6.13 mg, 11.76 μmol, 3% yield, 92% purity) as an off-white solid.

[0199] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.41 - 8.36 (m, 1H), 8.04 - 7.96 (m, 1H), 6.19 - 6.10 (m, 2H), 5.04 - 4.92 (m, 1H), 4.20 - 4.10 (m, 2H), 4.06 - 4.00 (m, 1H), 3.88 (br d, J = 7.5 Hz, 2H), 3.78 - 3.69 (m, 4H), 2.85 - 2.77 (m, 1H), 2.74 (s, 6H), 2.59 - 2.56 (m, 1H), 2.09 - 2.05 (m, 1H), 1.96 - 1.91 (m, 1H), 1.50 (s, 3H). MS (ESI) m / z.480.4 [M+H] +

[0200] Example 15. Synthesis of Compound 15 [ka] Step 1. Procedure for the preparation of compound 10, cyclopropyl(methyl)carbamic acid chloride. To a solution of N-methylcyclopropanamine (3.00 g, 42.2 mmol, 1.00 equiv) in dichloromethane (20.0 mL) was added bis(trichloromethyl)carbonate (20.0 g, 67.6 mmol, 1.60 equiv) and N,N-diisopropylethylamine (10.9 g, 84.4 mmol, 14.7 mL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give cyclopropyl(methyl)carbamic acid chloride (5.00 g, crude) as a brown solid.

[0201] Step 2. Procedure for the preparation of compound 8A N-cyclopropyl-3-hydroxy-N-methylazetidine-1-carboxamide. To a solution of azetidin-3-ol (4.51 g, 41.1 mmol, 1.10 equiv., hydrochloride salt) in dichloromethane (50.0 mL), N,N-diisopropylethylamine (9.68 g, 74.8 mmol, 13.0 mL, 2.00 equiv.) and potassium carbonate (5.17 g, 37.4 mmol, 1.00 equiv.) were added at 0° C., and then cyclopropyl(methyl)carbamic acid chloride (5.00 g, 37.4 mmol, 1.00 equiv.) was added to the mixture. The mixture was stirred at 25° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give N-cyclopropyl-3-hydroxy-N-methylazetidine-1-carboxamide (1.00 g, 5.88 mmol, 16% yield) as a yellow oil.

[0202] 1 H NMR (400 MHz, DMSO-d6) δ =5.51 (d, J = 6.1 Hz, 1H), 4.40 - 4.30 (m, 1H), 4.11 - 4.03 (m, 2H), 3.66 (dd, J = 4.8, 8.9 Hz, 2H), 2.71 (s, 3H), 2.54 (d, J = 3.5 Hz, 1H), 0.74 - 0.67 (m, 2H), 0.66 - 0.56 (m, 2H).

[0203] Step 3. Preparation procedure for compound 2 (4-bromo-2-fluoro-6-methylphenyl)methanol. To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (2.00 g, 8.58 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added borane dimethyl sulfide complex (10.0 M, 1.72 mL, 2.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with methanol (20 mL) at 0 °C and concentrated under reduced pressure to give (4-bromo-2-fluoro-6-methylphenyl)methanol (1.81 g, 8.26 mmol, 96% yield) as a white solid.

[0204] Step 4. Preparation procedure for compound 3, 5-bromo-2-(chloromethyl)-1-fluoro-3-methylbenzene. To a solution of (4-bromo-2-fluoro-6-methylphenyl)methanol (1.80 g, 8.22 mmol, 1.00 equiv.) in dichloromethane (20.0 mL) was added sulfurous dichloride (1.96 g, 16.4 mmol, 1.19 mL, 2.00 equiv.) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=80 / 1) to give 5-bromo-2-(chloromethyl)-1-fluoro-3-methylbenzene (1.53 g, 6.45 mmol, 78% yield) as a pale yellow oil.

[0205] 1 H NMR (400 MHz, CDCl3) δ = 7.19 (s, 1H), 7.14 (d, J = 9.1 Hz, 1H), 4.62 (s, 2H), 2.43 (s, 3H).

[0206] Step 5. Procedure for the preparation of compound 4, 2-(4-bromo-2-fluoro-6-methylphenyl)acetonitrile. To a solution of 5-bromo-2-(chloromethyl)-1-fluoro-3-methylbenzene (1.53 g, 6.45 mmol, 1.00 equiv.) in acetonitrile (15.0 mL) were added tetrabutylammonium fluoride (1.00 M, 19.3 mL, 3.00 equiv.) and trimethylsilanecarbonitrile (1.92 g, 19.3 mmol, 2.42 mL, 3.00 equiv.) at 0 °C. The mixture was stirred at 80 °C for 3 h. The reaction mixture was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 80 / 1) to give 2-(4-bromo-2-fluoro-6-methylphenyl)acetonitrile (1.50 g, crude) as a colorless oil.

[0207] Step 6. Procedure for the preparation of compound 5, methyl 4-(4-bromo-2-fluoro-6-methylphenyl)-4-cyanobutanoate. To a solution of 2-(4-bromo-2-fluoro-6-methylphenyl)acetonitrile (1.20 g, 5.26 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) was added sodium methoxide (56.8 mg, 1.05 mmol, 0.200 equiv) and methyl acrylate (498 mg, 5.79 mmol, 521 μL, 1.10 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give methyl 4-(4-bromo-2-fluoro-6-methylphenyl)-4-cyanobutanoate (1.30 g, 4.15 mmol, 87% yield) as a colorless oil.

[0208] Step 7. Procedure for the preparation of compound 6, 3-(4-bromo-2-fluoro-6-methylphenyl)piperidine-2,6-dione. To a solution of methyl 4-(4-bromo-2-fluoro-6-methylphenyl)-4-cyanobutanoate (1.30 g, 4.15 mmol, 1.00 equiv.) in acetic acid (10 mL) was added sulfuric acid (1.84 g, 18.7 mmol, 1.00 mL, 4.52 equiv.). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water and filtered. The filter cake was washed with petroleum ether and concentrated under reduced pressure to give 3-(4-bromo-2-fluoro-6-methylphenyl)piperidine-2,6-dione (1.06 g, 3.55 mmol, 85% yield) as a white solid.

[0209] 1H NMR (400 MHz, DMSO-d6) δ =10.90 (s, 1H), 7.45 - 7.27 (m, 2H), 4.13 (br dd, J = 5.2, 11.9 Hz, 1H), 2.88 - 2.71 (m, 1H), 2.54 (br d, J = 3.1 Hz, 1H), 2.33 (s, 3H), 2.13 - 1.93 (m, 2H).

[0210] Step 8. Procedure for the preparation of compound 7 tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin-3-yl)carbamate. A mixture of tert-butyl azetidin-3-ylcarbamate (275 mg, 1.60 mmol, 1.20 equiv.), 3-(4-bromo-2-fluoro-6-methylphenyl)piperidine-2,6-dione (400 mg, 1.33 mmol, 1.00 equiv.), [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (129 mg, 133 µmol, 0.100 equiv.), and cesium carbonate (1.30 g, 4.00 mmol, 3.00 equiv.) in dioxane (10.0 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin-3-yl)carbamate (251 mg, 641 umol, 48% yield) as a white solid.

[0211] 1H NMR (400 MHz, DMSO-d6) δ = 10.76 (s, 1H), 7.53 (br d, J = 7.4 Hz, 1H), 6.17 - 6.01 (m, 2H), 4.45 - 4.33 (m, 1H), 4.10 - 4.02 (m, 2H), 3.99 - 3.89 (m, 1H), 3.54 (br t, J = 6.8 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.59 - 2.53 (m, 1H), 2.22 (s, 3H), 2.09 - 2.00 (m, 1H), 1.95 - 1.87 (m, 1H), 1.42 - 1.37 (m, 9H).

[0212] Step 9. Procedure for the preparation of compound 8, 3-(4-(3-aminoazetidin-1-yl)-2-fluoro-6-methylphenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin-3-yl)carbamate (130 mg, 332 μmol, 1.00 equiv) in dichloromethane (2.50 mL) was added trifluoroacetic acid (1.25 g, 10.9 mmol, 812 μL, 33.0 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)-2-fluoro-6-methylphenyl)piperidine-2,6-dione (90.0 mg, crude) as a white solid. MS (ESI) m / z 292.2 [M+H] +

[0213] Step 10. Procedure for the preparation of 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin-3-yl)carbamate. To a solution of N-cyclopropyl-3-hydroxy-N-methylazetidine-1-carboxamide (100 mg, 587 μmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) was added di(1H-imidazol-1-yl)methanone (100 mg, 616 μmol, 1.05 equiv) at 25° C. The mixture was stirred at 25° C. for 12 hours. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2-fluoro-6-methylphenyl)piperidine-2,6-dione (89.0 mg, 305 μmol, 1.00 equiv), triethylamine (30.9 mg, 305 μmol, 42.5 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (46.5 mg, 305 μmol, 46.0 μL, 1.00 equiv) in dimethylformamide (5.00 mL). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin-3-yl)carbamate (24.67 mg, 47.5 μmol, 16% yield, 94% purity) as a white solid.

[0214] 1H NMR (400 MHz, DMSO-d6) δ = 10.92 - 10.64 (m, 1H), 8.08 (br d, J = 7.4 Hz, 1H), 6.21 - 5.97 (m, 2H), 5.01 (br s, 1H), 4.41 (br d, J = 6.9 Hz, 1H), 4.22 (dd, J = 6.8, 9.6 Hz, 2H), 4.11 - 4.03 (m, 2H), 3.97 - 3.89 (m, 1H), 3.81 (br dd, J = 3.9, 9.8 Hz, 2H), 3.58 (br t, J = 6.7 Hz, 2H), 2.80 - 2.74 (m, 1H), 2.72 (s, 3H), 2.58 (br d, J = 3.9 Hz, 2H), 2.21 (s, 3H), 2.01 (dt, J = 10.0, 12.4 Hz, 1H), 1.90 (br dd, J = 4.4, 6.4 Hz, 1H), 0.72 (br d, J = 5.0 Hz, 2H), 0.66 - 0.56 (m, 2H). MS (ESI) m / z 488.4 [M+H] +

[0215] Example 16. Synthesis of Compound 16 [ka] Step 1. Procedure for the preparation of compound 2, cyclopropyl(methyl)carbamic acid chloride. To a solution of N-methylcyclopropanamine (400 mg, 5.62 mmol, 1.00 equiv) in dichloromethane (10.0 mL) were added bis(trichloromethyl)carbonate (2.67 g, 9.00 mmol, 1.60 equiv) and N,N-diisopropylethylamine (1.45 g, 11.25 mmol, 1.96 mL, 2 equiv) at 25° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give cyclopropyl(methyl)carbamic acid chloride (750 mg, 5.61 mmol, 99% yield) as a reddish-brown solid.

[0216] Step 2. Procedure for the preparation of compound 3(S)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-1-carboxamide. To a solution of (S)-pyrrolidin-3-ol (300 mg, 3.44 mmol, 278 μL, 1.00 equiv) in dichloromethane (9.00 mL) was added N,N-diisopropylethylamine (890 mg, 6.89 mmol, 1.20 mL, 2.00 equiv) and cyclopropyl(methyl)carbamic acid chloride (736 mg, 5.51 mmol, 1.60 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give (S)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-1-carboxamide (200 mg, 1.09 mmol, 32% yield) as a colorless oil.

[0217] 1 H NMR (400 MHz, DMSO-d6) δ = 4.84 (d, J = 3.4 Hz, 1H), 4.26 - 4.13 (m, 1H), 3.49 - 3.41 (m, 2H), 3.26 (br s, 1H), 3.15 - 3.08 (m, 1H), 2.72 - 2.65 (m, 3H), 2.59 (tt, J = 3.6, 6.8 Hz, 1H), 1.85 - 1.75 (m, 1H), 1.74 - 1.63 (m, 1H), 0.70 - 0.59 (m, 2H), 0.55 - 0.46 (m, 2H).

[0218] Step 3. Procedure for the preparation of (S)-1-(cyclopropyl(methyl)carbamoyl)pyrrolidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (S)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-1-carboxamide (120 mg, 651 μmol, 1.00 equiv.) in tetrahydrofuran (5.00 mL) was added di(1H-imidazol-1-yl)methanone (127 mg, 782 μmol, 1.20 equiv.), and the mixture was stirred at 25° C. for 1 hour. The resulting solution was added to a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (150 mg, 383 μmol, 1.00 equiv, mesylate salt), triethylamine (38.8 mg, 383 μmol, 53.3 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (58.3 mg, 383 μmol, 57.8 μL, 1.00 equiv) in dimethylformamide (1.00 mL). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give (S)-1-(cyclopropyl(methyl)carbamoyl)pyrrolidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (35.54 mg, 68.90 μmol, yield 18%, purity 98%) as a white solid.

[0219] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.95 (br d, J = 7.3 Hz, 1H), 6.13 (d, J = 11.0 Hz, 2H), 5.08 (br s, 1H), 4.47 - 4.38 (m, 1H), 4.08 (br t, J = 7.6 Hz, 2H), 4.05 - 3.98 (m, 1H), 3.67 - 3.60 (m, 3H), 3.47 - 3.38 (m, 2H), 3.29 (br s, 1H), 2.84 - 2.75 (m, 1H), 2.70 (s, 3H), 2.61 (td, J = 3.2, 6.8 Hz, 1H), 2.18 - 1.74 (m, 5H), 0.75 - 0.68 (m, 1H), 0.67 - 0.60 (m, 1H), 0.56 - 0.50 (m, 2H). MS (ESI) m / z 506.1 [M+H] +

[0220] Example 17. Synthesis of Compound 17 [ka] Step 1. Procedure for the preparation of compound 2A azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (80.0 mg, 162 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added methanesulfonic acid (46.6 mg, 485 μmol, 34.6 μL, 3.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (79.0 mg, crude, mesylate salt) as a yellow oil. MS (ESI) m / z 395.2 [M+H]+

[0221] Step 2. Preparation of compound 2, methyl(phenyl)carbamic acid chloride. To a solution of N-methylaniline (25.0 mg, 233 μmol, 25.3 μL, 1.00 equiv) in dichloromethane (0.300 mL) was added bis(trichloromethyl)carbonate (69.2 mg, 233 μmol, 1.0 equiv) and N,N-diisopropylethylamine (60.3 mg, 467 μmol, 81.3 μL, 2.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give methyl(phenyl)carbamic acid chloride (39.0 mg, crude) as a yellow oil.

[0222] Step 3. Procedure for the preparation of 1-(methyl(phenyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (79.0 mg, 161 umol, 1.00 equiv, mesylate salt) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (62.5 mg, 483 umol, 84.2 uL, 3.00 equiv) and methyl(phenyl)carbamic acid chloride (32.8 mg, 193 umol, 1.20 equiv). The reaction mixture was stirred at 20° C. for 0.5 hours. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 32% to 62%, 9 min) and lyophilized to give 1-(methyl(phenyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (36.34 mg, 65.44 umol, 41% yield, 95% purity) as an off-white solid.

[0223] 1 H NMR (400MHz, DMSO-d6) δ =10.85 (s, 1H), 8.03 (br d, J = 7.3 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.29 - 7.20 (m, 3H), 6.13 (br d, J = 11.0 Hz, 2H), 4.84 - 4.72 (m, 1H), 4.41 - 4.29 (m, 1H), 4.09 - 3.98 (m, 3H), 3.77 - 3.68 (m, 2H), 3.59 (br t, J = 6.8 Hz, 2H), 3.31 - 3.30 (m, 2H), 3.13 (s, 3H), 2.83 - 2.72 (m, 1H), 2.42 (br s, 1H), 2.12 - 2.03 (m, 1H), 1.97 - 1.90 (m, 1H).

[0224] 1 H NMR (400MHz, DMSO-d6+D2O) δ = 10.86 (s, 1H), 8.04 (br d, J = 7.4 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.31 - 7.20 (m, 3H), 6.19 - 6.08 (m, 2H), 4.83 - 4.74 (m, 1H), 4.40 - 4.29 (m, 1H), 4.09 - 3.99 (m, 3H), 3.79 - 3.70 (m, 2H), 3.62 - 3.57 (m, 2H), 3.33 (br dd, J = 3.4, 9.8 Hz, 2H), 3.13 (s, 3H), 2.81 - 2.72 (m, 1H), 2.45 (br s, 1H), 2.10 - 2.01 (m, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 528.5 [M+H] +

[0225] Example 18. Synthesis of Compound 18

change

[0226] Step 2. Procedure for (R)-1-(dimethylcarbamoyl)pyrrolidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (R)-3-hydroxy-N,N-dimethylpyrrolidine-1-carboxamide (60.0 mg, 379 μmol, 476 μL, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (123 mg, 759 μmol, 2.00 equiv), and the reaction mixture was stirred at 20° C. for 1 hour. The resulting solution was added to a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (147 mg, 377 μmol, 1.00 equiv, mesylate salt), triethylamine (38.1 mg, 377 μmol, 52.4 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (57.3 mg, 377 μmol, 56.8 μL, 1.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20% to 50%, 10 min) and lyophilized to give (R)-1-(dimethylcarbamoyl)pyrrolidin-3-yl-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (17.97 mg, 37.10 umol, yield 10%, purity 99%) as a white solid.

[0227] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 7.97 (br d, J = 7.3 Hz, 1H), 6.14 (br d, J = 11.0 Hz, 2H), 5.08 (br s, 1H), 4.51 - 4.34 (m, 1H), 4.13 - 4.00 (m, 3H), 3.69 - 3.58 (m, 3H), 3.49 - 3.37 (m, 2H), 3.22 (br d, J = 11.9 Hz, 1H), 2.82 - 2.76 (m, 1H), 2.73 (s, 6H), 2.18 - 1.85 (m, 5H). MS (ESI) m / z.480.3 [M+H] +

[0228] Example 19. Synthesis of Compound 19 [ka] Step 1. Procedure for compound 2 4-hydroxy-N,N-dimethylpiperidine-1-carboxamide. To a solution of piperidin-4-ol (200 mg, 1.98 mmol, 1.00 equiv) in tetrahydrofuran (4.00 mL) was added dimethylcarbamic acid chloride (425 mg, 3.95 mmol, 363 μL, 2.00 equiv) and triethylamine (500 mg, 4.94 mmol, 688 μL, 2.50 equiv). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (250 mg, 1.45 mmol, 73% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3-d) δ=3.89 - 3.79 (m, 1H), 3.60 - 3.51 (m, 2H), 2.96 - 2.89 (m, 2H), 2.82 (s, 6H), 1.94 - 1.86 (m, 2H), 1.58 - 1.47 (m, 2H).

[0229] Step 2. Procedure for 1-(dimethylcarbamoyl)piperidin-4-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 4-hydroxy-N,N-dimethylpiperidine-1-carboxamide (100 mg, 581 umol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (113 mg, 697 umol, 1.20 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (166 mg, 425 μmol, 0.754 equiv, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (85.8 mg, 563 μmol, 84.9 μL, 1.00 equiv), and triethylamine (57.0 mg, 563 μmol, 78.4 μL, 1.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give 1-(dimethylcarbamoyl)piperidin-4-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (38.47 mg, 77.17 μmol, 13% yield, 99% purity) as a white solid.

[0230] 1H NMR (400 MHz, DMSO-d6) δ= 10.85 (s, 1H), 7.86 (br d, J = 7.5 Hz, 1H), 6.14 (d, J = 11.0 Hz, 2H), 4.75 - 4.61 (m, 1H), 4.49 - 4.36 (m, 1H), 4.09 (t, J = 7.7 Hz, 2H), 4.06 - 4.00 (m, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.41 - 3.33 (m, 2H), 2.98 - 2.87 (m, 2H), 2.83 - 2.76 (m, 1H), 2.72 (s, 6H), 2.54 (br s, 1H), 2.13 - 2.01 (m, 1H), 1.98 - 1.89 (m, 1H), 1.83 (br d, J = 9.0 Hz, 2H), 1.54 - 1.42 (m, 2H). MS (ESI) m / z 494.4 [M+H] +

[0231] Example 20. Synthesis of Compound 20 [ka] Step 1. Procedure for the preparation of compound 2, 4-(3-hydroxyazetidine-1-carbonyl)benzonitrile. To a solution of 4-cyanobenzoic acid (100 mg, 679 μmol, 1.00 equiv.) and azetidin-3-ol (89.3 mg, 815 μmol, 1.20 equiv., hydrochloride salt) in dimethylformamide (5.00 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (64.2 mg, 475 μmol, 0.700 equiv.), N,N-diisopropylethylamine (87.8 mg, 679 μmol, 118 μL, 1.00 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143 mg, 747 μmol, 1.10 equiv.). The reaction was stirred at 25°C for 12 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 4-(3-hydroxyazetidine-1-carbonyl)benzonitrile (110 mg, 543 μmol, 80% yield) as a white solid.

[0232] 1 H NMR (400 MHz, DMSO-d6) δ = 7.93 (br d, J = 8.4 Hz, 2H), 7.78 (br d, J = 8.4 Hz, 2H), 5.80 (br d, J = 6.0 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.45 - 4.38 (m, 1H), 4.32 - 4.22 (m, 1H), 4.03 (br dd, J = 3.6, 8.9 Hz, 1H), 3.80 (br dd, J = 4.0, 10.3 Hz, 1H).

[0233] Step 2. Procedure for the preparation of 1-(4-cyanobenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 4-(3-hydroxyazetidine-1-carbonyl)benzonitrile (110 mg, 543.99 μmol, 1.00 equiv.) in tetrahydrofuran (2.00 mL) was added di(1H-imidazol-1-yl)methanone (88.21 mg, 543.99 μmol, 1.00 equiv.). The mixture was stirred at 25° C. for 1 hour. The resulting solution was diluted with 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (157 mg, 401 μmol, 7.43 e-1 To a solution of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (82.2 mg, 540 μmol, 81.4 μL, 1.00 eq., mesylate salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (82.2 mg, 540 μmol, 81.4 μL, 1.00 eq.), and N,N-diisopropylethylamine (69.7 mg, 540 μmol, 94.0 μL, 1.00 eq.) in dimethylformamide (1.00 mL) was added. The reaction was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 26% to 56%, 58 min) to give 1-(4-cyanobenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (40.57 mg, 75.95 umol, yield 14%, purity 98%) as a white solid.

[0234] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.16 (br d, J = 7.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 6.16 (br d, J = 11.2 Hz, 2H), 5.15 - 5.07 (m, 1H), 4.59 - 4.53 (m, 1H), 4.45 - 4.35 (m, 2H), 4.26 (br d, J = 8.4 Hz, 1H), 4.10 (br t, J = 7.6 Hz, 2H), 4.06 - 4.01 (m, 1H), 3.97 (br d, J = 10.0 Hz, 1H), 3.66 (br t, J = 6.8 Hz, 2H), 2.76 (br dd, J = 5.2, 12.9 Hz, 1H), 2.48 (br s, 1H), 2.08 (br dd, J = 3.6, 12.9 Hz, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 524.1 [M+H] +

[0235] Example 21. Synthesis of Compound 21

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[0236] Step 2. Procedure for the preparation of 1-(4-methoxybenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (3-hydroxyazetidin-1-yl)(4-methoxyphenyl)methanone (100 mg, 483 umol, 1.00 equiv.) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (78.3 mg, 483 umol, 1.00 equiv.) at 0°C, and the mixture was stirred at 25°C for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (182 mg, 465 μmol, 1.00 equiv, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (70.7 mg, 465 μmol, 70.0 μL, 1.00 equiv), and N,N-diisopropylethylamine (60.0 mg, 465 μmol, 80.9 μL, 1.00 equiv) in dimethylformamide (1.00 mL), and the mixture was stirred at 25° C. for 11 hours. The mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 33% to 53%, 58 min) and lyophilized to give 1-(4-methoxybenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (19.31 mg, 37.5 umol, yield 8%, purity 96%) as a white solid.

[0237] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.15 (br d, J = 7.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.16 (d, J = 11.0 Hz, 2H), 5.18 - 5.07 (m, 1H), 4.68 - 4.51 (m, 1H), 4.47 - 4.39 (m, 1H), 4.37 - 4.28 (m, 1H), 4.23 (dt, J = 1.7, 3.2 Hz, 1H), 4.10 (br t, J = 7.6 Hz, 2H), 4.04 (br dd, J = 5.0, 12.6 Hz, 1H), 3.98 - 3.84 (m, 1H), 3.81 (s, 3H), 3.66 (br t, J = 6.8 Hz, 2H), 2.85 - 2.72 (m, 1H), 2.48 - 2.45 (m, 1H), 2.08 (dq, J = 4.2, 13.0 Hz, 1H), 2.00 - 1.89 (m, 1H). MS (ESI) m / z 529.2 [M+H] +

[0238] Example 22. Synthesis of Compound 22

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[0239] 1 H NMR (400 MHz, DMSO-d6) δ = 7.72 - 7.66 (m, 2H), 7.30 - 7.23 (m, 2H), 5.74 (br d, J = 4.8 Hz, 1H), 4.53 - 4.40 (m, 2H), 4.29 - 4.19 (m, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.78 (br d, J = 7.6 Hz, 1H).

[0240] Step 2. Procedure for 1-(4-fluorobenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (4-fluorophenyl)(3-hydroxyazetidin-1-yl)methanone (100 mg, 512 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (83.1 mg, 512 μmol, 1.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (196 mg, 501 μmol, 1.00 equiv, mesylate salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (76.3 mg, 501 μmol, 75.5 μL, 1.00 equiv), and N,N-diisopropylethylamine (64.7 mg, 501 μmol, 87.3 μL, 1.00 equiv) in N,N-dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in N,N-dimethylformamide (0.5 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30% to 60%, 9 min) and lyophilized to give 1-(4-fluorobenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (10.61 mg, 19.31 umol, yield 3%, purity 94%) as an off-white solid.

[0241] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.15 (d, J = 7.4 Hz, 1H), 7.72 (dd, J = 5.6, 8.8 Hz, 2H), 7.32 - 7.24 (m, 2H), 6.15 (d, J = 11.0 Hz, 2H), 5.15 - 5.07 (m, 1H), 4.62 - 4.51 (m, 1H), 4.47 - 4.39 (m, 1H), 4.39 - 4.31 (m, 1H), 4.29 - 4.19 (m, 1H), 4.13 - 4.07 (m, 2H), 4.06 - 4.00 (m, 1H), 3.98 - 3.88 (m, 1H), 3.65 (br t, J = 6.6 Hz, 2H), 2.84 - 2.72 (m, 1H), 2.48 - 2.44 (m, 1H), 2.12 - 2.02 (m, 1H), 1.98 - 1.90 (m, 1H). MS (ESI) m / z.517.0 [M+H] +

[0242] Example 23. Synthesis of Compound 23 [ka] Step 1. Procedure for the preparation of compound 2 (3-hydroxyazetidin-1-yl)(p-tolyl)methanone. To a solution of 4-methylbenzoic acid (500 mg, 3.67 mmol, 1.00 equiv.) in dimethylformamide (5.00 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (1.68 g, 4.41 mmol, 1.20 equiv.), N,N-diisopropylethylamine (1.42 g, 11.0 mmol, 1.92 mL, 3.00 equiv.), and azetidin-3-ol (322 mg, 4.41 mmol, 1.20 equiv., hydrochloride salt). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give (3-hydroxyazetidin-1-yl)(p-tolyl)methanone (350 mg, 1.76 mmol, 48% yield, 96% purity) as a yellow solid.

[0243] 1 H NMR (400 MHz, DMSO-d6) δ = 7.50 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 5.74 (br d, J = 5.9 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.43 (br d, J = 9.5 Hz, 1H), 4.23 (br d, J = 8.0 Hz, 1H), 4.00 (br d, J = 4.0 Hz, 1H), 3.76 (br d, J = 6.9 Hz, 1H), 2.34 (s, 3H).

[0244] Step 2. Procedure for the preparation of 1-(4-methylbenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (3-hydroxyazetidin-1-yl)(p-tolyl)methanone (100 mg, 523 umol, 1.00 equiv.) in tetrahydrofuran (2.00 mL) was added di(1H-imidazol-1-yl)methanone (84.8 mg, 523 umol, 1.00 equiv.) at 0°C, and the mixture was stirred at 20°C for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (154 mg, 522 μmol, 1.00 equiv, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (79.5 mg, 522 μmol, 78.7 μL, 1.00 equiv), and N,N-diisopropylethylamine (67.5 mg, 522 μmol, 91.0 μL, 1.00 equiv) in dimethylformamide (2.00 mL). The mixture was stirred at 20° C. for 12 hours. The reaction was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30% to 60%, 10 min) and lyophilized to give 1-(4-methylbenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (45.25 mg, 88.34 umol, yield 17%, purity 97%) as a white solid.

[0245] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.14 (br d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 6.15 (d, J = 11.0 Hz, 2H), 5.20 - 4.99 (m, 1H), 4.56 (br s, 1H), 4.48 - 4.39 (m, 1H), 4.38 - 4.28 (m, 1H), 4.28 - 4.15 (m, 1H), 4.10 (br t, J = 7.6 Hz, 2H), 4.03 (br dd, J = 5.0, 12.6 Hz, 1H), 3.92 (br d, J = 7.4 Hz, 1H), 3.65 (br t, J = 6.6 Hz, 2H), 2.85 - 2.70 (m, 1H), 2.47 (br s, 1H), 2.35 (s, 3H), 2.14 - 2.00 (m, 1H), 1.98 - 1.88 (m, 1H). MS (ESI) m / z 513.1 [M+H] +

[0246] Example 24. Synthesis of Compound 24 [ka] Step 1. Procedure for the preparation of compound 2, azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (100 mg, 202 umol, 1.00 equiv) in dichloromethane (1.00 mL) was added methanesulfonic acid (58.3 mg, 607 umol, 43.2 uL, 3.00 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 hours and then warmed to 20° C. The reaction mixture was stirred at 20° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (99.0 mg, crude, mesylate salt) as a yellow oil. MS (ESI) m / z 395.1 [M+H] +

[0247] Step 2. Procedure for the preparation of 1-benzoylazetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (99.0 mg, 202 μmol, 1.00 equiv, mesylate salt) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (78.3 mg, 606 μmol, 106 μL, 3.00 equiv) and benzoyl chloride (42.6 mg, 303 μmol, 35.2 μL, 1.50 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 52:48, 0.1% formic acid) and lyophilized to give 1-benzoylazetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (33.31 mg, 65.49 μmol, 32% yield, 98% purity) as a white solid.

[0248] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.15 (br d, J = 7.3 Hz, 1H), 7.64 (br d, J = 7.0 Hz, 2H), 7.56 - 7.50 (m, 1H), 7.49 - 7.41 (m, 2H), 6.16 (s, 1H), 6.14 (s, 1H), 5.18 - 5.06 (m, 1H), 4.65 - 4.51 (m, 1H), 4.48 - 4.32 (m, 2H), 4.30 - 4.17 (m, 1H), 4.10 (br t, J = 7.5 Hz, 2H), 4.03 (br dd, J = 5.0, 12.8 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.65 (br t, J = 6.6 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.48 - 2.46 (m, 1H), 2.12 - 2.03 (m, 1H), 1.99 - 1.89 (m, 1H). MS (ESI) m / z 499.2 [M+H] +

[0249] Example 25. Synthesis of Compound 25 [ka] Step 1. Procedure for the preparation of compound 2, cyclopropyl(methyl)carbamic acid chloride. To a solution of N-methylcyclopropanamine (500 mg, 7.03 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added bis(trichloromethyl)carbonate (2.09 g, 7.03 mmol, 1.00 equiv) and N,N-diisopropylethylamine (1.82 g, 14.1 mmol, 2.45 mL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give cyclopropyl(methyl)carbamic acid chloride (930 mg, crude) as a yellow solid.

[0250] Step 2. Procedure for the preparation of compound 3(R)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-1-carboxamide. To a solution of (R)-pyrrolidin-3-ol (500 mg, 5.74 mmol, 476 μL, 1.00 equiv) in dimethylformamide (5.00 mL) was added N,N-diisopropylethylamine (2.23 g, 17.2 mmol, 3.00 mL, 3.00 equiv) and cyclopropyl(methyl)carbamic acid chloride (919 mg, 6.89 mmol, 1.20 equiv) at 0° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give (R)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-1-carboxamide (370 mg, 2.01 mmol, 35% yield) as a white solid.

[0251] 1 H NMR (400MHz, DMSO-d6) δ = 4.84 (br d, J = 3.1 Hz, 1H), 4.19 (br s, 1H), 3.48 - 3.41 (m, 2H), 3.27 (br dd, J = 2.0, 3.6 Hz, 1H), 3.11 (br d, J = 11.1 Hz, 1H), 2.69 (s, 3H), 2.58 (td, J = 3.3, 6.9 Hz, 1H), 1.84 - 1.74 (m, 1H), 1.73 - 1.64 (m, 1H), 0.73 - 0.66 (m, 1H), 0.65 - 0.58 (m, 1H), 0.53 - 0.40 (m, 2H).

[0252] Step 3. Procedure for the preparation of (R)-1-(cyclopropyl(methyl)carbamoyl)pyrrolidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (R)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-1-carboxamide (50.0 mg, 271 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (88.0 mg, 542 μmol, 2.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The resulting solution was added to a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (75.0 mg, 269 μmol, 1.00 equiv, mesylate salt), triethylamine (27.3 mg, 270 μmol, 37.5 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (41.0 mg, 270 μmol, 40.6 μL, 1.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give (R)-1-(cyclopropyl(methyl)carbamoyl)pyrrolidin-3-yl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (26.33 mg, 51.56 μmol, 19% yield, 99% purity) as a white solid.

[0253] 1H NMR (400MHz, DMSO-d6) δ = 10.87 (s, 1H), 7.97 (br d, J = 7.5 Hz, 1H), 6.14 (br d, J = 11.0 Hz, 2H), 5.08 (br s, 1H), 4.50 - 4.33 (m, 1H), 4.09 - 4.00 (m, 3H), 3.67 - 3.59 (m, 3H), 3.47 - 3.35 (m, 2H), 3.29 (br s, 1H), 2.83 - 2.73 (m, 1H), 2.69 (s, 3H), 2.63 - 2.59 (m, 1H), 2.14 - 1.86 (m, 5H), 0.75 - 0.68 (m, 1H), 0.65 - 0.59 (m, 1H), 0.55 - 0.49 (m, 2H). MS (ESI) m / z.506.2 [M+H] +

[0254] Example 26. Synthesis of Compound 26 [ka] Step 1. Procedure for the preparation of compound 2 (4-chlorophenyl)(3-hydroxyazetidin-1-yl)methanone. A solution of 4-chlorobenzoic acid (500 mg, 3.19 mmol, 1.00 equiv.), azetidin-3-ol (700 mg, 6.39 mmol, 2.00 equiv., hydrochloride salt), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (1.82 g, 4.79 mmol, 1.50 equiv.), and N,N-diisopropylethylamine (1.24 g, 9.58 mmol, 1.67 mL, 3.00 equiv.) in dimethylformamide (5.00 mL) was stirred for 1 h at 25 °C. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (4-chlorophenyl)(3-hydroxyazetidin-1-yl)methanone (900 mg, crude) as a colorless oil.

[0255] 1 H NMR (400 MHz, DMSO-d6) δ = 7.73 - 7.62 (m, 2H), 7.58 - 7.46 (m, 2H), 5.76 (d, J = 6.0 Hz, 1H), 4.58 - 4.42 (m, 2H), 4.30 - 4.20 (m, 1H), 4.03 (q, J = 7.0 Hz, 1H), 3.88 - 3.70 (m, 1H).

[0256] Step 2. Procedure for the preparation of 1-(4-chlorobenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (4-chlorophenyl)-(3-hydroxyazetidin-1-yl)methanone (50.0 mg, 236 umol, 1.00 equiv.) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (38.3 mg, 236 umol, 1.00 equiv.), and the mixture was stirred at 25° C. for 1 hour. The resulting solution was added to a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (82.3 mg, 228 μmol, 1.00 equiv, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34.9 mg, 228 μmol, 34.5 μL, 1.00 equiv), and N,N-diisopropylethylamine (29.6 mg, 228 μmol, 39.9 μL, 1.00 equiv) in dimethylformamide (1.00 mL), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 34% to 64%, 9 min) and lyophilized to give 1-(4-chlorobenzoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (21.71 mg, 40.31 umol, yield 17%, purity 99%) as a white solid.

[0257] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.15 (br d, J = 7.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 6.15 (d, J = 11.1 Hz, 2H), 5.18 - 5.03 (m, 1H), 4.64 - 4.51 (m, 1H), 4.47 - 4.32 (m, 2H), 4.24 (br d, J = 7.0 Hz, 1H), 4.10 (br t, J = 7.4 Hz, 2H), 4.03 (br dd, J = 5.1, 12.5 Hz, 1H), 3.93 (br d, J = 9.6 Hz, 1H), 3.65 (br t, J = 6.6 Hz, 2H), 2.84 - 2.71 (m, 1H), 2.47 (br s, 1H), 2.14 - 2.02 (m, 1H), 1.99 - 1.89 (m, 1H). MS (ESI) m / z 533.0 [M+H] +

[0258] Example 27. Synthesis of Compound 27 [ka] Step 1. Procedure for the preparation of compound 2(S)-3-hydroxy-N,N-dimethylpyrrolidine-1-carboxamide. To a solution of (S)-pyrrolidin-3-ol (300 mg, 3.44 mmol, 278 uL, 1.00 equiv) in dichloromethane (5.00 mL) was added triethylamine (732 mg, 7.23 mmol, 1.01 mL, 2.10 equiv) and dimethylcarbamic chloride (407 mg, 3.79 mmol, 348 uL, 1.10 equiv) at 5° C. The reaction mixture was stirred at 25° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give (S)-3-hydroxy-N,N-dimethylpyrrolidine-1-carboxamide (250 mg, crude) as a yellow solid.

[0259] 1H NMR (400 MHz, DMSO-d6) δ = 4.89 - 4.82 (m, 1H), 4.25 - 4.14 (m, 1H), 3.45 - 3.38 (m, 2H), 3.21 (ddd, J = 3.7, 8.0, 10.1 Hz, 1H), 2.99 (s, 1H), 2.71 (s, 6H), 1.84 - 1.74 (m, 1H), 1.73 - 1.66 (m, 1H).

[0260] Step 2. Procedure for the preparation of (S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (S)-3-hydroxy-N,N-dimethylpyrrolidine-1-carboxamide (130 mg, 822 μmol, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added di(1H-imidazol-1-yl)methanone (200 mg, 1.23 mmol, 1.50 equiv), and the reaction mixture was stirred at 25° C. for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (150 mg, 383 μmol, 1.00 equiv, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (58.3 mg, 383 μmol, 57.8 μL, 1.00 equiv), and triethylamine (38.8 mg, 383 μmol, 53.3 μL, 1.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20% to 50%, 10 min) and lyophilized to give (S)-1-(dimethylcarbamoyl)pyrrolidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (45.43 mg, 93.80 umol, yield 24%, purity 99%) as a white solid.

[0261] 1H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 7.99 (br d, J = 7.1 Hz, 1H), 6.16 (d, J = 11.0 Hz, 2H), 5.10 (br s, 1H), 4.50 - 4.40 (m, 1H), 4.15 - 4.07 (m, 2H), 4.07 - 4.01 (m, 1H), 3.69 - 3.63 (m, 2H), 3.61 (br d, J = 4.5 Hz, 1H), 3.44 (dt, J = 7.3, 10.0 Hz, 1H), 3.33 - 3.29 (m, 1H), 3.24 (br d, J = 11.9 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.75 (s, 6H), 2.50 (br s, 1H), 2.16 - 1.87 (m, 4H). MS (ESI) m / z.480.3 [M+H] +

[0262] Example 28. Synthesis of Compound 28 [ka] Step 1. Preparation procedure for compound 2, 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene. To a solution of 5-bromo-1,3-dichloro-2-methylbenzene (10.0 g, 41.7 mmol, 1.00 equiv.) and N-bromosuccinimide (7.42 g, 41.7 mmol, 1.00 equiv.) in carbon tetrachloride (50.0 mL) was added dibenzoyl peroxide (1.01 g, 4.17 mmol, 0.100 equiv.) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25° C. Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine (40 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0) to give 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (16.7 g, crude) as a white solid.

[0263] 1 H NMR (400 MHz, DMSO-d6) δ = 7.87 (s, 2H), 4.74 (s, 2H).

[0264] Step 2. Preparation procedure for compound 3, 2-(4-bromo-2,6-dichlorophenyl)acetonitrile. To a solution of 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (12.0 g, 37.6 mmol, 1.00 equiv) and tetrabutylammonium fluoride (1.00 M, 113 mL, 3.00 equiv) in acetonitrile (70.0 mL) was added 2-bromo-5-(bromomethyl)pyridine (11.2 g, 113 mmol, 14.1 mL, 3.00 equiv). The mixture was stirred at 20° C. for 15 minutes. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The mixture was extracted with dichloromethane (3×200 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1) to give 2-(4-bromo-2,6-dichloro-phenyl)acetonitrile (9.00 g, 34.0 mmol, 90% yield) as a white solid.

[0265] 1 H NMR (400 MHz, DMSO-d6) δ = 7.93 (s, 2H), 4.15 (s, 2H).

[0266] Step 3. Procedure for the preparation of compound 4 tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate. To a mixture of 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (9.00 g, 34.0 mmol, 1.00 equiv.) and sodium methylate (184 mg, 3.40 mmol, 0.100 equiv.) in tetrahydrofuran (40.0 mL) was added tert-butyl acrylate (6.53 g, 51.0 mmol, 7.40 mL, 1.50 equiv.) at 0° C. The mixture was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure to give tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (12.0 g, crude) as a white solid. MS (ESI) m / z 393.8 [M+H+2] +

[0267] Step 4. Procedure for the preparation of compound 5, 3-(4-bromo-2,6-dichlorophenyl)piperidine-2,6-dione. To a mixture of tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (11.8 g, 30.0 mmol, 1.00 equiv) in acetic acid (20.0 mL) was added sulfuric acid (4.00 mL). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was triturated with water (150 mL) at 25° C. for 10 minutes and filtered. The filter cake was concentrated under reduced pressure to give 3-(4-bromo-2,6-dichlorophenyl)piperidine-2,6-dione (9.50 g, 28.2 mmol, 93% yield) as a white solid.

[0268] 1 H NMR (400 MHz, DMSO-d6) δ = 11.01 (s, 1H), 7.89 - 7.83 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 4.60 (dd, J = 5.6, 12.6 Hz, 1H), 2.91 - 2.80 (m, 1H), 2.58 - 2.52 (m, 1H), 2.36 (br dd, J = 4.2, 13.4 Hz, 1H), 1.94 - 1.88 (m, 1H).

[0269] Step 5. Procedure for the preparation of compound 6 tert-butyl (1-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-bromo-2,6-dichlorophenyl)piperidine-2,6-dione (300 mg, 890 μmol, 1.00 equiv.) in dioxane (5.00 mL), tert-butyl azetidin-3-ylcarbamate (307 mg, 1.78 mmol, 2.00 equiv.), sodium tert-butoxide (171 mg, 1.78 mmol, 2.00 equiv.), and methanesulfonato[2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (76.1 mg, 89.0 μmol, 0.100 equiv.) were added under a nitrogen atmosphere. The reaction mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. The resulting mixture was filtered through Celite, and water (50 ml) was added to the filtrate, followed by extraction with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give tert-butyl (1-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (87.0 mg, 201 μmol, 22% yield, 99% purity) as a white solid.

[0270] 1 H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 7.56 (br d, J = 7.6 Hz, 1H), 6.50 (dd, J = 2.2, 14.2 Hz, 2H), 4.40 (dd, J = 5.6, 12.6 Hz, 2H), 4.10 (t, J = 7.6 Hz, 2H), 3.62 (t, J = 6.8 Hz, 2H), 2.89 - 2.76 (m, 1H), 2.52 (br s, 1H), 2.30 (dq, J = 4.4, 13.3 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.39 (s, 9H).

[0271] Step 6. Procedure for the preparation of compound 7, 3-(4-(3-aminoazetidin-1-yl)-2,6-dichlorophenyl)piperidine-2,6-dione. To a mixture of tert-butyl (1-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (87.0 mg, 203 umol, 1.00 equiv) in trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)-2,6-dichlorophenyl)piperidine-2,6-dione (55.0 mg, crude) as a yellow oil. MS (ESI) m / z 328.1 [M+H] +

[0272] Step 7. Procedure for the preparation of compound 7A spiro[3.3]heptan-2-ylmethyl carbonochloridate. To a mixture of spiro[3.3]heptan-2-ylmethanol (60.0 mg, 475 μmol, 1.00 equiv) and bis(trichloromethyl)carbonate (212 mg, 713 μmol, 1.50 equiv) in dichloromethane (2.00 mL) was added N,N-diisopropylethylamine (123 mg, 951 μmol, 166 μL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give spiro[3.3]heptan-2-ylmethyl carbonochloridate (60.0 mg, crude) as a yellow oil.

[0273] Step 8. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl (1-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-dichlorophenyl)piperidine-2,6-dione (55.0 mg, 168 umol, 1.00 equiv) in dichloromethane (2.00 mL) was added N,N-diisopropylethylamine (43.3 mg, 335 umol, 58.4 uL, 2.00 equiv) at 0° C. for 15 minutes. Spiro[3.3]heptan-2-ylmethyl carbonochloridate (34.8 mg, 184 umol, 1.10 equiv) was then added. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (17.57 mg, 36.2 μmol, 21% yield, 99% purity) as a white solid.

[0274] 1 H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 7.82 (br d, J = 7.4 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 4.45 - 4.36 (m, 2H), 4.12 (t, J = 7.6 Hz, 2H), 3.90 (d, J = 7.0 Hz, 2H), 3.66 (br t, J = 6.6 Hz, 2H), 2.88 - 2.77 (m, 1H), 2.53 - 2.52 (m, 1H), 2.40 - 2.31 (m, 2H), 2.04 - 1.94 (m, 4H), 1.91 - 1.84 (m, 3H), 1.77 - 1.68 (m, 4H). MS (ESI) m / z 480.3 [M+H] +

[0275] Example 29. Synthesis of Compound 29 [ka] Step 1. Procedure for the preparation of compound 2, 1-(3-methylpyridin-2-yl)azetidin-3-ol. To a solution of azetidin-3-ol (985 mg, 9.00 mmol, 2.00 equiv, hydrochloride salt), cesium carbonate (4.40 g, 13.5 mmol, 3.00 equiv) in dimethyl sulfoxide (10.0 mL) was added 2-fluoro-3-methylpyridine (500 mg, 4.50 mmol, 454 μL, 1.00 equiv). The reaction was then stirred at 100° C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give 1-(3-methylpyridin-2-yl)azetidin-3-ol (330 mg, 2.01 mmol, 44% yield) as a yellow solid.

[0276] 1 H NMR (400 MHz, CDCl3) δ = 8.02 (dd, J = 1.1, 4.9 Hz, 1H), 7.23 (dd, J = 0.7, 7.2 Hz, 1H), 6.64 (dd, J = 5.1, 7.2 Hz, 1H), 4.72 - 4.60 (m, 1H), 4.36 - 4.32 (m, 2H), 3.94 (dd, J = 4.8, 9.4 Hz, 2H), 3.18 - 2.81 (m, 1H), 2.17 (s, 3H).

[0277] Step 2. Procedure for the preparation of 1-(3-methylpyridin-2-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(3-methylpyridin-2-yl)azetidin-3-ol (50 mg, 304 umol, 1.00 equiv) in tetrahydrofuran (0.50 mL) was added di(1H-imidazol-1-yl)methanone (59.3 mg, 365 umol, 1.20 equiv) at 0° C. The reaction was then stirred at 25° C. for 0.5 hours. To the mixture was then added dimethylformamide (0.50 mL), 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (119 mg, 304 umol, 1.00 equiv, mesylate salt), and N,N-diisopropylethylamine (59.0 mg, 456 umol, 79.6 uL, 1.50 equiv). The reaction was then stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 2 to 0 / 1) to give 1-(3-methylpyridin-2-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (68.02 mg, 140.11 umol, yield 44%, purity 98%) as a white solid.

[0278] 1H NMR (400 MHz, DMSO-d6) δ = 10.87 - 10.84 (m, 1H), 8.09 (br d, J = 7.4 Hz, 1H), 7.96 (br d, J = 4.0 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 6.68 (dd, J = 4.9, 7.1 Hz, 1H), 6.15 (d, J = 11.0 Hz, 2H), 5.16 - 5.09 (m, 1H), 4.47 - 4.40 (m, 1H), 4.32 (dd, J = 6.6, 9.3 Hz, 2H), 4.10 (t, J = 7.7 Hz, 2H), 4.03 (br dd, J = 4.8, 12.8 Hz, 1H), 3.91 (br dd, J = 4.2, 9.3 Hz, 2H), 3.65 (br t, J = 6.7 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.48 (br d, J = 3.0 Hz, 1H), 2.12 (s, 3H), 2.10 - 2.02 (m, 1H), 1.97 - 1.90 (m, 1H). MS (ESI) m / z 486.3 [M+H] +

[0279] Example 30. Synthesis of Compound 30 [ka] Step 1. Procedure for the preparation of compound 2, azetidine-1-carbonyl chloride. To a solution of azetidine (43.0 mg, 460 μmol, 50.8 μL, 1.00 equiv, hydrochloride salt) in dichloromethane (3.00 mL) was added bis(trichloromethyl)carbonate (205 mg, 689 μmol, 1.50 equiv) and N,N-diisopropylethylamine (89.1 mg, 689 μmol, 120 μL, 1.50 equiv) at 0° C. The reaction was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give azetidine-1-carbonyl chloride (54.0 mg, crude) as a yellow oil.

[0280] Step 2. Procedure for the preparation of compound 2A azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (200 mg, 404 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 33.4 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (205 mg, 403 μmol, 100% yield, trifluoroacetate salt) as a yellow oil. MS (ESI) m / z.395.1 [M+H] +

[0281] Step 3. Procedure for the preparation of 1-(azetidine-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (205 mg, 403 umol, 1.00 equiv, trifluoroacetate salt) in dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (104 mg, 806 umol, 140 uL, 2.00 equiv) and azetidine-1-carbonyl chloride (53.0 mg, 444 umol, 1.10 equiv) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20% to 50%, 10 min) and lyophilized to obtain the crude product. The crude product was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1, R f=0.08) and concentrated under reduced pressure to give a white solid, which was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 30:60, 0.1% formic acid) and lyophilized to give 1-(azetidine-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (8.57 mg, 17.77 μmol, 4% yield, 99% purity) as a white solid.

[0282] 1 H NMR (400 MHz, DMSO-d6) δ= 10.86 (s, 1H), 8.11 (br d, J = 7.1 Hz, 1H), 6.15 (d, J = 11.0 Hz, 2H), 5.10 - 4.98 (m, 1H), 4.46 - 4.38 (m, 1H), 4.15 - 4.06 (m, 4H), 4.03 (br dd, J = 5.3, 12.4 Hz, 1H), 3.81 (t, J = 7.6 Hz, 4H), 3.72 - 3.61 (m, 4H), 2.83 - 2.72 (m, 1H), 2.63 - 2.52 (m, 1H), 2.19 - 2.11 (m, 2H), 2.10 - 2.01 (m, 1H), 1.99 - 1.90 (m, 1H). MS (ESI) m / z.477.7 [M+H] +

[0283] Example 31. Synthesis of Compound 31 [ka] Step 1. Procedure for compound 2, 2-azaspiro[3.3]heptane-2-carbonyl chloride. To a solution of 2-azaspiro[3.3]heptane (75.0 mg, 561 μmol, 1.00 equiv, hydrochloride salt) in dichloromethane (3.00 mL) was added bis(trichloromethyl)carbonate (250 mg, 842 μmol, 1.50 equiv) and N,N-diisopropylethylamine (109 mg, 842 μmol, 147 μL, 1.50 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2-azaspiro[3.3]heptane-2-carbonyl chloride (89.6 mg, crude) as a yellow oil.

[0284] Step 2. Procedure for 1-(2-azaspiro[3.3]heptane-2-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (199 mg, 505 μmol, 1.00 equiv, trifluoroacetate salt) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (130 mg, 1.01 mmol, 176 μL, 2.00 equiv) and 2-azaspiro[3.3]heptane-2-carbonyl chloride (88.6 mg, 555 μmol, 1.10 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 19% to 49%, 15 min) and lyophilized to give 1-(2-azaspiro[3.3]heptane-2-carbonyl)azetidin-3-yl-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (17.95 mg, 33.99 umol, yield 7%, purity 98%) as a white solid.

[0285] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.16 - 8.02 (m, 1H), 6.16 (br d, J = 11.1 Hz, 2H), 5.02 (br d, J = 3.4 Hz, 1H), 4.53 - 4.33 (m, 1H), 4.18 - 4.00 (m, 5H), 3.74 - 3.60 (m, 4H), 2.87 - 2.73 (m, 1H), 2.60 - 2.54 (m, 1H), 2.15 - 2.02 (m, 5H), 1.99 - 1.90 (m, 1H), 1.82 - 1.68 (m, 2H). MS (ESI) m / z.518.1 [M+H] +

[0286] Example 32. Synthesis of Compound 32 [ka] Step 1. Preparation of compound 2, pyrrolidine-1-carbonyl chloride. To a solution of pyrrolidine (30.0 mg, 421 μmol, 35.2 μL, 1.00 equiv) in dichloromethane (1.00 mL) was added bis(trichloromethyl)carbonate (187 mg, 632 μmol, 1.50 equiv) and N,N-diisopropylethylamine (81.8 mg, 633 μmol, 110 μL, 1.50 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give pyrrolidine-1-carbonyl chloride (60.0 mg, crude) as a white solid.

[0287] Step 2. Procedure for the preparation of 1-(pyrrolidine-1-carbonyl)azetidin-3-yl (1-(3-fluoro-4-(6-oxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (160 mg, 252 μmol, 80% purity, 1.00 equivalents, trifluoroacetate salt) in dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (65.1 mg, 504 μmol, 87.7 μL, 2.00 equivalents) and pyrrolidine-1-carbonyl chloride (36.9 mg, 277 μmol, 30.6 μL, 1.10 equivalents) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 29% to 59%, 9 min) and lyophilized to give 1-(pyrrolidine-1-carbonyl)azetidin-3-yl (1-(3-fluoro-4-(6-oxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (8.78 mg, 17.15 umol, yield 6%, purity 96%) as a white solid.

[0288] 1 H NMR (400MHz, DMSO-d6) δ= 10.85 (s, 1H), 8.10 (br d, J = 7.4 Hz, 1H), 6.15 (d, J = 11.0 Hz, 2H), 5.01 (tt, J = 4.1, 6.6 Hz, 1H), 4.46 - 4.37 (m, 1H), 4.17 - 4.07 (m, 4H), 4.03 (br dd, J = 5.1, 12.6 Hz, 1H), 3.74 (br dd, J = 3.9, 9.5 Hz, 2H), 3.64 (br t, J = 6.7 Hz, 2H), 3.19 (br t, J = 6.6 Hz, 4H), 2.83 - 2.72 (m, 1H), 2.49 (br s, 1H), 2.12 - 2.01 (m, 1H), 1.98 - 1.90 (m, 1H), 1.78 - 1.71 (m, 4H). MS (ESI) m / z 492.1 [M+H] +

[0289] Example 33. Synthesis of Compound 33 [ka] Step 1. Procedure for the preparation of compound 2, 1-azaspiro[3.3]heptane-1-carbonyl chloride. To a solution of 1-azaspiro[3.3]heptane (45.0 mg, 337 μmol, 50.8 μL, 1.00 equiv, hydrochloride salt) in dichloromethane (3.00 mL) was added bis(trichloromethyl)carbonate (150 mg, 505 μmol, 1.50 equiv) and N,N-diisopropylethylamine (65.3 mg, 505 μmol, 88.0 μL, 1.50 equiv) at 0° C. The reaction was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1-azaspiro[3.3]heptane-1-carbonyl chloride (53.0 mg, crude) as a yellow oil.

[0290] Step 2. Procedure for the preparation of compound 2A azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (150 mg, 303 μmol, 1.00 equiv) in dichloromethane (4.00 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol, 0.800 mL, 35.6 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (154 mg, 303 μmol, 100% yield, trifluoroacetate salt) as a yellow oil. MS (ESI) m / z.395.1 [M+H] +

[0291] Step 3. Procedure for the preparation of 1-(1-azaspiro[3.3]heptane-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. A solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (153 mg, 301 umol, 1.00 equiv., trifluoroacetate salt) in dimethylformamide (2.00 mL) was treated with N,N-diisopropylethylamine (77.8 mg, 602 umol, 105 uL, 2.00 equiv.) and 1-azaspiro[ 3.3]Heptane-1-carbonyl chloride (52.8 mg, 331 μmol, 1.10 equiv.) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was filtered. The filtrate was purified by reverse phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, formic acid) and lyophilized to obtain the crude product. The crude product was then purified by preparative HPLC (column: Waters Purification by xbridge 150*25mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 22% to 52%, 8 min), addition of formic acid (20 μL), and lyophilization gave 1-(1-azaspiro[3.3]heptane-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (8.35 mg, 15.33 μmol, 5% yield, 95% purity) as a white solid.

[0292] 1H NMR (400 MHz, DMSO-d6) δ= 10.86 (s, 1H), 8.11 (br d, J = 7.1 Hz, 1H), 6.15 (br d, J = 11.3 Hz, 2H), 5.05 - 4.95 (m, 1H), 4.48 - 4.35 (m, 1H), 4.15 - 4.07 (m, 4H), 4.03 (br dd, J = 4.9, 12.4 Hz, 1H), 3.79 - 3.68 (m, 4H), 3.64 (br t, J = 6.4 Hz, 2H), 2.82 - 2.64 (m, 4H), 2.24 (br t, J = 7.2 Hz, 2H), 2.11 - 2.02 (m, 1H), 1.99 - 1.87 (m, 3H), 1.69 - 1.59 (m, 1H), 1.57 - 1.49 (m, 1H). MS (ESI) m / z.518.4 [M+H] +

[0293] Example 34. Synthesis of Compound 34 [ka] Step 1. Preparation of compound 2, phenethyl carbonochloridate. To a solution of 2-phenylethan-1-ol (400 mg, 3.27 mmol, 392 μL, 1.00 equiv) in dichloromethane (2.00 mL) was added bis(trichloromethyl)carbonate (1.46 g, 4.91 mmol, 1.50 equiv) and N,N-diisopropylethylamine (1.27 g, 9.82 mmol, 1.71 mL, 3.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give phenethyl carbonochloridate (300 mg, crude) as a yellow solid.

[0294] Step 2. Procedure for the preparation of phenethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 256 μmol, 1.00 equiv, mesylate salt) in dichloromethane (5.00 mL) was added N,N-diisopropylethylamine (99.1 mg, 767 μmol, 134 μL, 3.00 equiv) and phenethyl carbonochloridate (70.8 mg, 383 μmol, 1.50 equiv). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give phenethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (18.41 mg, 40.69 μmol, 16% yield, 98% purity) as a pale yellow solid.

[0295] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.84 (br d, J = 7.1 Hz, 1H), 7.34 - 7.21 (m, 5H), 6.14 (br d, J = 11.3 Hz, 2H), 4.41 (br dd, J = 6.1, 7.2 Hz, 1H), 4.18 (t, J = 6.9 Hz, 2H), 4.12 - 4.05 (m, 2H), 4.02 (br d, J = 5.3 Hz, 1H), 3.63 (br t, J = 6.1 Hz, 2H), 2.87 (t, J = 6.8 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.48 (br s, 1H), 2.13 - 2.02 (m, 1H), 1.99 - 1.91 (m, 1H). MS (ESI) m / z 444.3 [M+H] +

[0296] Example 35. Synthesis of Compound 35 [ka] Step 1. Procedure for compound 1A 4-(trifluoromethoxy)benzyl carbonochloridate. To a solution of (4-(trifluoromethoxy)phenyl)methanol (500 mg, 2.60 mmol, 376 μL, 1.00 equiv) in dichloromethane (5.00 mL) was added bis(trichloromethyl)carbonate (1.16 g, 3.90 mmol, 1.50 equiv) and N,N-diisopropylethylamine (673 mg, 5.20 mmol, 907 μL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-(trifluoromethoxy)benzyl carbonochloridate (600 mg, crude) as a colorless oil.

[0297] Step 2. Procedure for 4-(trifluoromethoxy)benzyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 4-(trifluoromethoxy)benzyl carbonochloridate (200 mg, 786 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added N,N-diisopropylethylamine (203 mg, 1.57 mmol, 274 μL, 2.00 equiv) and 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (232 mg, 593 μmol, 0.754 equiv, mesylate salt). The mixture was stirred at 25° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 40% to 70%, 8 min) and lyophilized to give 4-(trifluoromethoxy)benzyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (33.91 mg, 65.39 umol, yield 8%, purity 99%) as an off-white solid.

[0298] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.02 (br d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.15 (d, J = 11.1 Hz, 2H), 5.07 (s, 2H), 4.49 - 4.40 (m, 1H), 4.10 (t, J = 7.6 Hz, 2H), 4.06 - 4.00 (m, 1H), 3.64 (br t, J = 6.6 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.57 - 2.52 (m, 1H), 2.12 - 2.02 (m, 1H), 1.97 - 1.90 (m, 1H). MS (ESI) m / z 514.0 [M+H] +

[0299] Example 36. Synthesis of Compound 36 [ka] Step 1. Preparation of Compound 2, piperidine-1-carbonyl chloride. To a solution of piperidine (45.0 mg, 528 μmol, 52.2 μL, 1.00 equiv) in dichloromethane (1.00 mL) was added bis(trichloromethyl)carbonate (235 mg, 792 μmol, 1.50 equiv) and N,N-diisopropylethylamine (102 mg, 793 μmol, 138 μL, 1.50 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give piperidine-1-carbonyl chloride (62.0 mg, crude) as a yellow solid.

[0300] Step 2. Procedure for the preparation of 1-(piperidine-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (194 mg, 381 μmol, 1.00 equiv, trifluoroacetate salt) in dimethylformamide (2.00 mL) was added N,N-diisopropylethylamine (98.7 mg, 763 μmol, 133 μL, 2.00 equiv) and piperidine-1-carbonyl chloride (62.0 mg, 420 μmol, 52.5 μL, 1.10 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 29% to 59%, 9 min) and lyophilized to give 1-(piperidine-1-carbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (19.75 mg, 38.68 umol, 10% yield, 99% purity) as a white solid.

[0301] 1 H NMR (400MHz, DMSO-d6) δ= 10.91 - 10.77 (m, 1H), 8.14 - 8.03 (m, 1H), 6.15 (br d, J = 11.0 Hz, 2H), 5.07 - 4.93 (m, 1H), 4.48 - 4.35 (m, 1H), 4.17 - 4.07 (m, 4H), 4.03 (br dd, J = 4.9, 12.7 Hz, 1H), 3.75 (br dd, J = 3.8, 9.5 Hz, 2H), 3.64 (br t, J = 6.8 Hz, 2H), 3.20 - 3.14 (m, 4H), 2.82 - 2.73 (m, 1H), 2.48 - 2.45 (m, 1H), 2.14 - 2.03 (m, 1H), 1.99 - 1.90 (m, 1H), 1.52 (br d, J = 4.3 Hz, 2H), 1.42 (br d, J = 3.8 Hz, 4H). MS (ESI) m / z 506.2 [M+H] +

[0302] Example 37. Synthesis of Compound 37 [ka] Step 1. Procedure for the preparation of benzyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (300 mg, 767 μmol, 1.00 equiv, mesylate salt) in dimethylformamide (2.00 mL) was added N,N-diisopropylethylamine (198 mg, 1.53 mmol, 267 μL, 2.00 equiv) and benzyl carbonochloridate (131 mg, 767 μmol, 109 μL, 1.00 equiv). The reaction mixture was stirred at 0° C. for 0.15 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 0 to 1 / 1) and concentrated under reduced pressure to give a solid. The solid was diluted with water (10 mL) and lyophilized to give benzyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (237.14 mg, 546.72 umol, 71% yield, 99% purity) as a white solid.

[0303] 1H NMR (400 MHz, DMSO-d) δ = 10.87 (s, 1H), 7.99 (br d, J = 7.4 Hz, 1H), 7.40 - 7.29 (m, 5H), 6.16 (s, 1H), 6.14 (s, 1H), 5.04 (s, 2H), 4.50 - 4.40 (m, 1H), 4.10 (t, J = 7.6 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.64 (t, J = 6.8 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.50 - 2.45 (m, 1H), 2.07 (dq, J = 3.7, 12.9 Hz, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 430.0 [M+H] +

[0304] Example 38. Synthesis of Compound 38 [ka] Step 1. Acid 38-1 (0.5 g, 2.4 mmol) was dissolved in a mixture of compound 38-2 / DXN (2 / 10 mL), then triethylamine (0.4 mL, 3 mmol) and DPPA (0.6 mL, 3 mmol) were added, and the reaction mixture was stirred at 40 °C for 1 h and refluxed overnight. The resulting mixture was cooled to room temperature, and ethyl acetate (40 mL) was added; the organic layer was washed with 10% aqueous KCO (5 × 30 mL) and brine (1 × 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give crude product 38-3 (0.3 g, 29%), which was used in the next step without further purification.

[0305] 1H NMR (400 MHz, Chloroform-d) δ 4.79 (s, 1H), 3.96 (d, J = 7.0 Hz, 2H), 2.74 (s, 1H), 2.38 (s, 1H), 2.07 - 2.00 (m, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.87 (t, J = 7.4 Hz, 2H), 1.80 - 1.72 (m, 2H), 1.72 - 1.65 (m, 2H), 1.19 (s, 12H), 0.87 (d, J = 5.3 Hz, 1H), 0.83 - 0.73 (m, 1H), 0.08 - -0.07 (m, 1H).

[0306] Step 2. A mixture of compound 38-3 (0.25 g, 0.75 mmol), compound 38-4 (0.23 g, 0.75 mmol), and KCO (0.2 g, 1.5 mmol) in DXN / HO (5:2, 15 mL) was purged with argon, and cataCXium A Pd G (0.03 g) and cataCXium A (0.015 g) were added. The reaction mixture was heated at 90 °C overnight. The mixture was then cooled to room temperature and filtered. The solution was concentrated under reduced pressure, and the residue was diluted with EtOAc and water. The organic layer was washed with water, brine, dried over NaSO, and evaporated in vacuo. The residue was purified by HPLC to give compound 38 (25.5 mg, 8% yield).

[0307] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.33 (d, J = 10.1 Hz, 1H), 6.93 (d, J = 10.2 Hz, 2H), 6.59 - 6.37 (m, 1H), 5.25 - 5.00 (m, 1H), 4.19 (dd, J = 12.8, 5.2 Hz, 1H), 3.95 (d, J = 6.9 Hz, 2H), 3.28 (d, J = 7.1 Hz, 2H), 2.88 - 2.72 (m, 1H), 2.45 - 2.28 (m, 2H), 2.16 - 1.94 (m, 6H), 1.88 (t, J = 7.4 Hz, 2H), 1.81 - 1.63 (m, 4H). HPLC purity: 100%; retention time: 1.446 min; C in HRMS (ESI). 23 H 26 Calculated for F2N2O4: 432.19; Found: 431.0 [MH] -

[0308] Example 39. Synthesis of Compound 39 [ka] Step 1. Procedure for compound 2 (((1s,3s)-3-isopropoxycyclobutoxy)methyl)benzene. To a solution of (1s,3s)-3-(benzyloxy)cyclobutanol (200 mg, 1.12 mmol, 1.00 equiv) in toluene (5.00 mL) was added 2-iodopropane (382 mg, 2.24 mmol, 224 μL, 2.00 equiv). Argentiooxysilver (520 mg, 2.24 mmol, 2.00 equiv) was then added to the mixture, and the reaction mixture was stirred at 72 °C under a nitrogen atmosphere in the dark for 48 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 10 / 1) to give (((1s,3s)-3-isopropoxycyclobutoxy)methyl)benzene (100 mg, crude) as a colorless oil.

[0309] 1 H NMR (400 MHz, CDCl3-d) δ = 7.42 - 7.32 (m, 4H), 7.31 - 7.27 (m, 1H), 4.44 (s, 2H), 3.72 - 3.56 (m, 3H), 2.68 - 2.60 (m, 2H), 2.03 - 1.94 (m, 2H), 1.15 (d, J = 6.1 Hz, 6H).

[0310] Step 2. Procedure for the preparation of compound 3 (1s,3s)-3-isopropoxycyclobutanol. To a solution of (((1s,3s)-3-isopropoxycyclobutoxy)methyl)benzene (50.0 mg, 227 μmol, 1.00 equiv) in methanol (1.00 mL) was added palladium on activated carbon (100 mg, 10% purity). The mixture was stirred under a hydrogen atmosphere of 15 psi at 25° C. for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (1s,3s)-3-isopropoxycyclobutanol (59.0 mg, crude) as a colorless oil. 1 H NMR (400 MHz, CDCl-d) δ = 3.95 - 3.85 (m, 1H), 3.64 - 3.53 (m, 2H), 2.77 - 2.66 (m, 2H), 1.99 - 1.83 (m, 3H), 1.14 - 1.11 (m, 6H).

[0311] Step 3. Procedure for compound 4 (1s,3s)-3-isopropoxycyclobutyl carbonochloridate. To a solution of (1s,3s)-3-isopropoxycyclobutanol (59.0 mg, 453 μmol, 1.00 equiv) in dichloromethane (2.00 mL) was added bis(trichloromethyl)carbonate (202 mg, 680 μmol, 1.50 equiv) and N,N-diisopropylethylamine (117 mg, 906 μmol, 158 μL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give (1s,3s)-3-isopropoxycyclobutylcarbonochloridate (87.3 mg, crude) as a colorless oil.

[0312] Step 4. Procedure for spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (135 mg, 457 μmol, 1.00 equiv) in dichloromethane (3.00 mL) was added N,N-diisopropylethylamine (118 mg, 914 μmol, 159 μL, 2.00 equiv) and (1s,3s)-3-isopropoxycyclobutylcarbonochloridate (87.0 mg, 452 μmol, 0.998 equiv). The mixture was stirred at 25° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 34% to 64%, min) and lyophilized to give a white solid of (1s,3s)-3-isopropoxycyclobutyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (12.97mg, 25.55umol, yield 6%, purity 98%, formate salt).

[0313] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (br s, 1H), 8.44 (s, 1H), 7.87 (br d, J = 7.5 Hz, 1H), 6.14 (d, J = 11.1 Hz, 2H), 4.52 - 4.43 (m, 1H), 4.43 - 4.34 (m, 1H), 4.11 - 4.00 (m, 3H), 3.72 - 3.65 (m, 1H), 3.65 - 3.58 (m, 2H), 3.57 - 3.49 (m, 1H), 2.83 - 2.72 (m, 1H), 2.69 - 2.61 (m, 2H), 2.47 (br s, 1H), 2.14 - 2.00 (m, 1H), 1.99 - 1.89 (m, 1H), 1.87 - 1.76 (m, 2H), 1.05 (d, J = 6.1 Hz, 6H). MS (ESI) m / z 452.1 [M+H] +

[0314] Example 40. Synthesis of Compound 40 [ka] Step 1. Procedure for compound 2 tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)azetidine-1-carboxylate. To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g, 28.9 mmol, 1.00 equiv.) in dichloromethane (50.0 mL) was added 4-nitrophenyl carbonochloridate (20.4 g, 101 mmol, 3.50 equiv.) and triethylamine (14.6 g, 144 mmol, 20.1 mL, 5.00 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)azetidine-1-carboxylate (9.00 g, 5.32 mmol, 18% yield, 20% purity) as a yellow oil.

[0315] 1 H NMR (400 MHz, CDCl3-d) δ = 8.33 - 8.26 (m, 2H), 7.42 - 7.36 (m, 2H), 5.31 - 5.20 (m, 1H), 4.35 (dd, J = 6.7, 10.4 Hz, 2H), 4.10 (dd, J = 4.0, 10.5 Hz, 2H), 1.48 (s, 9H).

[0316] Step 2. Procedure for compound 3 tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate. To a solution of tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)azetidine-1-carboxylate (4.49 g, 2.66 mmol, 20% purity, 1.00 equiv.) in dimethylformamide (10.0 mL) was added 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (1.00 g, 2.66 mmol, 1.00 equiv., methanesulfonic acid) and triethylamine (538 mg, 5.31 mmol, 740 μL, 2.00 equiv.). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (1.20 g, crude) as a yellow solid.

[0317] 1H NMR (400 MHz, CDCl3-d) δ = 8.06 (br s, 1H), 5.97 (d, J = 10.4 Hz, 2H), 5.51 (br d, J = 7.8 Hz, 1H), 5.20 - 5.03 (m, 1H), 4.71 - 4.51 (m, 1H), 4.24 - 4.17 (m, 4H), 3.93 - 3.88 (m, 2H), 3.68 (br t, J = 5.9 Hz, 2H), 2.85 - 2.74 (m, 1H), 2.71 - 2.60 (m, 1H), 2.31 (dq, J = 4.6, 12.9 Hz, 1H), 2.17 - 2.07 (m, 1H), 1.44 (s, 9H).

[0318] Step 3. Procedure for compound 4 azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl-3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (250 mg, 506 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.00 mL). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (199 mg, 505 μmol, 99% yield) as a yellow oil.

[0319] 1H NMR (400 MHz, DMSO-d6) δ = 10.82 - 10.62 (m, 1H), 8.21 - 8.09 (m, 1H), 6.28 - 6.18 (m, 1H), 6.08 (d, J = 11.0 Hz, 1H), 5.03 (br t, J = 6.2 Hz, 1H), 4.35 - 4.15 (m, 6H), 3.57 (br d, J = 7.1 Hz, 1H), 3.52 - 3.42 (m, 1H), 3.34 (br d, J = 5.6 Hz, 1H), 3.23 (br d, J = 6.4 Hz, 1H), 3.13 - 2.90 (m, 1H), 2.74 - 2.68 (m, 1H), 2.51 - 2.45 (m, 1H), 2.06 - 1.94 (m, 1H), 1.91 - 1.83 (m, 1H).

[0320] Step 4. Procedure for compound 4A cyclopropyl(methyl)carbamic acid chloride. To a solution of N-methylcyclopropanamine (40.0 mg, 562 μmol, 1.00 equiv) in dichloromethane (3.00 mL) were added bis(trichloromethyl)carbonate (250 mg, 844 μmol, 1.50 equiv) and N,N-diisopropylethylamine (109 mg, 844 μmol, 147 μL, 1.50 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give cyclopropyl(methyl)carbamic acid chloride (75.0 mg, 561 μmol, 99% yield) as a yellow oil.

[0321] Step 5. Procedure for 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (199 mg, 505 umol, 1.00 equiv.) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (130 mg, 1.01 mmol, 176 uL, 2.00 equiv.) and cyclopropyl(methyl)carbamic acid chloride (74.1 mg, 555 umol, 1.10 equiv.). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 17% to 47%, 9 min). To the mixture was added formic acid (0.1 mL), and the mixture was lyophilized to give 1-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (29.91 mg, 59.64 umol, 12% yield, 98% purity) as a white solid.

[0322] 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 (br s, 1H), 8.11 (br d, J = 7.6 Hz, 1H), 6.16 (d, J = 11.0 Hz, 2H), 5.12 - 4.96 (m, 1H), 4.48 - 4.36 (m, 1H), 4.23 (dd, J = 6.6, 9.6 Hz, 2H), 4.10 (br t, J = 7.5 Hz, 2H), 4.04 (br dd, J = 5.4, 12.7 Hz, 1H), 3.82 (br dd, J = 3.8, 9.8 Hz, 2H), 3.70 - 3.62 (m, 2H), 2.86 - 2.75 (m, 2H), 2.73 (s, 3H), 2.57 (br d, J = 3.4 Hz, 1H), 2.13 - 2.03 (m, 1H), 2.00 - 1.89 (m, 1H), 0.77 - 0.70 (m, 2H), 0.68 - 0.58 (m, 2H). MS (ESI) m / z.492.0 [M+H] +

[0323] Example 41. Synthesis of Compound 41 [ka] Step 1. Procedure for the preparation of compound 2, cyclopropyl(3-hydroxyazetidin-1-yl)methanone. To a solution of azetidin-3-ol (524 mg, 4.78 mmol, 1.00 equiv, hydrochloride salt) and N,N-diisopropylethylamine (1.85 g, 14.4 mmol, 2.50 mL, 3.00 equiv) in tetrahydrofuran (5.00 mL) was added cyclopropanecarbonyl chloride (500 mg, 4.78 mmol, 435 μL, 1.00 equiv) at 0° C. The reaction was then stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=0 / 1) to give cyclopropyl(3-hydroxyazetidin-1-yl)methanone (550 mg, 3.90 mmol, 81% yield) as a white solid.

[0324] 1 H NMR (400 MHz, CDCl3) δ = 4.65 (tt, J = 4.4, 6.8 Hz, 1H), 4.49 - 3.82 (m, 4H), 3.57 (br s, 1H), 1.45 - 1.37 (m, 1H), 0.97 - 0.89 (m, 2H), 0.81 - 0.72 (m, 2H).

[0325] Step 2. Procedure for the preparation of compound 3, 1-(cyclopropanecarbonyl)azetidin-3-yl(4-nitrophenyl)carbonate. To a solution of cyclopropyl(3-hydroxyazetidin-1-yl)methanone (200 mg, 1.42 mmol, 1.00 equiv) in dichloromethane (3.00 mL) was added triethylamine (717 mg, 7.08 mmol, 986 μL, 5.00 equiv) at 0° C. After 15 minutes, 4-nitrophenyl carbonochloridate (857 mg, 4.25 mmol, 3.00 equiv) was added to the mixture. The reaction was then stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1) to give 1-(cyclopropanecarbonyl)azetidin-3-yl(4-nitrophenyl)carbonate (240 mg, 392 μmol, 27% yield, 50% purity) as a yellow solid.

[0326] 1 H NMR (400 MHz, CDCl3) δ = 8.34 - 8.28 (m, 2H), 7.43 - 7.38 (m, 2H), 5.38 - 5.32 (m, 1H), 4.69 - 4.49 (m, 2H), 4.25 - 4.12 (m, 2H), 1.41 - 1.39 (m, 1H), 1.00 - 0.97 (m, 2H), 0.78 (br dd, J = 3.0, 8.3 Hz, 2H).

[0327] Step 3. Procedure for the preparation of 1-(cyclopropanecarbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(cyclopropanecarbonyl)azetidin-3-yl(4-nitrophenyl)carbonate (50.0 mg, 163 μmol, 1.00 equiv.), 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (63.9 mg, 163 μmol, 1.00 equiv., methanesulfonic acid) in dimethylformamide (0.500 mL) was added triethylamine (33.1 mg, 327 μmol, 45.5 μL, 2.00 equiv.). The reaction was then stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [column: Waters xbridge 150*25mm10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 13% to 43%, 13 min) and lyophilized to give 1-(cyclopropanecarbonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (34.37 mg, 73.58 umol, yield 90%, purity 99%) as a white solid.

[0328] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (br s, 1H), 8.15 (br d, J = 7.5 Hz, 1H), 6.17 (s, 1H), 6.14 (s, 1H), 5.12 - 5.07 (m, 1H), 4.56 - 4.50 (m, 1H), 4.45 - 4.39 (m, 1H), 4.11 (br d, J = 7.6 Hz, 4H), 4.06 - 4.01 (m, 1H), 3.73 - 3.69 (m, 1H), 3.65 (br d, J = 6.9 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.48 (br s, 1H), 2.12 - 2.03 (m, 1H), 1.96 - 1.90 (m, 1H), 1.55 - 1.50 (m, 1H), 0.72 - 0.67 (m, 4H). MS (ESI) m / z 463.1 [M+H] +

[0329] Example 42. Synthesis of Compound 42 [ka] Step 1. Procedure for the preparation of compound 2, 1-(cyclopropylsulfonyl)azetidin-3-ol. To a solution of azetidin-3-ol (779 mg, 7.11 mmol, 1.00 equiv, hydrochloride salt), N,N-diisopropylethylamine (2.76 g, 21.3 mmol, 3.72 mL, 3.00 equiv) in tetrahydrofuran (5.00 mL) was added cyclopropanesulfonyl chloride (1.00 g, 7.11 mmol, 1.00 equiv) at 0 °C. The reaction was then stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 0 / 1) to give 1-(cyclopropylsulfonyl)azetidin-3-ol (1.25 g, 7.05 mmol, 99% yield) as an orange oil.

[0330] 1 H NMR (400 MHz, CDCl3) δ = 4.64 - 4.57 (m, 1H), 4.11 - 4.07 (m, 2H), 3.92 - 3.87 (m, 2H), 2.95 (br s, 1H), 2.38 (tt, J = 4.9, 8.0 Hz, 1H), 1.17 - 1.12 (m, 2H), 1.05 - 1.00 (m, 2H).

[0331] Step 2. Procedure for the preparation of compound 3, 1-(cyclopropylsulfonyl)azetidin-3-yl(4-nitrophenyl)carbonate. To a solution of 1-(cyclopropylsulfonyl)azetidin-3-ol (400 mg, 2.26 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added triethylamine (1.14 g, 11.3 mmol, 1.57 mL, 5.00 equiv) at 0 °C. After 15 min, 4-nitrophenyl carbonochloridate (1.36 g, 6.77 mmol, 3.00 equiv) was added to the mixture. The reaction was then stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1) to give 1-(cyclopropylsulfonyl)azetidin-3-yl(4-nitrophenyl)carbonate (550 mg, 1.12 mmol, 49% yield, 70% purity) as an off-white solid.

[0332] 1 H NMR (400 MHz, CDCl3) δ = 8.32 - 8.27 (m, 2H), 7.42 - 7.37 (m, 2H), 5.28 (tt, J = 5.0, 6.6 Hz, 1H), 4.31 - 4.25 (m, 2H), 4.04 - 4.00 (m, 2H), 2.40 - 2.37 (m, 1H), 1.18 (br dd, J = 1.8, 2.9 Hz, 2H), 1.06 - 1.03 (m, 2H).

[0333] Step 3. Procedure for the preparation of 1-(cyclopropylsulfonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(cyclopropylsulfonyl)azetidin-3-yl(4-nitrophenyl)carbonate (50.0 mg, 146 μmol, 1.00 equiv.), 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (57.2 mg, 146 μmol, 1.00 equiv., methanesulfonic acid) in dimethylformamide (0.500 mL) was added triethylamine (29.6 mg, 292 μmol, 40.7 μL, 2.00 equiv.). The reaction was then stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20% to 80%, 8 min) and lyophilized to give 1-(cyclopropylsulfonyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (13.01 mg, 25.84 umol, yield 17%, purity 99%) as a white solid.

[0334] 1 H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.19 (br d, J = 7.4 Hz, 1H), 6.17 (s, 1H), 6.15 (s, 1H), 5.12 - 5.06 (m, 1H), 4.47 - 4.38 (m, 1H), 4.18 - 4.09 (m, 4H), 4.04 (br dd, J = 5.1, 12.6 Hz, 1H), 3.86 (br dd, J = 4.9, 9.1 Hz, 2H), 3.66 (br t, J = 6.8 Hz, 2H), 3.30 - 3.19 (m, 1H), 2.82 - 2.73 (m, 2H), 2.11 - 2.03 (m, 1H), 1.98 - 1.92 (m, 1H), 1.05 - 1.02 (m, 2H), 0.97 - 0.93 (m, 2H). MS (ESI) m / z 499.1 [M+H] +

[0335] Example 43. Synthesis of Compound 43 [ka] Step 1. Procedure for the preparation of compound 2 (cyclopropylmethyl)(methyl)carbamic acid chloride. To a solution of 1-cyclopropyl-N-methyl-methanamine (35.0 mg, 411 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added bis(trichloromethyl)carbonate (195 mg, 658 μmol, 1.60 equiv) and N,N-diisopropylethylamine (106 mg, 822 μmol, 143 μL, 2.00 equiv) at 25° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (cyclopropylmethyl)(methyl)carbamic acid chloride (60.0 mg, crude) as a yellow solid.

[0336] Step 2. Procedure for preparation of compound 3, azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (250 mg, 506 umol, 1.00 equiv) in dichloromethane (4.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 26.7 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (190 mg, 482 umol, 95% yield) as a yellow solid. MS (ESI) m / z 395.0 [M+H] +

[0337] Step 3. Procedure for the preparation of 1-((cyclopropylmethyl)(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (159 mg, 403 umol, 1.00 equiv.) in dichloromethane (5.00 mL) was added N,N-diisopropylethylamine (156 mg, 1.21 mmol, 211 uL, 3.00 equiv.) and (cyclopropylmethyl)(methyl)carbamic acid chloride (53.6 mg, 363 umol, 0.900 equiv.). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 29% to 59%, 9 min) and lyophilized to give 1-((cyclopropylmethyl)(methyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (30.53 mg, 59.79 umol, yield 14.83%, purity 99%) as a white solid.

[0338] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.10 (br d, J = 7.5 Hz, 1H), 6.15 (d, J = 11.0 Hz, 2H), 5.09 - 4.94 (m, 1H), 4.48 - 4.37 (m, 1H), 4.18 - 4.00 (m, 5H), 3.75 (br dd, J = 4.0, 9.5 Hz, 2H), 3.64 (br t, J = 6.7 Hz, 2H), 3.00 (d, J = 6.8 Hz, 2H), 2.80 (s, 3H), 2.75 (br dd, J = 5.2, 12.9 Hz, 1H), 2.53 - 2.51 (m, 1H), 2.07 (br dd, J = 3.5, 13.3 Hz, 1H), 1.99 - 1.84 (m, 1H), 0.94 - 0.85 (m, 1H), 0.50 - 0.33 (m, 2H), 0.23 - 0.13 (m, 2H). MS (ESI) m / z 506.1 [M+H] +

[0339] Example 44. Synthesis of Compound 44 [ka] Step 1. Procedure for the preparation of compound 8A spiro[3.3]heptan-2-ylmethyl carbonochloridate. To a solution of spiro[3.3]heptan-2-ylmethanol (60.0 mg, 475 μmol, 1.00 equiv) in dichloromethane (2.00 mL) was added bis(trichloromethyl)carbonate (226 mg, 761 μmol, 1.60 equiv) and N,N-diisopropylethylamine (123 mg, 951 μmol, 166 μL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give spiro[3.3]heptan-2-ylmethyl carbonochloridate (80 mg, crude) as a yellow solid.

[0340] Step 2. Procedure for the preparation of compound 2 (4-bromo-2-fluoro-3-methoxyphenyl)methanol. To a solution of 4-bromo-2-fluoro-3-methoxybenzoic acid (3.70 g, 14.9 mmol, 1.00 equiv.) in tetrahydrofuran (20.0 mL) was added dropwise borane tetrahydrofuran complex (1.00 M, 59.4 mL, 4.00 equiv.) at 0 °C under a nitrogen atmosphere. After the addition, the mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by the slow addition of methanol (20.0 mL) at 25 °C and then diluted with water (10.0 mL). The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1) to give 4-bromo-2-fluoro-3-methoxyphenyl)methanol (3.00 g, 12.8 mmol, 86% yield) as a colorless oil.

[0341] 1 H NMR (400 MHz, DMSO-d6) δ = 7.44 (dd, J = 1.5, 8.4 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 5.37 (t, J = 5.8 Hz, 1H), 4.52 (d, J = 5.5 Hz, 2H), 3.86 (d, J = 0.8 Hz, 3H).

[0342] Step 3. Preparation procedure for compound 3, 1-bromo-4-(chloromethyl)-3-fluoro-2-methoxybenzene. To a solution of (4-bromo-2-fluoro-3-methoxy-phenyl)methanol (3.00 g, 12.8 mmol, 1.00 equiv.) in dichloromethane (30.0 mL) was added thionyl chloride (3.04 g, 25.5 mmol, 1.85 mL, 2.00 equiv.). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1) to give 1-bromo-4-(chloromethyl)-3-fluoro-2-methoxybenzene (2.60 g, 10.3 mmol, 80% yield) as a colorless oil.

[0343] 1 H NMR (400 MHz, CDCl3-d) δ = 7.25 (dd, J = 1.9, 8.4 Hz, 1H), 7.03 - 6.89 (m, 1H), 4.52 (d, J = 1.3 Hz, 2H), 3.90 (d, J = 1.4 Hz, 3H).

[0344] Step 4. Procedure for the preparation of compound 4, 2-(4-bromo-2-fluoro-3-methoxyphenyl)acetonitrile. To a solution of 1-bromo-4-(chloromethyl)-3-fluoro-2-methoxybenzene (2.60 g, 103 mmol, 1.00 equiv.) in acetonitrile (40.0 mL), trimethylsilanecarbonitrile (3.05 g, 30.8 mmol, 3.85 mL, 3.00 equiv.) and tetrabutylammonium fluoride (1.00 M, 30.77 mL, 3.00 equiv.) were added. The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by adding water (10 mL) and then extracted with ethyl acetate (3 × 10 mL). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 50 / 1) to give 2-(4-bromo-2-fluoro-3-methoxyphenyl)acetonitrile (2.00 g, 8.19 mmol, 80% yield) as a white solid.

[0345] 1 H NMR (400 MHz, CDCl3-d) δ = 7.29 (dd, J = 1.0, 8.4 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 3.90 (s, 3H), 3.65 (s, 2H).

[0346] Step 5. Procedure for the preparation of compound 5, methyl 4-(4-bromo-2-fluoro-3-methoxyphenyl)-4-cyanobutanoate. To a solution of 2-(4-bromo-2-fluoro-3-methoxyphenyl)acetonitrile (500 mg, 2.05 mmol, 1.00 equiv) in tetrahydrofuran (6.00 mL) was added sodium methylate (16.6 mg, 307 umol, 0.150 equiv) at 0° C., and then methyl acrylate (194 mg, 2.25 mmol, 203 uL, 1.10 equiv) was added to the mixture at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted by adding water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give methyl 4-(4-bromo-2-fluoro-3-methoxyphenyl)-4-cyanobutanoate (600 mg, 1.82 mmol, 89% yield) as a white solid.

[0347] 1 H NMR (400 MHz, CDCl3-d) δ = 7.31 (dd, J = 1.9, 8.5 Hz, 1H), 6.98 (dd, J = 7.1, 8.4 Hz, 1H), 4.24 - 4.11 (m, 1H), 3.90 (d, J = 1.4 Hz, 3H), 2.45 (q, J = 7.4 Hz, 2H), 2.16 (dq, J = 2.3, 7.3 Hz, 2H)

[0348] Step 6. Procedure for the preparation of compound 6, 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione. To a solution of methyl 4-(4-bromo-2-fluoro-3-methoxyphenyl)-4-cyanobutanoate (500 mg, 1.51 mmol, 1.00 equiv) in acetic acid (5.00 mL) was added sulfuric acid (920 mg, 9.38 mmol, 0.500 mL, 6.19 equiv). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was diluted with water (10 mL) and filtered. The filter cake was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (5 mL) and then filtered. The second filter cake was concentrated under reduced pressure to give 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione (450 mg, 1.42 mmol, 94% yield) as a gray solid.

[0349] 1 H NMR (400 MHz, DMSO-d6) δ = 10.92 (s, 1H), 7.44 (dd, J = 1.6, 8.4 Hz, 1H), 7.09 - 6.95 (m, 1H), 4.10 (br dd, J = 4.9, 12.7 Hz, 1H), 3.86 (s, 3H), 2.78 - 2.70 (m, 1H), 2.56 - 2.52 (m, 1H), 2.28 - 2.17 (m, 1H), 2.10 - 1.96 (m, 1H).

[0350] Step 7. Procedure for the preparation of compound 6 tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate. A mixture of 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione (100 mg, 316 μmol, 1.00 equiv.), tert-butyl azetidin-3-ylcarbamate (81.7 mg, 475 μmol, 1.50 equiv.), cesium carbonate (309 mg, 949 μmol, 3.00 equiv.), and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (30.8 mg, 31.6 μmol, 0.100 equiv.) in dioxane (3.00 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. under nitrogen for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate (50.0 mg, 123 μmol, 39% yield) as a yellow oil. MS (ESI) m / z 407.9 [M+H] +

[0351] Step 8. Procedure for the preparation of compound 8, 3-(4-(3-aminoazetidin-1-yl)-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate (50.0 mg, 123 μmol, 1.00 equiv) in dichloromethane (4.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 110 equiv). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione (30 mg, 97.6 μmol, 80% yield) as a white solid. MS (ESI) m / z 308.0 [M+H] +

[0352] Step 9. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2-fluoro-3-methoxyphenyl)piperidine-2,6-dione (30.0 mg, 97.6 μmol, 1.00 equiv) in dichloromethane (2.00 mL) was added N,N-diisopropylethylamine (37.9 mg, 293 μmol, 51.0 μL, 3.00 equiv) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (18.4 mg, 97.6 μmol, 1.00 equiv). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate (10.84 mg, 23.35 μmol, 23.92% yield, 99% purity) as a white solid.

[0353] 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 7.77 (br d, J = 7.4 Hz, 1H), 6.81 (t, J = 8.1 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.14 (t, J = 7.6 Hz, 2H), 3.85 (m, 3H), 3.69 (s, 3H), 3.65 (t, J = 7.1 Hz, 2H), 2.72 - 2.68 (m, 1H), 2.38 - 2.33 (m, 1H), 2.21 - 2.04 (m, 2H), 2.03 - 1.84 (m, 7H), 1.80 - 1.69 (m, 4H). MS (ESI) m / z 460.2 [M+H] +

[0354] Example 45. Synthesis of Compound 45 [ka] Step 1. Procedure for the preparation of 1-(dimethylcarbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(dimethylcarbamoyl)azetidin-3-yl(4-nitrophenyl)carbonate (50.0 mg, 113 μmol, 70% purity, 1.00 equiv.), 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (44.3 mg, 113 μmol, 1.00 equiv., methanesulfonic acid) in dimethylformamide (0.500 mL) was added triethylamine (22.9 mg, 226 μmol, 31.5 μL, 2.00 equiv.). The reaction was then stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 21% to 51%, 58 min) and lyophilized to give 1-(dimethylcarbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (20.40mg, 42.51umol, yield 37%, purity 97%) as a white solid.

[0355] 1H NMR (400 MHz, DMSO-d) δ = 10.85 (br s, 1H), 8.10 (br d, J = 6.4 Hz, 1H), 6.15 (br d, J = 11.3 Hz, 2H), 5.00 (br s, 1H), 4.42 (br d, J = 6.1 Hz, 1H), 4.20 - 4.07 (m, 4H), 4.07 - 4.01 (m, 1H), 3.76 (br d, J = 5.3 Hz, 2H), 3.65 (br s, 2H), 2.75 (br s, 8H), 2.14 - 2.02 (m, 1H), 1.96 (br s, 1H). MS (ESI) m / z 466.1 [M+H] +

[0356] Example 46. Synthesis of Compound 46 [ka] Step 1. Procedure for the preparation of compound 3 (((1s,3s)-3-(tert-butoxy)cyclobutoxy)methyl)benzene. To a solution of (1s,3s)-3-(benzyloxy)cyclobutanol (100 mg, 561 μmol, 1.00 equiv.), perchloric acid (84.6 mg, 841 μmol, 50.9 μL, 1.50 equiv.) in dichloromethane (2.00 mL) was added 2-methylprop-1-ene (2.40 M, 2.34 mL, 10.0 equiv.) at −70° C. The reaction was then stirred at −40° C. for 12 hours. The reaction was neutralized with saturated aqueous sodium carbonate (5 mL) and then extracted with dichloromethane (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1) to give (((1s,3s)-3-(tert-butoxy)cyclobutoxy)methyl)benzene (110 mg, 469 umol, 83% yield) as a colorless oil.

[0357] 1H NMR (400 MHz, CDCl3) δ = 7.28 - 7.17 (m, 5H), 4.33 (s, 2H), 3.69 - 3.52 (m, 2H), 2.55 - 2.48 (m, 2H), 1.97 - 1.89 (m, 2H), 1.10 (s, 9H).

[0358] Step 2. Procedure for the preparation of compound 4 (1s,3s)-3-(tert-butoxy)cyclobutanol. To a solution of (((1s,3s)-3-(tert-butoxy)cyclobutoxy)methyl)benzene (110 mg, 469 μmol, 1.00 equiv) in methanol (5.00 mL) was added palladium on activated carbon (220 mg, 10% purity) under a nitrogen atmosphere. The reaction was then stirred at 25° C. under a hydrogen atmosphere at 15 psi for 2 hours. The suspension was filtered, and the filter cake was washed with acetonitrile (10 mL). The combined filtrates were concentrated under reduced pressure to give (1s,3s)-3-(tert-butoxy)cyclobutanol (56.0 mg, 388 μmol, 82% yield) as a colorless oil.

[0359] 1 H NMR (400 MHz, CDCl3) δ = 3.88 (quin, J = 7.3 Hz, 1H), 3.72 - 3.63 (m, 1H), 2.73 - 2.65 (m, 2H), 1.94 - 1.87 (m, 2H), 1.83 (br s, 1H), 1.17 (s, 9H).

[0360] Step 3. Procedure for the preparation of compound 1A (1s,3s)-3-(tert-butoxy)cyclobutyl carbonochloridate. To a solution of (1s,3s)-3-(tert-butoxy)cyclobutanol (56.0 mg, 388 μmol, 1.00 equiv) in dichloromethane (0.500 mL) was added bis(trichloromethyl)carbonate (115 mg, 388 μmol, 1.00 equiv) and N,N-diisopropylethylamine (150 mg, 1.16 mmol, 203 μL, 3.00 equiv) at 0° C. The reaction was then stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give (1s,3s)-3-(tert-butoxy)cyclobutylcarbonochloridate (80.2 mg, crude) as an orange solid.

[0361] Step 4. Procedure for the preparation of (1s,3s)-3-(tert-butoxy)cyclobutyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (1s,3s)-3-(tert-butoxy)cyclobutyl carbonochloridate (80.2 mg, 388 μmol, 1.00 equiv), 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (152 mg, 388 μmol, 1.00 equiv, methanesulfonic acid) in dichloromethane (0.50 mL) was added N,N-diisopropylethylamine (201 mg, 1.55 mmol, 270 μL, 4.00 equiv). The reaction was then stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 32% to 62%, 8 min) and lyophilized to give (1s,3s)-3-(tert-butoxy)cyclobutyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (42.44mg, 82.14umol, yield 21%, purity 99%, formate salt) as a yellow solid.

[0362] 1H NMR (400 MHz, DMSO-d) δ = 10.86 (s, 1H), 8.39 (br s, 1H), 7.86 (br d, J = 7.3 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.50 - 4.43 (m, 1H), 4.42 - 4.35 (m, 1H), 4.07 (br t, J = 7.8 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.83 - 3.76 (m, 1H), 3.61 (br t, J = 6.8 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.64 - 2.58 (m, 2H), 2.47 (br s, 1H), 2.12 - 2.02 (m, 1H), 1.98 - 1.91 (m, 1H), 1.85 - 1.77 (m, 2H), 1.10 (s, 9H). MS (ESI) m / z 466.2 [M+H] +

[0363] Example 47. Synthesis of Compound 47 [ka] Step 1. Procedure for (1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutanol (50.0 mg, 247 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (40.1 mg, 247 μmol, 1.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The resulting solution was added to a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (97.0 mg, 248 μmol, 1.00 equiv, methanesulfonic acid), triethylamine (25.1 mg, 248 μmol, 34.5 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (37.7 mg, 248 μmol, 37.4 μL, 1.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=2 / 1) to give (1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (29.29 mg, 52.58 μmol, 21% yield, 94% purity) as a white solid.

[0364] 1H NMR (400 MHz, DMSO-d6) δ =10.83 (s, 1H), 7.86 (br d, J = 7.3 Hz, 1H), 6.12 (d, J = 11.1 Hz, 2H), 4.89 (td, J = 3.5, 6.8 Hz, 1H), 4.46 (t, J = 6.2 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.11 - 3.97 (m, 3H), 3.60 (t, J = 6.8 Hz, 2H), 2.82 - 2.70 (m, 1H), 2.45 (br s, 1H), 2.32 - 2.22 (m, 2H), 2.21 - 2.13 (m, 2H), 2.05 (dq, J = 3.5, 13.0 Hz, 1H), 1.96 - 1.84 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H). MS (ESI) m / z 524.0 [M+H] +

[0365] Example 48. Synthesis of Compound 48 [ka] Step 1. Procedure for the preparation of (1s,3s)-3-((isopropyldimethylsilyl)oxy)cyclobutyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of (1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutanol (50.0 mg, 247 umol, 1.00 equiv) in tetrahydrofuran (0.500 mL) was added di(1H-imidazol-1-yl)methanone (40.1 mg, 247 umol, 1.00 equiv) at 0° C. The reaction was then stirred at 25° C. for 0.5 h. To the mixture was then added dimethylformamide (0.500 mL), 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 255 umol, 1.00 equiv, methanesulfonic acid), triethylamine (25.9 mg, 255 umol, 35.6 uL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (38.9 mg, 255 umol, 38.5 uL, 1.00 equiv). The reaction was then stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=2 / 1) to give (1s,3s)-3-((isopropyldimethylsilyl)oxy)cyclobutyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (47.32 mg, 89.46 μmol, 35% yield, 99% purity) as a white solid.

[0366] 1H NMR (400 MHz, DMSO-d) δ = 10.85 (s, 1H), 7.86 (br d, J = 7.4 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.47 - 4.36 (m, 2H), 4.08 (br t, J = 7.8 Hz, 2H), 4.05 - 3.92 (m, 2H), 3.61 (br t, J = 6.8 Hz, 2H), 2.83 - 2.74 (m, 1H), 2.67 (tdd, J = 3.3, 6.3, 9.3 Hz, 2H), 2.49 - 2.46 (m, 1H), 2.11 - 2.01 (m, 1H), 1.96 - 1.90 (m, 1H), 1.87 - 1.78 (m, 2H), 0.85 (s, 9H), 0.02 (s, 6H). MS (ESI) m / z 524.2 [M+H] +

[0367] Example 49. Synthesis of Compound 49 [ka] Step 1. Procedure for the preparation of ((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of ((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol (50.0 mg, 231 µmol, 1.00 equiv) in tetrahydrofuran (0.500 mL) was added di(1H-imidazol-1-yl)methanone (56.2 mg, 347 µmol, 1.50 equiv). The mixture was stirred at 20° C. for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (85.0 mg, 217 μmol, 1.00 equiv, methanesulfonic acid), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (33.1 mg, 217 μmol, 32.7 μL, 1.00 equiv), and triethylamine (22.0 mg, 217 μmol, 30.2 μL, 1.00 equiv) in tetrahydrofuran (0.500 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was dissolved in dimethylformamide (0.5 mL) and then filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 18:82) and lyophilized to give ((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (11.08 mg, 19.58 μmol, 9% yield, 95% purity) as a white solid.

[0368] 1H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 7.83 (br d, J = 6.1 Hz, 1H), 6.14 (s, 1H), 6.12 (s, 1H), 4.47 - 4.31 (m, 1H), 4.15 - 4.00 (m, 4H), 3.93 (d, J = 6.1 Hz, 2H), 3.67 - 3.59 (m, 2H), 2.83 - 2.71 (m, 1H), 2.52 (br s, 1H), 2.29 - 2.24 (m, 2H), 2.07 (br dd, J = 3.9, 13.3Hz, 1H), 1.99 - 1.91 (m, 2H), 1.65 - 1.52 (m, 2H), 0.85 (s, 9H), 0.06 - -0.05 (m, 6H). MS (ESI) m / z 538.3 [M+H] +

[0369] Example 50. Synthesis of Compound 50 [ka] Step 1. Procedure for the preparation of ((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of ((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol (50.0 mg, 231 umol, 1.00 equiv.) in tetrahydrofuran (0.500 mL), di(1H-imidazol-1-yl)methanone (37.5 mg, 231 umol, 1.00 equiv.) was added at 0°C, and the mixture was stirred at 20°C for 2 hours. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (88.3 mg, 225 μmol, 1.00 equiv, methanesulfonic acid), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34.3 mg, 225 μmol, 34.0 μL, 1.00 equiv), and N,N-diisopropylethylamine (58.3 mg, 451 μmol, 78.6 μL, 2.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 53% to 83%, 8 min) and lyophilized to give ((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (9.35 mg, 16.69 umol, yield 7%, purity 96%) as a white solid.

[0370] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (br s, 1H), 7.86 (br d, J = 7.6 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.45 - 4.36 (m, 2H), 4.09 (t, J = 7.8 Hz, 2H), 4.03 (br dd, J = 5.7, 13.7 Hz, 1H), 3.98 (d, J = 7.3 Hz, 2H), 3.62 (br t, J = 6.7 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.52 (br s, 1H), 2.32 - 2.27 (m, 1H), 2.07 (br d, J = 4.6 Hz, 1H), 2.06 - 2.01 (m, 2H), 2.01 - 1.97 (m, 1H), 1.97 - 1.88 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H). MS (ESI) m / z 538.6 [M+H] +

[0371] Example 51. Synthesis of Compound 51 [ka] Step 1. Preparation procedure for compound 2, cyclohexylmethyl carbonochloridate. To a solution of cyclohexylmethanol (45.0 mg, 394 μmol, 48.4 μL, 1.00 equiv) in dichloromethane (1.00 mL) was added bis(trichloromethyl)carbonate (187 mg, 631 μmol, 1.60 equiv) and N,N-diisopropylethylamine (102 mg, 788 μmol, 137 μL, 2.00 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give cyclohexylmethyl carbonochloridate (69.0 mg, 391 μmol, 99% yield) as a yellow oil.

[0372] Step 2. Procedure for the preparation of cyclohexylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 256 μmol, 1.00 equiv, methanesulfonic acid) in tetrahydrofuran (2.00 mL) was added N,N-diisopropylethylamine (66.0 mg, 511 μmol, 89.0 μL, 2.00 equiv) and cyclohexylmethyl carbonochloridate (67.7 mg, 383 μmol, 1.50 equiv). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 46% to 76%, 15 min) and lyophilized to give cyclohexylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (13.07 mg, 29.11 umol, 11% yield, 97% purity) as an off-white solid.

[0373] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.94 - 7.66 (m, 1H), 6.14 (d, J = 11.1 Hz, 2H), 4.47 - 4.32 (m, 1H), 4.13 - 3.97 (m, 3H), 3.78 (d, J = 6.5 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 2.84 - 2.70 (m, 1H), 2.11 - 2.02 (m, 1H), 2.00 - 1.86 (m, 1H), 1.67 (br d, J = 9.8 Hz, 4H), 1.61 (br d, J = 3.6 Hz, 1H), 1.57 - 1.49 (m, 1H), 1.29 - 1.05 (m, 4H), 0.99 - 0.87 (m, 2H). MS (ESI) m / z 457.9 [M+Na]+

[0374] Example 52. Synthesis of Compound 52 [ka] Step 1. Procedure for the preparation of compound 2 ((1r,4r)-4-methylcyclohexyl)methanol. To a solution of (1r,4r)-4-methylcyclohexanecarboxylic acid (100 mg, 703 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added borane dimethyl sulfide complex (10.0 M, 141 μL, 2.00 equiv) at 0°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with methanol (20.0 mL) and concentrated under reduced pressure to give ((1r,4r)-4-methylcyclohexyl)methanol (80.0 mg, 624 μmol, 89% yield) as a colorless oil.

[0375] 1 H NMR(400 MHz, CDCl3-d) δ = 3.46 (d, J = 6.4 Hz, 2H), 1.80 - 1.75 (m, 2H), 1.75 - 1.68 (m, 2H), 1.44 - 1.39 (m, 2H), 1.36 - 1.27 (m, 1H), 1.02 - 0.95 (m, 2H), 0.95 - 0.91 (m, 2H), 0.89 (d, J = 6.6 Hz, 3H).

[0376] Step 2. Procedure for the preparation of ((1r,4r)-4-methylcyclohexyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of ((1r,4r)-4-methylcyclohexyl)methanol (35.0 mg, 273 umol, 1.00 equiv.) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (44.0 mg, 273 umol, 1.00 equiv.) at 0°C, and the mixture was stirred at 20°C for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (106 mg, 270 μmol, 1.00 equiv, methanesulfonic acid), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (41.1 mg, 270 μmol, 40.7 μL, 1.00 equiv), and N,N-diisopropylethylamine (69.8 mg, 540 μmol, 94.0 μL, 2.00 equiv) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 52% to 82%, 9 min) and lyophilized to give ((1r,4r)-4-methylcyclohexyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (13.95 mg, 28.86 umol, yield 11%, purity 93%) as a white solid.

[0377] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.80 (br d, J = 7.3 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.45 - 4.35 (m, 1H), 4.08 (t, J = 7.6 Hz, 2H), 4.03 (br dd, J = 5.4, 12.8 Hz, 1H), 3.78 (d, J = 6.5 Hz, 2H), 3.62 (t, J = 6.8 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.52 (br s, 1H), 2.11 - 2.03 (m, 1H), 1.96 - 1.90 (m, 1H), 1.67 (br d, J = 9.4 Hz, 4H), 1.51 - 1.43 (m, 1H), 1.30 - 1.23 (m, 1H), 1.00 - 0.87 (m, 4H), 0.85 (d, J = 6.5 Hz, 3H). MS (ESI) m / z 450.1 [M+H] +

[0378] Example 53. Synthesis of Compound 53 [ka] Step 1. Procedure for compound 2 (4,4-dimethylcyclohexyl)methanol. To a solution of 4,4-dimethylcyclohexanecarboxylic acid (300 mg, 1.92 mmol, 1.00 equiv) in tetrahydrofuran (3.00 mL) was added borane dimethyl sulfide complex (10.0 M, 384 μL, 2.00 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. The mixture was quenched with methanol (10 mL) and concentrated under reduced pressure to give (4,4-dimethylcyclohexyl)methanol (265 mg, 1.86 mmol, 97% yield) as a colorless oil.

[0379] 1H NMR (400 MHz, CDCl3-d) δ = 3.48 (d, J = 6.3 Hz, 2H), 1.64 (br s, 1H), 1.60 - 1.55 (m, 2H), 1.43 - 1.36 (m, 3H), 1.22 - 1.09 (m, 4H), 0.91 (s, 3H), 0.88 (s, 3H).

[0380] Step 2. Procedure for compound 3 (4,4-dimethylcyclohexyl)methyl carbonochloridate. To a solution of (4,4-dimethylcyclohexyl)methanol (50.0 mg, 351 μmol, 1.00 equiv) in dichloromethane (0.500 mL) was added triethylamine (71.1 mg, 703 μmol, 97.8 μL, 2.00 equiv) and triphosgene (104 mg, 351 μmol, 1.00 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give (4,4-dimethylcyclohexyl)methyl carbonochloridate (71.9 mg, crude) as a white solid.

[0381] Step 3. Procedure for (4,4-dimethylcyclohexyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (65.0 mg, 166 μmol, 1.00 equiv, methanesulfonic acid) and (4,4-dimethylcyclohexyl)methyl carbonochloridate (67.9 mg, 332 μmol, 2.00 equiv) in N,N-dimethylformamide (1.00 mL) was added triethylamine (50.4 mg, 498 μmol, 69.3 μL, 3.00 equiv). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was dissolved in N,N-dimethylformamide (0.5 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 52% to 82%, 9 min) and lyophilized to give (4,4-dimethylcyclohexyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (23.55 mg, 50.30 umol, yield 30%, purity 99%) as a white solid.

[0382] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.81 (br d, J = 7.1 Hz, 1H), 6.14 (d, J = 11.0 Hz, 2H), 4.46 - 4.35 (m, 1H), 4.08 (t, J = 7.6 Hz, 2H), 4.03 (br dd, J = 5.1, 12.6 Hz, 1H), 3.82 (br d, J = 5.9 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.53 - 2.51 (m, 1H), 2.07 (dq, J = 4.0, 12.9 Hz, 1H), 1.98 - 1.89 (m, 1H), 1.53 - 1.44 (m, 3H), 1.35 (br d, J = 7.4 Hz, 2H), 1.18 - 1.09 (m, 4H), 0.88 (s, 3H), 0.86 (s, 3H). MS (ESI) m / z 464.3 [M+H] +

[0383] Example 54. Synthesis of Compounds 54 and 55 [ka] Step 1. Procedure for the preparation of compound 2 tert-butyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate. To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (200 mg, 658 μmol, 1.00 equiv.) in dioxane (3.00 mL) was added CuI (25.1 mg, 132 μmol, 0.200 equiv.), KCO (273 mg, 1.97 mmol, 3.00 equiv.), (R)-tert-butyl(2-oxopyrrolidin-3-yl)carbamate (132 mg, 658 μmol, 1.00 equiv.), and DMEDA (29.0 mg, 329 μmol, 35.4 μL, 0.500 equiv.). The reaction mixture was stirred at 130° C. for 4 hours under a nitrogen atmosphere using a microwave. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 50:50, 0.1% formic acid) and lyophilized to give tert-butyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (120 mg, 283 μmol, 43% yield) as an off-white solid.

[0384] 1H NMR (400 MHz, DMSO-d6) δ = 10.96 (s, 1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.30 (br d, J = 8.5 Hz, 1H), 4.43 - 4.31 (m, 1H), 4.21 (dd, J = 5.1, 12.6 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.73 - 3.64 (m, 1H), 2.86 - 2.75 (m, 1H), 2.55 (br d, J = 3.1 Hz, 1H), 2.40 - 2.34 (m, 1H), 2.19 - 2.09 (m, 1H), 2.01 (br d, J = 5.8 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.40 (s, 9H).

[0385] Step 2. Procedure for the preparation of compound 3, 3-(4-((R)-3-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. To a solution of tert-butyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (120 mg, 283 μmol, 1.00 equiv) in dioxane (2.00 mL) was added hydrochloric acid / dioxane (4.00 M, 2.00 mL, 28.2 equiv). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-((R)-3-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (110 mg, crude, hydrochloride salt) as a yellow solid.

[0386] 1H NMR (400 MHz, DMSO-d6) δ = 10.98 (s, 1H), 8.62 (br s, 2H), 7.55 (s, 1H), 7.52 (s, 1H), 4.33 - 4.20 (m, 2H), 3.96 - 3.90 (m, 1H), 3.86 - 3.77 (m, 1H), 2.88 - 2.77 (m, 1H), 2.56 (br d, J = 3.4 Hz, 1H), 2.43 - 2.40 (m, 1H), 2.21 - 2.12 (m, 1H), 2.10 (br d, J = 10.9 Hz, 1H), 2.05 - 1.99 (m, 1H).

[0387] Step 3. Procedure for the preparation of compound 3A spiro[3.3]heptan-2-ylmethyl carbonochloridate. To a solution of spiro[3.3]heptan-2-ylmethanol (45.0 mg, 357 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added bis(trichloromethyl)carbonate (106 mg, 357 μmol, 1.00 equiv) and N,N-diisopropylethylamine (92.2 mg, 713 μmol, 124 μL, 2.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give spiro[3.3]heptan-2-ylmethyl carbonochloridate (67.0 mg, crude) as a yellow oil.

[0388] Step 4. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl ((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate and spiro[3.3]heptan-2-ylmethyl ((R)-1-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate. To a solution of 3-(4-((R)-3-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (60.0 mg, 167 μmol, 1.00 equiv, hydrochloride salt) in dimethylformamide (0.500 mL) was added N,N-diisopropylethylamine (64.7 mg, 500 μmol, 87.2 μL, 3.00 equiv) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (62.9 mg, 334 μmol, 2.00 equiv). The reaction mixture was stirred at 20° C. for 0.5 hours. The reaction mixture was filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 40:60, 0.1% formic acid) and lyophilized to give the crude product. The crude product was purified by preparative HPLC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [isopropanol-acetonitrile]; B%: 60% to 60%, A6; 44 min) and concentrated under reduced pressure to give two portions. The first portion was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 43% to 73%, 9 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl ((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (8.25 mg, 13.88 μmol, 8% yield, 80% purity) as a white solid. The other portion was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 43% to 73%, 9 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl ((R)-1-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (7.67 mg, 15.65 umol, yield 9%, purity 97%) as a white solid.

[0389] 1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.58 (br d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 4.46 - 4.33 (m, 1H), 4.26 - 4.17 (m, 1H), 3.96 - 3.85 (m, 2H), 3.83 - 3.75 (m, 1H), 3.74 - 3.65 (m, 1H), 2.87 - 2.76 (m, 1H), 2.57 - 2.52 (m, 1H), 2.39 - 2.34 (m, 2H), 2.18 - 2.12 (m, 1H), 2.08 - 1.93 (m, 6H), 1.92 - 1.86 (m, 2H), 1.79 - 1.69 (m, 4H). SFC:RT:1.258 points. MS (ESI) m / z 475.9 [M+H] +

[0390] 1 H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.58 (br d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 4.40 (q, J = 9.3 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.96 - 3.86 (m, 2H), 3.83 - 3.75 (m, 1H), 3.74 - 3.64 (m, 1H), 2.87 - 2.75 (m, 1H), 2.58 - 2.52 (m, 1H), 2.41 - 2.34 (m, 2H), 2.20 - 2.09 (m, 1H), 2.08 - 1.92 (m, 6H), 1.91 - 1.85 (m, 2H), 1.81 - 1.67 (m, 4H). SFC:RT:2.629 points. MS (ESI) m / z 476.0 [M+H] + .

[0391] Example 55. Synthesis of Compound 56

change

[0392] Step 2. Procedure for the preparation of compound 2 tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate. A mixture of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (200 mg, 658 μmol, 1.00 equiv.), tert-butyl (3-methylazetidin-3-yl)carbamate (220 mg, 987 μmol, 1.50 equiv., hydrochloride salt), cesium carbonate (643 mg, 1.97 mmol, 3.00 equiv.), and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (64.0 mg, 65.8 μmol, 0.100 equiv.) in dioxane (3.00 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (170 mg, 415 μmol, yield 63%) as a white solid.

[0393] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.40 (br s, 1H), 6.14 (d, J = 11.3 Hz, 2H), 4.03 (br dd, J = 4.9, 12.3 Hz, 1H), 3.85 (br d, J = 6.5 Hz, 2H), 3.68 (d, J = 7.8 Hz, 2H), 2.84 - 2.72 (m, 1H), 2.08 (s, 2H), 1.98 - 1.89 (m, 1H), 1.49 (s, 3H), 1.39 (s, 9H)

[0394] Step 3. Procedure for the preparation of compound 3, 3-(4-(3-amino-3-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (120 mg, 293 μmol, 1.00 equiv) in dichloromethane (2.50 mL) was added trifluoroacetic acid (1.85 g, 16.2 mmol, 1.20 mL, 55.3 equiv) at 25° C. The mixture was then stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-(3-amino-3-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (80.0 mg, 259 μmol, 88% yield) as a white solid.

[0395] 1H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 8.37 (br s, 2H), 6.30 (d, J = 10.9 Hz, 2H), 4.06 (br dd, J = 4.9, 12.3 Hz, 1H), 3.95 - 3.88 (m, 2H), 3.88 - 3.80 (m, 2H), 3.11 (br d, J = 6.3 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.11 - 2.03 (m, 1H), 2.00 - 1.93 (m, 1H), 1.56 (s, 3H).

[0396] Step 3. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate. To a solution of 3-(4-(3-amino-3-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (30.0 mg, 97.0 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added N,N-diisopropylethylamine (12.5 mg, 97.0 μmol, 16.9 μL, 1.00 equiv) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (27.45 mg, 145.48 μmol, 1.5 equiv) at 25° C. The mixture was then stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (13.75 mg, 29.8 μmol, 31% yield, 96% purity) as a white solid.

[0397] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 7.72 (br s, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.03 (br dd, J = 5.0, 12.5 Hz, 1H), 3.93 - 3.80 (m, 4H), 3.70 (d, J = 7.6 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.37 - 2.31 (m, 1H), 2.14 - 1.90 (m, 7H), 1.89 - 1.82 (m, 2H), 1.74 (br dd, J = 7.3, 15.0 Hz, 4H), 1.49 (s, 3H). MS (ESI) m / z 462.2 [M+H] +

[0398] Example 56. Synthesis of Compound 57 [ka] Step 1. Procedure for the preparation of compound 2, 3-(4-bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione. To a mixture of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (2.00 g, 6.58 mmol, 1.00 equiv) in dimethylformamide (20.0 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.00 g, 13.2 mmol, 1.98 mL, 2.00 equiv), followed by the dropwise addition of (2-(chloromethoxy)ethyl)trimethylsilane (1.97 g, 11.8 mmol, 2.10 mL, 1.80 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 4 hours. Water (20 mL) was added to the mixture, which was then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (2.80 g, 6.45 mmol, 98% yield) as a brown oil.

[0399] 1 H NMR (400 MHz, DMSO-d6) δ = 7.52 (br d, J = 8.5 Hz, 2H), 5.10 (s, 2H), 4.41 (br dd, J = 4.4, 12.8 Hz, 1H), 3.55 - 3.49 (m, 2H), 3.07 - 2.86 (m, 2H), 2.36 - 2.28 (m, 1H), 2.05 - 2.01 (m, 1H), 0.83 (br t, J = 8.0 Hz, 2H), -0.03 (s, 9H).

[0400] Step 2. Procedure for the preparation of compound 3 tert-butyl ((3S)-1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate. To a solution of 3-(4-bromo-2,6-difluorophenyl)-1-(2-trimethylsilylethoxymethyl)piperidine-2,6-dione (195 mg, 449 μmol, 1.00 equiv.) in dioxane (5.00 mL) was added (S)-tert-butyl(5-oxopyrrolidin-3-yl)carbamate (90.0 mg, 449 μmol, 1.00 equiv.), copper iodide (85.6 mg, 449 μmol, 1.00 equiv.), potassium carbonate (186 mg, 1.35 mmol, 3.00 equiv.), and N,N'-dimethylethylenediamine (39.6 mg, 449 μmol, 48.4 μL, 1.00 equiv.). The reaction was stirred at 110°C for 12 hours. The reaction mixture was filtered. The filtrate was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) and concentrated under reduced pressure to give tert-butyl ((3S)-1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (130 mg, 235 μmol, 52% yield) as a white solid.

[0401] 1H NMR (400 MHz, DMSO-d6) δ = 7.48 (s, 1H), 7.45 (s, 1H), 5.10 (s, 2H), 4.36 (br dd, J = 5.2, 13.2 Hz, 1H), 4.24 - 4.17 (m, 1H), 4.07 (br dd, J = 7.0, 10.1 Hz, 1H), 3.63 - 3.58 (m, 2H), 3.54 - 3.49 (m, 2H), 2.99 (br dd, J = 4.9, 9.7 Hz, 1H), 2.88 (br d, J = 10.1 Hz, 1H), 2.77 - 2.72 (m, 1H), 2.45 (br d, J = 12.8 Hz, 1H), 2.19 - 2.14 (m, 1H), 2.02 (br d, J = 5.9 Hz, 1H), 1.39 (s, 9H), 0.86 - 0.81 (m, 2H), -0.02 (s, 9H).

[0402] Step 3. Procedure for the preparation of compound 2 3-(4-((S)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)-1-(hydroxymethyl)piperidine-2,6-dione. To a solution of tert-butyl ((3S)-1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (130 mg, 235 μmol, 1.00 equiv) in dichloromethane (3.00 mL) was added trifluoroacetic acid (924 mg, 8.10 mmol, 0.600 mL, 34.5 equiv). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-(4-((S)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)-1-(hydroxymethyl)piperidine-2,6-dione (80.0 mg, 226 μmol, 96% yield) as a white solid. MS (ESI) m / z.353.8 [M+H] +

[0403] Step 4. Procedure for the preparation of compound 3, 3-(4-((S)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. A solution of 3-(4-((S)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)-1-(hydroxymethyl)piperidine-2,6-dione (80.0 mg, 226 umol, 1.00 equiv.) in acetonitrile (3.00 mL) was diluted with ammonium hydroxide (455 mg, 32.5 umol, 0.500 mL, 0.25% purity, 1.43 e-1 (equivalent) was added. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-(4-((S)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (70.0 mg, 217 μmol, 96% yield) as a white solid. MS (ESI) m / z. 323.8 [M+H] +

[0404] Step 5. Procedure for the preparation of compound 3A spiro[3.3]heptan-2-ylmethyl carbonochloridate. To a solution of spiro[3.3]heptan-2-ylmethanol (55.0 mg, 436 μmol, 1.00 equiv) in dichloromethane (0.500 mL) was added bis(trichloromethyl)carbonate (129 mg, 436 μmol, 1.00 equiv) at 0° C., followed by N,N-diisopropylethylamine (225 mg, 1.74 mmol, 304 μL, 4.00 equiv), and the reaction mixture was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford spiro[3.3]heptan-2-ylmethyl carbonochloridate (82.0 mg, crude) as a yellow solid.

[0405] Step 6. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate. To a solution of 3-(4-((S)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (70.0 mg, 217 μmol, 1.00 equiv.) in dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (56.0 mg, 433 μmol, 75.4 μL, 2.00 equiv.) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (81.7 mg, 433 μmol, 2.00 equiv.). The reaction mixture was stirred at 20° C. for 0.5 hours. The reaction mixture was filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give spiro[3.3]heptan-2-ylmethyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (22.19 mg, 46.20 μmol, 21% yield, 99% purity) as a white solid.

[0406] 1 H NMR (400 MHz, DMSO-d6) δ = 10.95 (s, 1H), 7.77 - 7.65 (m, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.25 - 4.17 (m, 2H), 4.07 (dd, J = 7.1, 10.3 Hz, 1H), 3.89 (br d, J = 6.8 Hz, 2H), 3.63 (br dd, J = 2.9, 9.9 Hz, 1H), 2.90 (dd, J = 8.2, 17.3 Hz, 1H), 2.85 - 2.76 (m, 1H), 2.55 (br d, J = 2.5 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.40 - 2.33 (m, 1H), 2.18 - 2.08 (m, 1H), 2.04 (br s, 1H), 2.00 (br d, J = 8.6 Hz, 2H), 1.95 (br t, J = 7.4 Hz, 2H), 1.89 - 1.84 (m, 2H), 1.77 - 1.68 (m, 4H). MS (ESI) m / z.476.1 [M+H]+

[0407] Example 57. Synthesis of Compound 58 [ka] Step 1. Procedure for the preparation of compound 2 tert-butyl ((3R)-1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate. To a solution of 3-(4-bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (300 mg, 691 μmol, 1.00 equiv.) and (R)-tert-butyl(5-oxopyrrolidin-3-yl)carbamate (138 mg, 691 μmol, 1.00 equiv.) in dioxane (20.0 mL), copper iodide (132 mg, 691 μmol, 1.00 equiv.), potassium carbonate (286 mg, 2.07 mmol, 3.00 equiv.), and N,N'-dimethylethane-1,2-diamine (60.9 mg, 691 μmol, 74.3 μL, 1.00 equiv.) were added under a nitrogen atmosphere. The reaction was stirred at 110 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) and concentrated under reduced pressure to give tert-butyl ((3R)-1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (310 mg, 560 μmol, yield 81%) as a yellow oil.

[0408] 1H NMR (400 MHz, DMSO-d6) δ = 7.48 (s, 1H), 7.46 (s, 1H), 5.10 (s, 2H), 4.36 (br dd, J = 4.9, 12.9 Hz, 1H), 4.20 (br s, 1H), 4.10 - 4.06 (m, 1H), 3.60 (br dd, J = 2.9, 10.1 Hz, 1H), 3.57 - 3.48 (m, 2H), 3.03 - 2.92 (m, 1H), 2.88 (dd, J = 8.1, 17.4 Hz, 1H), 2.73 (br d, J = 17.1 Hz, 1H), 2.45 (dd, J = 4.4, 17.3 Hz, 2H), 2.24 - 2.09 (m, 1H), 1.39 (s, 9H), 0.83 (br d, J = 8.0 Hz, 2H), 0.05 - -0.09 (m, 9H).

[0409] Step 2. Procedure for the preparation of compound 3 (4-((R)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)-1-(hydroxymethyl)piperidine-2,6-dione. To a solution of tert-butyl ((3R)-1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (100 mg, 181 umol, 1.00 equiv) in dichloromethane (1.00 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 100 uL, 7.48 equiv). The reaction was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 3-(4-((R)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)-1-(hydroxymethyl)piperidine-2,6-dione (63.0 mg, 178 umol, 99% yield) as a white solid. MS (ESI) m / z.375.9 [M+Na] +

[0410] Step 3. Procedure for the preparation of compound 4 3-(4-((R)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. To a solution of 3-(4-((R)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)-1-(hydroxymethyl)piperidine-2,6-dione (63.0 mg, 178 μmol, 1.00 equiv) in acetonitrile (1.00 mL) was added ammonium hydroxide (182 mg, 1.30 mmol, 200 μL, 25% purity, 7.28 equiv). The reaction was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-(4-((R)-4-amino-2-oxopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (57.0 mg, 176 μmol, 99% yield) as a white solid. MS (ESI) m / z 324.0 [M+H] +

[0411] Step 4. Procedure for the preparation of compound 4A (spiro[3.3]heptan-2-ylmethyl carbonochloridate). To a solution of spiro[3.3]heptan-2-ylmethanol (40.0 mg, 317 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added bis(trichloromethyl)carbonate (94.1 mg, 317 μmol, 1.00 equiv) and triethylamine (64.2 mg, 634 μmol, 88.2 μL, 2.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give spiro[3.3]heptan-2-ylmethyl carbonochloridate (58.0 mg, crude) as a white solid.

[0412] Step 5. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate. To a solution of spiro[3.3]heptan-2-ylmethyl carbonochloridate (55.0 mg, 153 μmol, 1.00 equiv., hydrochloride salt) in dimethylformamide (1.00 mL) was added spiro[3.3]heptan-2-ylmethyl carbonochloridate (58.0 mg, 306 μmol, 2.00 equiv.) and triethylamine (46.4 mg, 459 μmol, 63.8 μL, 3.00 equiv.). The reaction mixture was stirred at 25° C. for 10 minutes. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 31% to 61%, 10 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (10.41 mg, 21.67 umol, yield 14%, purity 99%) as a white solid.

[0413] 1 H NMR (400 MHz, DMSO-d6) δ=10.95 (s, 1H), 7.71 (br d, J = 5.9 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.30 - 4.16 (m, 2H), 4.08 (dd, J = 6.9, 10.3 Hz, 1H), 3.89 (br d, J = 6.9 Hz, 2H), 3.63 (dd, J = 3.1, 10.3 Hz, 1H), 2.90 (dd, J = 8.2, 17.3 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.55 (br d, J = 3.3 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.35 (td, J = 7.5, 14.7 Hz, 1H), 2.19 - 2.06 (m, 1H), 2.06 - 1.92 (m, 5H), 1.91 - 1.83 (m, 2H), 1.80 - 1.64 (m, 4H). MS (ESI) m / z.476.1 [M+H] +

[0414] Example 58. Synthesis of Compound 59 [ka] Step 1. Procedure for compound 2, methyl 4-(4-bromo-2-fluorophenyl)-4-cyanobutanoate. To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (10.0 g, 46.7 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) was added methyl acrylate (4.42 g, 51.3 mmol, 4.63 mL, 1.10 equiv.) at 0° C. To the mixture was added sodium methoxide (504 mg, 9.34 mmol, 0.200 equiv.). The mixture was stirred at 20° C. for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 0 to 10 / 1) to give methyl 4-(4-bromo-2-fluorophenyl)-4-cyanobutanoate (8.40 g, 27.9 mmol, 59% yield) as a white solid.

[0415] 1 H NMR (400 MHz, DMSO-d6) δ = 7.69 - 7.62 (m, 1H), 7.53 - 7.49 (m, 1H), 7.48 - 7.43 (m, 1H), 4.46 (t, J = 7.5 Hz, 1H), 3.58 (d, J = 2.1 Hz, 3H), 2.47 - 2.41 (m, 2H), 2.25 - 2.06 (m, 2H).

[0416] Step 2. Procedure for the preparation of compound 3, 3-(4-bromo-2-fluorophenyl)piperidine-2,6-dione. To a solution of methyl 4-(4-bromo-2-fluorophenyl)-4-cyanobutanoate (7.40 g, 24.6 mmol, 1.00 equiv.) in acetic acid (70.0 mL) was added sulfuric acid (12.8 g, 131 mmol, 7.00 mL, 5.33 equiv.). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was poured into ice water (200 mL) and filtered. The filter cake was concentrated under reduced pressure to give 3-(4-bromo-2-fluorophenyl)piperidine-2,6-dione (7.00 g, 24.4 mmol, 99% yield) as a white solid.

[0417] 1 H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.56 - 7.51 (m, 1H), 7.43 - 7.38 (m, 1H), 7.34 - 7.27 (m, 1H), 4.11 - 4.03 (m, 1H), 2.79 - 2.69 (m, 1H), 2.57 - 2.52 (m, 1H), 2.26 - 2.14 (m, 1H), 2.03 - 1.95 (m, 1H).

[0418] Step 3. Procedure for compound 4 tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-bromo-2-fluorophenyl)piperidine-2,6-dione (500 mg, 1.75 mmol, 1.00 equiv.) in dioxane (10.0 mL), tert-butyl azetidin-3-ylcarbamate (300 mg, 1.75 mmol, 1.00 equiv.), cesium carbonate (1.71 g, 5.24 mmol, 3.00 equiv.), and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (85.0 mg, 87.3 µmol, 0.0500 equiv.) were added under a nitrogen atmosphere. The mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 33% to 63%, 10 min) and lyophilized to give tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate (206 mg, 545 umol, 31% yield) as a brown solid.

[0419] 1 H NMR (400 MHz, DMSO-d6) δ = 10.8 (s, 1H), 7.53 (br d, J = 7.4 Hz, 1H), 7.04 (t, J = 8.5 Hz, 1H), 6.29 - 6.16 (m, 2H), 4.48 - 4.32 (m, 1H), 3.90 - 3.81 (m, 1H), 3.56 (t, J = 6.8 Hz, 2H), 2.79 - 2.53 (m, 2H), 2.19 - 2.06 (m, 1H), 1.98 - 1.90 (m, 1H), 1.39 (s, 9H).

[0420] Step 4. Procedure for Compound 5 3-(4-(3-aminoazetidin-1-yl)-2-fluorophenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate (86.0 mg, 227 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol, 0.200 mL, 42.4 equiv). The mixture was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)-2-fluorophenyl)piperidine-2,6-dione (89.0 mg, crude, trifluoroacetate salt) as a colorless oil. MS (ESI) m / z 277.9 [M+H] +

[0421] Step 5. Procedure for spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate. To a solution of spiro[3.3]heptan-2-ylmethanol (50.0 mg, 396 μmol, 1.00 equiv) in tetrahydrofuran (0.500 mL) was added di(1H-imidazol-1-yl)methanone (64.2 mg, 396 μmol, 1.00 equiv) at 0° C. The mixture was stirred at 20° C. for 1 hour. The resulting mixture was added to a solution of 3-(4-(3-aminoazetidin-1-yl)-2-fluorophenyl)piperidine-2,6-dione (88.8 mg, 227 μmol, 1.00 equiv, trifluoroacetate salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34.5 mg, 227 μmol, 34.2 μL, 1.00 equiv), and triethylamine (22.9 mg, 227 μmol, 31.6 μL, 1.00 equiv) in tetrahydrofuran (0.250 mL) and dimethylformamide (0.250 mL). The mixture was stirred at 20° C. for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 46% to 76%, 10 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate (12.21 mg, 28.15 umol, 12% yield, 99% purity) as an off-white solid.

[0422] 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 7.80 (br d, J = 7.4 Hz, 1H), 7.04 (t, J = 8.6 Hz, 1H), 6.27 - 6.19 (m, 2H), 4.46 - 4.35 (m, 1H), 4.06 (t, J = 7.5 Hz, 2H), 3.89 (d, J = 7.0 Hz, 2H), 3.88 - 3.82 (m, 1H), 3.58 (t, J = 6.8 Hz, 2H), 2.76 - 2.54 (m, 2H), 2.39 - 2.31 (m, 1H), 2.18 - 2.06 (m, 1H), 2.05 - 1.92 (m, 5H), 1.91 - 1.84 (m, 2H), 1.79 - 1.66 (m, 4H). MS (ESI) m / z 430.1 [M+H] +

[0423] Example 59. Synthesis of Compound 60 [ka] Step 1. Preparation procedure for compound 2, 4-bromo-1-(bromomethyl)-2-chlorobenzene. To a solution of 4-bromo-2-chloro-1-methylbenzene (10.0 g, 48.7 mmol, 6.49 mL, 1.00 equiv.) in trichloromethane (100 mL) was added (E)-2,2'-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (799 mg, 4.87 mmol, 0.100 equiv.) and N-bromosuccinimide (8.66 g, 48.7 mmol, 1.00 equiv.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1) to give 4-bromo-1-(bromomethyl)-2-chlorobenzene (16.9 g, crude) as a yellow oil.

[0424] 1H NMR (400MHz, DMSO-d6) δ = 7.80 - 7.74 (m, 1H), 7.60 - 7.54 (m, 2H), 4.72 - 4.69 (m, 2H).

[0425] Step 2. Preparation procedure for compound 3, 2-(4-bromo-2-chlorophenyl)acetonitrile. To a solution of 4-bromo-1-(bromomethyl)-2-chlorobenzene (16.9 g, 59.4 mmol, 1.00 equiv.) in acetonitrile (160 mL), trimethylsilyl cyanide (17.7 g, 178 mmol, 22.3 mL, 3.00 equiv.) and tetrabutylammonium fluoride (46.6 g, 178 mmol, 42.0 mL, 3.00 equiv.) were added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 2-(4-bromo-2-chlorophenyl)acetonitrile (8.78 g, 38.1 mmol, 64% yield) as a yellow oil.

[0426] 1 H NMR (400MHz, DMSO-d6) δ = 7.83 - 7.79 (m, 1H), 7.65 - 7.59 (m, 1H), 7.50 (d, J = 8.3 Hz, 1H), 4.08 (s, 2H).

[0427] Step 3. Procedure for the preparation of compound 4, methyl 4-(4-bromo-2-chlorophenyl)-4-cyanobutanoate. To a solution of 2-(4-bromo-2-chlorophenyl)acetonitrile (8.78 g, 38.1 mmol, 1.00 equiv.) in tetrahydrofuran (80.0 mL) was added methyl acrylate (3.61 g, 41.9 mmol, 3.77 mL, 1.10 equiv.) and sodium methoxide (206 mg, 3.81 mmol, 0.100 equiv.) at 0 °C. The mixture was then stirred at 25 °C for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-(4-bromo-2-chlorophenyl)-4-cyanobutanoate (9.78 g, 30.9 mmol, 81% yield) as a yellow oil.

[0428] 1 H NMR (400MHz, DMSO-d6) δ = 7.83 (s, 1H), 7.66 (dd, J = 1.9, 8.4 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.54 (dd, J = 6.6, 8.3 Hz, 1H), 3.58 (s, 3H), 2.49 - 2.43 (m, 2H), 2.24 - 2.12 (m, 2H).

[0429] Step 4. Procedure for the preparation of compound 5, 3-(4-bromo-2-chlorophenyl)piperidine-2,6-dione. To a solution of methyl 4-(4-bromo-2-chlorophenyl)-4-cyanobutanoate (9.78 g, 30.9 mmol, 1.00 equiv.) in acetic acid (100 mL) was added sulfuric acid (18.0 g, 183 mmol, 9.78 mL, 5.94 equiv.). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was quenched with water (50 mL) and then filtered. The filter cake was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 3-(4-bromo-2-chlorophenyl)piperidine-2,6-dione (3.86 g, 12.8 mmol, 41% yield) as a white solid.

[0430] 1 H NMR (400MHz, DMSO-d6) δ = 10.93 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 2.0, 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.22 (dd, J = 4.9, 12.6 Hz, 1H), 2.85 - 2.69 (m, 1H), 2.56 (br t, J = 3.4 Hz, 1H), 2.34 - 2.22 (m, 1H), 1.99 - 1.93 (m, 1H).

[0431] Step 5. Procedure for the preparation of compound 6 tert-butyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-bromo-2-chlorophenyl)piperidine-2,6-dione (50.0 mg, 165 μmol, 1.00 equiv.) in toluene (1.00 mL), tert-butyl azetidin-3-ylcarbamate (56.9 mg, 331 μmol, 2.00 equiv.), sodium tert-butoxide (95.3 mg, 992 μmol, 6.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (15.1 mg, 16.5 μmol, 0.100 equiv.), and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (15.8 mg, 33.1 μmol, 0.200 equiv.) were added. The reaction mixture was stirred at 110 °C for 45 min under a nitrogen atmosphere using a microwave. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (1 mL) and then filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 45:55, 0.1% formic acid) and lyophilized to give tert-butyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (50.0 mg, 127 μmol, yield 77%) as a yellow solid.

[0432] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 7.53 (br d, J = 7.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.37 (dd, J = 2.1, 8.4 Hz, 1H), 4.47 - 4.24 (m, 1H), 4.15 - 3.95 (m, 3H), 3.57 (t, J = 6.8 Hz, 2H), 2.73 (ddd, J = 5.3, 12.6, 17.3 Hz, 1H), 2.47 (br s, 1H), 2.21 (dq, J = 4.2, 12.7 Hz, 1H), 1.97 - 1.87 (m, 1H), 1.39 (s, 9H).

[0433] Step 6. Procedure for the preparation of compound 7, 3-(4-(3-aminoazetidin-1-yl)-2-chlorophenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (50.0 mg, 127 μmol, 1.00 equiv) in dichloromethane (0.500 mL) was added trifluoroacetic acid (77.0 mg, 675 μmol, 0.0500 mL, 5.32 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)-2-chlorophenyl)piperidine-2,6-dione (50.0 mg, crude, trifluoroacetate salt) as a yellow oil. MS (ESI) m / z 293.8 [M+H] +

[0434] Step 7. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a solution of spiro[3.3]heptan-2-ylmethanol (20.0 mg, 158 μmol, 1.00 equiv) in tetrahydrofuran (0.300 mL) was added di(1H-imidazol-1-yl)methanone (25.7 mg, 158 μmol, 1.00 equiv), and the reaction mixture was stirred at 20° C. for 1 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2-chlorophenyl)piperidine-2,6-dione (50.0 mg, 123 μmol, 1.00 equiv, trifluoroacetate salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (18.7 mg, 123 μmol, 18.5 μL, 1.00 equiv), and N,N-diisopropylethylamine (15.9 mg, 123 μmol, 21.4 μL, 1.00 equiv) in dimethylformamide (0.500 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (0.5 mL) and then filtered. The filtrate was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 30:70, 0.1% formic acid) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (14.15 mg, 31.10 μmol, 25% yield, 98% purity) as a white solid.

[0435] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 7.80 (br d, J = 7.8 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.38 (dd, J = 2.3, 8.4 Hz, 1H), 4.48 - 4.34 (m, 1H), 4.08 (t, J = 7.6 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.59 (t, J = 6.8 Hz, 2H), 2.73 (ddd, J = 5.2, 12.5, 17.4 Hz, 1H), 2.48 - 2.44 (m, 1H), 2.41 - 2.33 (m, 1H), 2.27 - 2.15 (m, 1H), 2.05 - 1.99 (m, 2H), 1.99 - 1.90 (m, 3H), 1.90 - 1.85 (m, 2H), 1.79 - 1.67 (m, 4H). MS (ESI) m / z 468.0 [M+Na] +

[0436] Example 60. Synthesis of Compound 61 [ka] Step 1. Procedure for the preparation of compound 2 tert-butyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate. To a solution of 3-(4-bromo-2,6-difluoro-phenyl)piperidine-2,6-dione (300 mg, 987 μmol, 1.00 equiv.), (S)-tert-butyl pyrrolidin-3-ylcarbamate (276 mg, 1.48 mmol, 1.50 equiv.) in dioxane (3.00 mL), cesium carbonate (964 mg, 2.96 mmol, 3.00 equiv.) and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (96.0 mg, 99.0 μmol, 0.100 equiv.) were added. The mixture was stirred at 110° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 50:50, 0.1% formic acid) and lyophilized to give tert-butyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (200 mg, 488 μmol, 50% yield) as a white solid.

[0437] 1 H NMR (400 MHz, DMSO-d6) δ = 10.83 (br s, 1H), 7.19 (br d, J = 5.9 Hz, 1H), 6.18 (br d, J = 12.4 Hz, 2H), 4.18 - 3.98 (m, 2H), 3.46 - 3.40 (m, 1H), 3.38 - 3.34 (m, 1H), 3.25 - 3.18 (m, 1H), 3.01 (br dd, J = 4.2, 9.2 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.67 (br s, 1H), 2.15 - 2.03 (m, 2H), 1.95 - 1.83 (m, 2H), 1.39 (s, 9H).

[0438] Step 2. Procedure for the preparation of compound 3, 3-(4-((S)-3-aminopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. To a solution of tert-butyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (200 mg, 489 μmol, 1.00 equiv) in dioxane (2.00 mL) was added hydrochloric acid / dioxane (4.00 M) (2.00 mL). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-(4-((S)-3-aminopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (115 mg, 372 μmol, 76% yield, hydrochloride salt) as a pink solid. MS (ESI) m / z 309.8 [M+H] +

[0439] Step 3. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate. To a solution of spiro[3.4]octan-2-ylmethanol (50.0 mg, 396 μmol, 1.00 equiv) in tetrahydrofuran (0.300 mL) was added di(1H-imidazol-1-yl)methanone (96.4 mg, 594 μmol, 1.50 equiv), and the reaction mixture was stirred at 20° C. for 1 h. The resulting solution was added to a mixture of 3-(4-((S)-3-aminopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (115 mg, 372 μmol, hydrochloride salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (55.5 mg, 365 μmol, 55.0 μL, 1.00 equiv.), and triethylamine (37.0 mg, 3645 μmol, 51.0 μL, 1.00 equiv.) in dimethylformamide (1.50 mL). The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was dissolved in dimethylformamide (1.5 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 51% to 81%, 10 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl ((3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (10.00 mg, 21.67 umol, yield 28%, purity 99%) as a white solid.

[0440] 1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 7.56 - 7.37 (m, 1H), 6.20 (s, 1H), 6.17 (s, 1H), 4.20 - 4.13 (m, 1H), 4.04 - 3.98 (m, 1H), 3.89 (br d, J = 7.0 Hz, 2H), 3.44 (br dd, J = 6.9, 9.1 Hz, 1H), 3.40 - 3.35 (m, 1H), 3.26 - 3.18 (m, 1H), 3.05 (br dd, J = 4.5, 9.9 Hz, 1H), 2.85 - 2.72 (m, 1H), 2.57 (br s, 1H), 2.42 - 2.31 (m, 1H), 2.18 - 2.11 (m, 1H), 2.10 (br d, J = 3.8 Hz, 3H), 2.00 - 1.90 (m, 4H), 1.87 (br d, J = 7.5 Hz, 2H), 1.79 - 1.68 (m, 4H). MS (ESI) m / z 462.1 [M+H] +

[0441] Example 61. Synthesis of Compound 62 [ka] Step 1. Procedure for the preparation of compound 2, methyl 4-(4-bromophenyl)-4-cyanobutanoate. To a solution of 2-(4-bromophenyl)acetonitrile (5.00 g, 25.5 mmol, 1.00 equiv) in tetrahydrofuran (50.0 mL) was added lithium diisopropylamide (2.00 M, 19.2 mL, 1.50 equiv) under a nitrogen atmosphere at −70° C., and the mixture was stirred at −70° C. for 30 minutes. After 30 minutes, methyl 3-bromopropanoate (4.69 g, 28.1 mmol, 3.06 mL, 1.10 equiv) was added dropwise to the mixture at −70° C. The reaction was then stirred at 25° C. for 3.5 hours. The mixture was quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and then extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1) to give methyl 4-(4-bromophenyl)-4-cyanobutanoate (2.50 g, 8.86 mmol, 35% yield) as a colorless oil.

[0442] 1 H NMR (400 MHz, CDCl3) δ = 7.55 - 7.51 (m, 2H), 7.25 - 7.22 (m, 2H), 3.97 (t, J = 7.5 Hz, 1H), 3.69 (s, 3H), 2.56 - 2.43 (m, 2H), 2.19 (q, J = 7.4 Hz, 2H).

[0443] Step 2. Procedure for the preparation of compound 3, 3-(4-bromophenyl)piperidine-2,6-dione. To a solution of methyl 4-(4-bromophenyl)-4-cyanobutanoate (2.70 g, 9.57 mmol, 1.00 equiv) in acetic acid (20.0 mL) was added sulfuric acid (2.00 mL). The reaction was then stirred at 90° C. for 2 hours. The reaction mixture was added dropwise to cold water and stirred for 0.5 hours. The mixture was filtered. The filter cake was concentrated under reduced pressure to give 3-(4-bromophenyl)piperidine-2,6-dione (1.60 g, 5.97 mmol, 62% yield) as a white solid.

[0444] 1H NMR (400 MHz, CDCl3) δ = 8.10 (br s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 3.74 (dd, J = 5.3, 10.3 Hz, 1H), 2.80 - 2.65 (m, 2H), 2.32 - 2.21 (m, 2H).

[0445] Step 3. Procedure for the preparation of compound 4 tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-bromophenyl)piperidine-2,6-dione (400 mg, 1.49 mmol, 1.00 equiv.), tert-butyl azetidin-3-ylcarbamate (308 mg, 1.79 mmol, 1.20 equiv.) in dioxane (20.0 mL), cesium carbonate (1.46 g, 4.48 mmol, 3.00 equiv.), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide, 3-chloropyridine, and dichloropalladium (40.0 mg, 41.1 µmol, 2.76 e-2 equiv.) were added under a nitrogen atmosphere. The reaction mixture was then stirred at 110 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with a solution of dichloromethane / isopropanol = 3 / 1 (2 × 20 mL). The combined organic layers were washed with brine (2 × 10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to give tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (140 mg, 389 μmol, 26% yield) as a white solid.

[0446] 1H NMR (400 MHz, CDCl3) δ = 7.89 (br s, 1H), 7.06 (d, J = 8.1 Hz, 2H), 6.46 (d, J = 8.1 Hz, 2H), 5.01 - 4.89 (m, 1H), 4.66 - 4.54 (m, 1H), 4.21 (br t, J = 7.3 Hz, 2H), 3.70 (dd, J = 5.3, 9.4 Hz, 1H), 3.61 (br t, J = 6.4 Hz, 2H), 2.76 - 2.61 (m, 2H), 2.27 - 2.18 (m, 2H), 1.46 (s, 9H).

[0447] Step 4. Procedure for the preparation of compound 5, 3-(4-(3-aminoazetidin-1-yl)phenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (220 mg, 612 umol, 1.00 equiv) in dichloromethane (3.00 mL) was added trifluoroacetic acid (813 mg, 7.13 mmol, 528 uL, 11.7 equiv). The reaction was then stirred at 25° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)phenyl)piperidine-2,6-dione (158 mg, crude, trifluoroacetate salt) as a brown oil. MS (ESI) m / z 260.1 [M+H] +

[0448] Step 5. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl (1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate. To a solution of spiro[3.3]heptan-2-ylmethanol (50.0 mg, 396 μmol, 1.00 equiv) in tetrahydrofuran (0.500 mL) was added di(1H-imidazol-1-yl)methanone (64.2 mg, 396.2 μmol, 1.00 equiv) at 0° C. The reaction was then stirred at 25° C. for 0.5 h. To the mixture was then added tetrahydrofuran (0.500 mL), 3-(4-(3-aminoazetidin-1-yl)phenyl)piperidine-2,6-dione (108 mg, 289 μmol, 1.00 equiv, trifluoroacetate salt), triethylamine (29.3 mg, 289 μmol, 40.3 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (44.0 mg, 289 μmol, 43.6 μL, 1.00 equiv). The reaction was then stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 45% to 75%, 10 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (35.16 mg, 82.03 umol, yield 28%, purity 96%) as an off-white solid.

[0449] 1H NMR (400 MHz, DMSO-d) δ = 10.7 (s, 1H), 7.76 (br d, J = 7.3 Hz, 1H), 7.00 (d, J = 7.9 Hz, 2H), 6.39 (br d, J = 8.0 Hz, 2H), 4.44 - 4.38 (m, 1H), 4.05 (t, J = 7.3 Hz, 2H), 3.89 (br d, J = 6.8 Hz, 2H), 3.70 (br dd, J = 4.9, 10.6 Hz, 1H), 3.54 (br t, J = 6.6 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.47 - 2.42 (m, 1H), 2.37 - 2.32 (m, 1H), 2.13 - 2.08 (m, 1H), 2.04 - 1.95 (m, 5H), 1.89-1.86 (m, 2H), 1.76-1.70 (m, 4H). MS (ESI) m / z 412.1 [M+H] +

[0450] Example 62. Synthesis of Compound 63 [ka] Step 1. Preparation procedure for compound 2, 1-bromo-4-(bromomethyl)-3-chloro-2-methoxybenzene. To a solution of 1-bromo-3-chloro-2-methoxy-4-methyl-benzene (4.00 g, 17.0 mmol, 1.00 equiv.) in carbon tetrachloride (40.0 mL), N-bromosuccinimide (3.02 g, 17.0 mmol, 1.00 equiv.) and azodiisobutyronitrile (139 mg, 849 mmol, 0.0500 equiv.) were added. The reaction mixture was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / to 10 / 1) to give 1-bromo-4-(bromomethyl)-3-chloro-2-methoxybenzene (2.70 g, 8.59 mmol, 51% yield) as a colorless oil.

[0451] 1H NMR (400 MHz, DMSO-d6) δ = 7.65 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 3H).

[0452] Step 2. Preparation procedure for compound 3, 2-(4-bromo-2-chloro-3-methoxyphenyl)acetonitrile. To a solution of 1-bromo-4-(bromomethyl)-3-chloro-2-methoxybenzene (2.70 g, 8.59 mmol, 1.00 equiv) in acetonitrile (5.00 mL) was added trimethylsilyl cyanide (2.56 g, 25.8 mmol, 3.22 mL, 3.00 equiv) and tetrabutylammonium fluoride (1.00 M, 25.8 mL, 3.00 equiv). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) and concentrated under reduced pressure to give 2-(4-bromo-2-chloro-3-methoxyphenyl)acetonitrile (2.25 g, crude) as a colorless oil.

[0453] 1 H NMR (400 MHz, DMSO-d6) δ = 7.68 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.08 (s, 2H), 3.80 (s, 3H).

[0454] Step 3. Procedure for the preparation of compound 4, methyl 4-(4-bromo-2-chloro-3-methoxyphenyl)-4-cyanobutanoate. To a solution of 2-(4-bromo-2-chloro-3-methoxyphenyl)acetonitrile (2.25 g, 8.64 mmol, 1.00 equiv.) and methyl acrylate (818 mg, 9.50 mmol, 856 μL, 1.10 equiv.) in tetrahydrofuran (20.0 mL) was added sodium methoxide (46.7 mg, 864 μmol, 0.100 equiv.) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-(4-bromo-2-chloro-3-methoxyphenyl)-4-cyanobutanoate (2.90 g, 8.37 mmol, 97% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.69 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.52 (dd, J = 6.6, 8.3 Hz, 1H), 3.82 - 3.74 (m, 3H), 3.58 - 3.52 (m, 3H), 2.45 - 2.41 (m, 2H), 2.20 - 2.02 (m, 2H).

[0455] Step 4. Procedure for the preparation of compound 5, 3-(4-bromo-2-chloro-3-methoxyphenyl)piperidine-2,6-dione. To a solution of methyl 4-(4-bromo-2-chloro-3-methoxyphenyl)-4-cyanobutanoate (2.90 g, 8.37 mmol, 1.00 equiv.) in acetic acid (30.0 mL) was added sulfuric acid (5.48 g, 55.9 mmol, 2.98 mL, 6.68 equiv.). The mixture was stirred at 90° C. for 2 hours. The mixture was poured into ice water (20.0 mL) and filtered. The filter cake was dried under reduced pressure to give 3-(4-bromo-2-chloro-3-methoxyphenyl)piperidine-2,6-dione (1.49 g, 4.48 mmol, 54% yield) as a white solid.

[0456] 1H NMR (400 MHz, DMSO-d6) δ = 10.93 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.25 (dd, J = 5.0, 12.4 Hz, 1H), 3.81 (s, 3H), 2.82 - 2.71 (m, 1H), 2.55 (br t, J = 3.3 Hz, 1H), 2.30 (br dd, J = 4.3, 12.9 Hz, 1H), 2.04 - 1.91 (m, 1H).

[0457] Step 5. Procedure for the preparation of compound 6 tert-butyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-bromo-2-chloro-3-methoxy-phenyl)piperidine-2,6-dione (400 mg, 1.20 mmol, 1.00 equiv.), tert-butyl azetidin-3-ylcarbamate (269 mg, 1.56 mmol, 1.30 equiv.), and cesium carbonate (1.18 g, 3.61 mmol, 3.00 equiv.) in dioxane (4.00 mL) was added [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (40.0 mg, 41.12 mmol, 3.42 e -2 (equivalent) was added. The reaction mixture was stirred at 100° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=100 / 1 to 1 / 1) and concentrated under reduced pressure to give tert-butyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)azetidin-3-yl)carbamate (70.0 mg, 165 μmol, 14% yield) as a yellow solid.

[0458] 1H NMR (400 MHz, DMSO-d6) δ = 10.82 (s, 1H), 7.50 (br d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 4.46 - 4.30 (m, 1H), 4.13 (br t, J = 7.6 Hz, 2H), 4.08 - 4.05 (m, 1H), 3.66 - 3.57 (m, 5H), 2.77 - 2.69 (m, 1H), 2.41 - 2.38 (m, 1H), 2.27 - 2.17 (m, 1H), 1.95 - 1.89 (m, 1H), 1.39 (s, 9H).

[0459] Step 6. Procedure for the preparation of compound 7, 3-(4-(3-aminoazetidin-1-yl)-2-chloro-3-methoxyphenyl)piperidine-2,6-dione. To a solution of tert-butyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)azetidin-3-yl)carbamate (60.0 mg, 142 μmol, 1.00 equiv) in dichloromethane (1.00 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 0.100 mL, 9.54 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-[4-(3-aminoazetidin-1-yl)-2-chloro-3-methoxy-phenyl]piperidine-2,6-dione (45.0 mg, crude) as a yellow solid.

[0460] 1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.27 (br d, J = 4.0 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 4.36 (br t, J = 8.5 Hz, 1H), 4.20 - 4.16 (m, 2H), 4.09 (br d, J = 4.9 Hz, 1H), 3.85 (dd, J = 4.6, 8.6 Hz, 2H), 3.64 (s, 3H), 2.79 - 2.66 (m, 2H), 2.24 - 2.19 (m, 2H).

[0461] Step 7. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)azetidin-3-yl)carbamate. To a solution of spiro[3.3]heptan-2-ylmethanol (20.0 mg, 158 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (51.4 mg, 317 μmol, 2.00 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2-chloro-3-methoxyphenyl)piperidine-2,6-dione (45.0 mg, 139 μmol, 1.00 equiv) in tetrahydrofuran (0.500 mL) and dimethylformamide (0.500 mL), triethylamine (14.1 mg, 139 μmol, 19.4 μL, 1.00 equiv), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (21.2 mg, 139 μmol, 21.0 μL, 1.00 equiv). The reaction mixture was stirred at 25° C. for 16 hours. Then, di(1H-imidazol-1-yl)methanone (51.4 mg, 317 umol, 2.00 eq) was added to a solution of spiro[3.3]heptan-2-ylmethanol (20.0 mg, 158 umol, 1.00 eq) in tetrahydrofuran (1.00 mL), and the resulting solution was added to the mixture. Finally, the reaction mixture was stirred at 25° C. for 48 hours. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 50% to 80%, 10 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl (1-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)azetidin-3-yl)carbamate (9.01 mg, 18.74 umol, yield 13%, purity 99%) as a white solid.

[0462] 1H NMR (400 MHz, DMSO-d6) δ = 10.82 (s, 1H), 7.77 (br d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 4.47 - 4.31 (m, 1H), 4.14 (br t, J = 7.5 Hz, 2H), 4.05 (dd, J = 5.0, 12.1 Hz, 1H), 3.89 (d, J = 7.0 Hz, 2H), 3.70 - 3.59 (m, 5H), 2.78 - 2.69 (m, 1H), 2.49 - 2.43 (m, 1H), 2.40 - 2.31 (m, 1H), 2.27 - 2.15 (m, 1H), 2.06 - 1.92 (m, 5H), 1.91 - 1.84 (m, 2H), 1.80 - 1.66 (m, 4H). MS (ESI) m / z.476.1 [M+H] +

[0463] Example 63. Synthesis of Compound 64 [ka] Step 1. Procedure for the preparation of compound 2 tert-butyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate. To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 329 μmol, 1.00 equiv.) in dioxane (2.00 mL), cesium carbonate (321 mg, 987 μmol, 3.00 equiv.), (R)-tert-butyl pyrrolidin-3-ylcarbamate (91.9 mg, 493 μmol, 1.50 equiv.), and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1-yl)palladium (32.0 mg, 32.9 μmol, 0.100 equiv.) were added. The reaction mixture was stirred at 110° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give tert-butyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (70.0 mg, 171 μmol, 52% yield) as a yellow oil.

[0464] 1 H NMR (400 MHz, CDCl3) δ = 8.01 (br d, J = 5.1 Hz, 1H), 6.10 (s, 1H), 6.07 (s, 1H), 4.71 (br s, 1H), 4.35 (br s, 1H), 3.95 (dd, J = 5.1, 12.3 Hz, 1H), 3.55 (dd, J = 6.1, 9.8 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.34 - 3.26 (m, 1H), 3.12 (dd, J = 4.0, 9.8 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.73 - 2.61 (m, 1H), 2.39 - 2.24 (m, 2H), 2.19 - 2.09 (m, 1H), 1.99 - 1.91 (m, 1H), 1.46 (s, 9H).

[0465] Step 2. Procedure for the preparation of compound 3, 3-(4-((R)-3-aminopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. To a solution of tert-butyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (70.0 mg, 171 umol, 1.00 equiv) in dioxane (1.00 mL) was added hydrochloric acid / dioxane (4.00 M, 1.75 mL, 40.9 equiv). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-((R)-3-aminopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (59.0 mg, 171 umol, 99% yield, hydrochloride salt) as a yellow solid.

[0466] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.45 - 8.16 (m, 2H), 6.29 (s, 1H), 6.26 (s, 1H), 4.04 (br dd, J = 5.1, 12.7 Hz, 1H), 3.93 (br s, 1H), 3.55 - 3.49 (m, 1H), 3.47 - 3.39 (m, 1H), 3.35 - 3.24 (m, 2H), 2.80 - 2.75 (m, 1H), 2.53 - 2.52 (m, 1H), 2.33 - 2.25 (m, 1H), 2.15 - 2.02 (m, 2H), 1.98 - 1.90 (m, 1H).

[0467] Step 3. Procedure for the preparation of spiro[3.3]heptan-2-ylmethyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate. To a solution of spiro[3.4]octan-2-ylmethanol (25.0 mg, 198 μmol, 1.00 equiv) in tetrahydrofuran (0.300 mL) was added di(1H-imidazol-1-yl)methanone (48.2 mg, 297 μmol, 1.50 equiv), and the reaction mixture was stirred at 20° C. for 1 h. The resulting solution was added to a mixture of 3-(4-((R)-3-aminopyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (59.0 mg, 171 μmol, 99% yield, hydrochloride salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (26.0 mg, 171 μmol, 25.7 μL, 1.00 equiv.), and N,N-diisopropylethylamine (22.1 mg, 171 μmol, 29.7 μL, 1.00 equiv.) in dimethylformamide (0.500 mL). The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (1.5 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 52% to 82%, 9 min) and lyophilized to give spiro[3.3]heptan-2-ylmethyl ((3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (22.10 mg, 47.41 umol, yield 28%, purity 99%) as a white solid.

[0468] 1H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 7.48 (br d, J = 6.5 Hz, 1H), 6.20 (s, 1H), 6.17 (s, 1H), 4.21 - 4.10 (m, 1H), 4.01 (br dd, J = 5.1, 12.5 Hz, 1H), 3.89 (br d, J = 6.9 Hz, 2H), 3.48 - 3.41 (m, 1H), 3.34 (br s, 1H), 3.26 - 3.18 (m, 1H), 3.04 (br dd, J = 4.3, 9.4 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.52 (br d, J = 1.9 Hz, 1H), 2.43 - 2.34 (m, 1H), 2.18 - 2.11 (m, 1H), 2.10 - 1.99 (m, 3H), 1.99 - 1.89 (m, 4H), 1.86 (br d, J = 7.5 Hz, 2H), 1.78 - 1.67 (m, 4H)。

[0469] 1 H NMR (400 MHz, DMSO-d6, T=80℃) δ = 10.55 (br s, 1H), 7.16 (br d, J = 3.6 Hz, 1H), 6.18 (s, 1H), 6.15 (s, 1H), 4.22 - 4.13 (m, 1H), 3.99 (dd, J = 5.4, 12.4 Hz, 1H), 3.92 (d, J = 6.8 Hz, 2H), 3.47 (dd, J = 6.7, 9.8 Hz, 1H), 3.41 - 3.32 (m, 1H), 3.29 - 3.19 (m, 1H), 3.05 (br s, 1H), 2.84 - 2.71 (m, 1H), 2.54 (br d, J = 3.8 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.22 - 2.14 (m, 1H), 2.13 - 2.02 (m, 3H), 2.01 - 1.92 (m, 4H), 1.92 - 1.87 (m, 2H), 1.82 - 1.69 (m, 4H)。MS (ESI) m / z 462.2 [M+H]+ .

[0470] Example 64. Synthesis of Compound 65 [ka] Step 1. Procedure for the preparation of compound 2, diethyl 2-(2-cyclopropylpropan-2-yl)malonate. To a solution of copper iodide (19.0 g, 100 mmol, 2.00 equiv) in tetrahydrofuran (125 mL) at −40° C. under a nitrogen atmosphere was added bromo(cyclopropyl)magnesium (0.500 g, 400 mL, 4.00 equiv). After stirring for 15 minutes, the suspension was warmed and stirred at 20° C. for 20 minutes before being cooled back to −40° C. A solution of diethyl 2-(propan-2-ylidene)malonate (10.0 g, 50.0 mmol, 1.00 equiv) in tetrahydrofuran (125 mL) was added, and the reaction was warmed to 20° C. for 12 hours. The reaction mixture was then quenched with saturated sodium bicarbonate (50 mL) and filtered. The filtrate was extracted with ethyl acetate (3×125 mL). The combined extracts were dried over sodium sulfate and concentrated to a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) and concentrated under reduced pressure to give diethyl 2-(1-cyclopropyl-1-methyl-ethyl)propanedioate (4.30 g, crude) as a colorless oil.

[0471] 1 H NMR (400 MHz, CDCl3-d) δ = 4.18 (q, J = 7.1 Hz, 4H), 3.35 (s, 1H), 1.27 (t, J = 7.1 Hz, 6H), 1.06 - 1.01 (m, 1H), 0.98 (s, 6H), 0.35 - 0.29 (m, 2H), 0.28 - 0.20 (m, 2H).

[0472] Step 2. Preparation of compound 3, ethyl 3-cyclopropyl-3-methylbutanoate. To a solution of diethyl 2-(2-cyclopropylpropan-2-yl)malonate (1.00 g, 4.13 mmol, 1.00 equiv) and lithium chloride (1.05 g, 24.8 mmol, 507 uL, 6.00 equiv) in dimethyl sulfoxide (25.0 mL) and water (0.300 mL). The mixture was stirred at 170° C. for 12 hours. The mixture was then stirred at 150° C. for 12 hours. The reaction mixture was quenched with water (20 mL) and extracted with methyl tert-butyl ether (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) and concentrated under reduced pressure to give ethyl 3-cyclopropyl-3-methylbutanoate (190 mg, crude) as a colorless oil.

[0473] 1 H NMR (400 MHz, CDCl3-d) δ = 4.17 - 4.07 (m, 2H), 2.26 (s, 2H), 1.30 - 1.26 (m, 3H), 0.89 (s, 6H), 0.84 - 0.79 (m, 1H), 0.36 - 0.28 (m, 2H), 0.21 (br d, J = 4.6 Hz, 2H).

[0474] Step 3. Preparation procedure for compound 4, 3-cyclopropyl-3-methylbutan-1-ol. To a solution of ethyl 3-cyclopropyl-3-methylbutanoate (100 mg, 587 μmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) was added lithium aluminum hydride (33.4 mg, 881 μmol, 1.50 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. The reaction was quenched by the addition of water (5 mL), 15% sodium hydroxide (5 mL), and water (15.00 mL). The mixture was then filtered. The filtrate was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-cyclopropyl-3-methylbutan-1-ol (60.0 mg, 468 mol, 80% yield) as a colorless oil.

[0475] 1 H NMR (400 MHz, CDCl3-d) δ = 3.79 (t, J = 7.5 Hz, 2H), 1.60 (t, J = 7.5 Hz, 2H), 0.78 (s, 6H), 0.72 - 0.63 (m, 1H), 0.32 - 0.26 (m, 2H), 0.22 - 0.16 (m, 2H).

[0476] Step 4. Procedure for the preparation of 3-cyclopropyl-3-methylbutyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-cyclopropyl-3-methylbutan-1-ol (10.0 mg, 78.0 µmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (19.0 mg, 117 µmol, 1.50 equiv), and the mixture was stirred at 25°C for 1 hour. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (31.9 mg, 77.8 μmol, 1.00 equiv, trifluoroacetate salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (11.9 mg, 77.8 μmol, 11.7 μL, 1.00 equiv), and triethylamine (7.88 mg, 77.8 μmol, 10.8 μL, 1.00 equiv) in dimethylformamide (0.500 mL) and tetrahydrofuran (0.500 mL). The reaction mixture was stirred at 25° C. for 24 hours. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 50% to 80%, 8 min) and lyophilized to give 3-cyclopropyl-3-methylbutyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (5.49 mg, 11.85 umol, yield 15%, purity 97%) as a white solid.

[0477] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.76 (br d, J = 7.0 Hz, 1H), 6.14 (d, J = 11.1 Hz, 2H), 4.51 - 4.32 (m, 1H), 4.07 (br s, 5H), 3.63 (br t, J = 6.7 Hz, 2H), 2.83 - 2.69 (m, 1H), 2.47 (br s, 1H), 2.14 - 2.02 (m, 1H), 1.99 - 1.88 (m, 1H), 1.54 (br t, J = 7.6 Hz, 2H), 0.74 (s, 6H), 0.71 - 0.61 (m, 1H), 0.27 - 0.21 (m, 2H), 0.18 - 0.12 (m, 2H). MS (ESI) m / z.472.0 [M+Na] +

[0478] Example 65. Synthesis of Compound 66 [ka] Step 1. Preparation procedure for compound 2, 4-methylpent-4-en-1-ol. To a solution of ethyl 4-methylpent-4-enoate (2.00 g, 14.1 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added lithium aluminum hydride (1.07 g, 28.1 mmol, 2.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was quenched with water (1.07 mL), 15% sodium hydroxide (1.07 mL), and water (3.21 mL), then filtered, and the filtrate was concentrated under reduced pressure to give 4-methylpent-4-en-1-ol (600 mg, 5.99 mmol, 43% yield) as a yellow oil.

[0479] 1H NMR (400 MHz, CDCl3-d) δ = 4.75 - 4.70 (m, 2H), 3.67 (t, J = 6.5 Hz, 2H), 2.11 (t, J = 7.6 Hz, 2H), 1.75 (s, 3H), 1.74 - 1.67 (m, 2H).

[0480] Step 2. Preparation procedure for compound 3, benzyl (4-methylpent-4-en-1-yl) carbonate. To a solution of 4-methylpent-4-en-1-ol (500 mg, 4.99 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added pyridine (790 mg, 9.98 mmol, 806 μL, 2.00 equiv), 4-dimethylaminopyridine (30.5 mg, 250 μmol, 0.0500 equiv), and benzyl carbonochloridate (937 mg, 5.49 mmol, 781 μL, 1.10 equiv). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to give benzyl (4-methylpent-4-en-1-yl)carbonate (600 mg, 2.56 mmol, 51% yield) as a yellow oil.

[0481] 1 H NMR (400 MHz, CDCl3-d) δ = 7.44 - 7.30 (m, 5H), 5.17 (s, 2H), 4.75 (s, 1H), 4.70 (d, J = 1.0 Hz, 1H), 4.17 (t, J = 6.6 Hz, 2H), 2.10 (t, J = 7.6 Hz, 2H), 1.87 - 1.79 (m, 2H), 1.73 (s, 3H).

[0482] Step 3. Procedure for the preparation of compound 4, benzyl (3-(1-methylcyclopropyl)propyl) carbonate. To a solution of diethylzinc (1.00 M, 1.28 mL, 3.00 equiv.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (146 mg, 1.28 mmol, 94.8 µL, 3.00 equiv.) in dichloromethane (1.00 mL) dropwise over 25 minutes at 0 °C under a nitrogen atmosphere. To this suspension was added diiodomethane (343 mg, 1.28 mmol, 103 µL, 3.00 equiv.) in dichloromethane (1.00 mL) dropwise over 10 minutes at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 0 °C for 25 minutes, at which point benzyl 4-methylpent-4-enyl carbonate (100 mg, 427 µmol, 1.00 equiv.) was added. The reaction mixture was stirred at 0 °C for 30 minutes and then warmed to 20 °C for 11 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (2.00 mL) and then extracted with ethyl acetate (3 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (3-(1-methylcyclopropyl)propyl)carbonate (100 mg, 403 μmol, 94% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.42 - 7.30 (m, 5H), 5.12 (s, 2H), 4.09 (t, J = 6.7 Hz, 2H), 1.69 - 1.63 (m, 2H), 1.25 - 1.21 (m, 2H), 0.98 (s, 3H), 0.21 (d, J = 2.4 Hz, 4H).

[0483] Step 4. Procedure for the preparation of compound 5, 3-(1-methylcyclopropyl)propan-1-ol. To a solution of benzyl 3-(1-methylcyclopropyl)propyl carbonate (100 mg, 403 μmol, 1.00 equiv) in dioxane (1.00 mL) was added palladium on activated carbon (100 mg, 10% purity). The reaction mixture was stirred under a hydrogen atmosphere of 15 psi at 20° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-(1-methylcyclopropyl)propan-1-ol (30.0 mg, 263 μmol, 65% yield) as a yellow oil.

[0484] 1 H NMR (400 MHz, CDCl3-d) δ = 3.66 (t, J = 6.6 Hz, 2H), 1.70 - 1.64 (m, 2H), 1.31 - 1.29 (m, 2H), 1.04 (s, 3H), 0.25 (br d, J = 4.8 Hz, 4H).

[0485] Step 5. Procedure for the preparation of 3-(1-methylcyclopropyl)propyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(1-methylcyclopropyl)propan-1-ol (30.0 mg, 263 μmol, 1.00 equiv) in tetrahydrofuran (0.300 mL) was added di(1H-imidazol-1-yl)methanone (63.9 mg, 394 μmol, 1.50 equiv) at 0° C. The mixture was stirred at 20° C. for 2 hours. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (85.0 mg, 208 μmol, 1.00 equiv, trifluoroacetate salt), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (31.6 mg, 208 μmol, 31.3 μL, 1.00 equiv), and N,N-diisopropylethylamine (40.3 mg, 312 μmol, 54.3 μL, 1.50 equiv) in tetrahydrofuran (0.300 mL) and dimethylformamide (0.300 mL). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 47% to 77%, 9 min) and lyophilized to give 3-(1-methylcyclopropyl)propyl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (21.16 mg, 48.11 umol, yield 23%, purity 99%) as a white solid.

[0486] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.79 (br d, J = 6.6 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.48 - 4.33 (m, 1H), 4.08 (br t, J = 7.6 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.95 (br t, J = 6.4 Hz, 2H), 3.62 (br t, J = 6.4 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.56 (br d, J = 5.1 Hz, 1H), 2.12 - 2.05 (m, 1H), 2.03 - 1.92 (m, 1H), 1.66 - 1.58 (m, 2H), 1.27 - 1.20 (m, 2H), 0.99 (s, 3H), 0.22 (br d, J = 2.4 Hz, 4H). MS (ESI) m / z 436.0 [M+H] +

[0487] Example 66. Synthesis of Compound 67 [ka] Step 1. Procedure for the preparation of compound 2, 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione. A solution of tert-butyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (200 mg, 505 μmol, 1.00 equiv.) in methyl tert-butyl ether (1.00 mL) was added to a mixture of sulfuric acid (151 mg, 1.52 mmol, 82.5 μL, 98% purity, 3.00 equiv.) and methyl tert-butyl ether (2.00 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was diluted with acetonitrile (15 mL) and stirred for 15 minutes. The mixture was then filtered, and the filter cake was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (145 mg, 258 umol, 51% yield, 70% purity, sulfate salt) as a yellow solid.

[0488] 1 H NMR (400 MHz, DMSO-d6) δ = 10.88 - 10.83 (m, 1H), 8.30 (br s, 4H), 6.27 (br d, J = 11.1 Hz, 2H), 4.11 (br s, 2H), 4.06 (br d, J = 5.6 Hz, 1H), 3.92 (br dd, J = 6.9, 11.3 Hz, 1H), 3.81 (br d, J = 3.9 Hz, 2H), 2.84 - 2.72 (m, 2H), 1.99 - 1.88 (m, 2H).

[0489] Step 2. Procedure for the preparation of compound 2A spiro[3.5]nonan-2-yl 1H-imidazole-1-carboxylate. To a solution of spiro[3.5]nonan-2-ol (40.0 mg, 285 μmol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added di(1H-imidazol-1-yl)methanone (37.0 mg, 228 μmol, 0.800 equiv) at 0° C. The mixture was stirred at 20° C. for 1 hour. The mixture was used directly in the next step.

[0490] Step 3. Procedure for the preparation of spiro[3.5]nonan-2-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (143 mg, 256 μmol, 70% purity, 1.00 equiv., sulfate salt) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (38.9 mg, 256 μmol, 38.6 μL, 1.00 equiv.) and N,N-diisopropylethylamine (33.1 mg, 256 μmol, 44.6 μL, 1.00 equiv.). The mixture was stirred at 20° C. for 0.5 h. Then, spiro[3.5]nonan-2-yl 1H-imidazole-1-carboxylate (60.0 mg, 256 umol, 1.00 equiv) was added to the mixture. The mixture was stirred at 20° C. for 11.5 hours. N,N-diisopropylethylamine (66.2 mg, 512 umol, 89.2 uL, 2.00 equiv) was added to the mixture. The mixture was stirred at 20° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 53% to 83%, 10 min) and lyophilized to give spiro[3.5]nonan-2-yl(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (6.67 mg, 14.31 umol, yield 5%, purity 99%) as an off-white solid.

[0491] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.82 (br d, J = 7.3 Hz, 1H), 6.14 (d, J = 11.1 Hz, 2H), 4.82 (quin, J = 7.2 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.08 (br t, J = 7.8 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.61 (br t, J = 6.8 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.47 (br s, 1H), 2.20 - 2.13 (m, 2H), 2.10 - 2.00 (m, 1H), 1.99 - 1.88 (m, 1H), 1.67 - 1.60 (m, 2H), 1.43 - 1.29 (m, 10H). MS (ESI) m / z 462.1 [M+H] +

[0492] Example 67. Synthesis of Compound 68 [ka] Step 1. Procedure for the preparation of compound 2 (3-isopropylcyclobutyl)methanol. To a solution of 3-isopropylcyclobutanecarboxylic acid (200 mg, 1.41 mmol, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added borane dimethyl sulfide complex (10.0 M, 281 μL, 2.00 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched with methanol (20 mL) and concentrated under reduced pressure to give (3-isopropylcyclobutyl)methanol (160 mg, crude) as a white solid.

[0493] 1H NMR (400 MHz, CDCl3-d) δ = 3.66 (d, J = 7.5 Hz, 1H), 3.52 (d, J = 6.4 Hz, 1H), 2.35 - 2.21 (m, 1H), 2.15 - 2.03 (m, 1H), 1.97 - 1.81 (m, 1H), 1.80 - 1.76 (m, 2H), 1.55 - 1.41 (m, 1H), 1.40 - 1.16 (m, 2H), 0.79 (t, J = 6.8 Hz, 6H).

[0494] Step 2. Procedure for the preparation of compound 3 (3-isopropylcyclobutyl)methyl 1H-imidazole-1-carboxylate. To a solution of (3-isopropylcyclobutyl)methanol (50.0 mg, 390 μmol, 1.00 equiv) in tetrahydrofuran (0.500 mL) was added di(1H-imidazol-1-yl)methanone (95.0 mg, 585 μmol, 1.50 equiv). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give (3-isopropylcyclobutyl)methyl 1H-imidazole-1-carboxylate (86.0 mg, crude), which was used directly in the next step.

[0495] Step 3. Procedure for the preparation of (3-isopropylcyclobutyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (70.3 mg, 227 μmol, 1.00 equiv, hydrochloride salt) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (58.9 mg, 387 μmol, 58.3 μL, 1.00 equiv), triethylamine (39.2 mg, 387 μmol, 53.9 μL, 1.00 equiv), and (3-isopropylcyclobutyl)methyl 1H-imidazole-1-carboxylate (55.0 mg, 227 μmol, 1.00 equiv). The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with dimethylformamide (1 mL) and then filtered. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 52% to 82%, 9 min), and lyophilized to obtain (3-isopropylcyclobutyl)methyl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (22.00 mg, 48.45 μmol, yield 13%, purity 99%) as a white solid.

[0496] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 7.83 (br t, J = 6.6 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.41 (br dd, J = 2.2, 4.8 Hz, 1H), 4.08 (t, J = 7.7 Hz, 2H), 4.05 - 4.00 (m, 2H), 3.86 (d, J = 6.3 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.54 (br d, J = 1.4 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.05 (br d, J = 4.0 Hz, 1H), 2.03 - 1.99 (m, 1H), 1.99 - 1.89 (m, 2H), 1.76 - 1.72 (m, 2H), 1.53 - 1.38 (m, 1H), 1.37 - 1.32 (m, 1H), 0.76 (t, J = 7.3 Hz, 6H). MS (ESI) m / z 450.3 [M+H] +

[0497] Example 68. Synthesis of Compound 69 [ka] Step 1. Procedure for the preparation of compound 2, 1-(benzo[d]oxazol-2-yl)azetidin-3-ol. To a solution of 2-chloro-1,3-benzoxazole (500 mg, 3.26 mmol, 370 μL, 1.00 equiv.) and azetidin-3-ol (428 mg, 3.91 mmol, 1.20 equiv., mesylate salt) in dimethylformamide (5.00 mL) was added potassium carbonate (450 mg, 3.26 mmol, 1.00 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 1-(benzo[d]oxazol-2-yl)azetidin-3-ol (600 mg, 3.15 mmol, 97% yield) as a yellow solid.

[0498] 1 H NMR (400 MHz, DMSO-d6) δ = 7.42 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 5.90 (d, J = 6.6 Hz, 1H), 4.70 - 4.63 (m, 1H), 4.40 (t, J = 7.6 Hz, 2H), 3.98 (dd, J = 4.8, 8.6 Hz, 2H).

[0499] Step 2. Procedure for the preparation of 1-(benzo[d]oxazol-2-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of 1-(benzo[d]oxazol-2-yl)azetidin-3-ol (80.0 mg, 421 umol, 1.00 equiv) in tetrahydrofuran (1.00 mL) was added 1,1'-carbonyldiimidazole (68.2 mg, 421 umol, 1.00 equiv) at 0° C. The mixture was stirred at 25° C. for 0.5 hours to give a solution. To the resulting solution was added a solution of 3-(4-(3-aminoazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (165 mg, 422 μmol, 1.00 equiv, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (64.3 mg, 422 μmol, 63.6 μL, 1.00 equiv), and N,N-diisopropylethylamine (54.6 mg, 422 μmol, 73.5 μL, 1.00 equiv) in dimethylformamide (1.00 mL). The mixture was stirred at 25° C. for 12 hours. The mixture was filtered to obtain the filtrate. The filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 33% to 63%, 9 min) and lyophilized to give 1-(benzo[d]oxazol-2-yl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (26.07 mg, 49.4 umol, yield 12%, purity 97%) as a white solid.

[0500] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 8.20 (br d, J = 7.0 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.16 (d, J = 11.0 Hz, 2H), 5.32 - 5.23 (m, 1H), 4.52 (dd, J = 7.0, 9.2 Hz, 2H), 4.49 - 4.42 (m, 1H), 4.16 - 4.09 (m, 4H), 4.04 (br dd, J = 5.1, 12.6 Hz, 1H), 3.67 (brt, J = 6.8 Hz, 2H), 2.84 - 2.74 (m, 1H), 2.49 - 2.40 (m, 1H), 2.12 - 2.05 (m, 1H), 2.00 - 1.90 (m, 1H). MS (ESI) m / z 512.1 [M+H] +

[0501] Example 69. Synthesis of Compound 70 [ka] Step 1. Procedure for compound 2 azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-1-carboxylate (100 mg, 202 μmol, 1.00 equiv) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 66.8 equiv). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (70.0 mg, crude) as a colorless oil. MS (ESI) m / z 395.0 [M+H] +

[0502] Step 2. Procedure for the preparation of compound 2A methyl(o-tolyl)carbamic acid chloride. To a solution of N,2-dimethylaniline (30.0 mg, 248 μmol, 30.6 μL, 1.00 equiv) in dichloromethane (2.00 mL) was added N,N-diisopropylethylamine (96.0 mg, 743 μmol, 129 μL, 3.00 equiv) and bis(trichloromethyl)carbonate (88.2 mg, 297 μmol, 1.20 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give methyl(o-tolyl)carbamyl chloride (40.0 mg, crude) as a colorless oil.

[0503] Step 3. Procedure for 1-(methyl(o-tolyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (70.0 mg, 178 μmol, 1.00 equiv.) in dichloromethane (2.00 mL) was added N,N-diisopropylethylamine (68.8 mg, 533 μmol, 92.8 μL, 3.00 equiv.) and methyl(o-tolyl)carbamic acid chloride (39.1 mg, 213 μmol, 1.20 equiv.). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 62% to 92%, 9 min) and lyophilized to give 1-(methyl(o-tolyl)carbamoyl)azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (31.22 mg, 55.92 umol, yield 31.50%, purity 97%) as a yellow solid.

[0504] 1 H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.03 (br d, J = 7.5 Hz, 1H), 7.29 (br d, J = 2.8 Hz, 1H), 7.23 (br d, J = 3.3 Hz, 3H), 6.13 (br d, J = 11.3 Hz, 2H), 4.77 (br d, J = 3.1 Hz, 1H), 4.40 - 4.28 (m, 1H), 4.10 - 3.99 (m, 3H), 3.65 (br t, J = 7.6 Hz, 2H), 3.58 (br t, J = 6.5 Hz, 2H), 3.28 - 3.18 (m, 2H), 3.01 (s, 3H), 2.82 - 2.72 (m, 1H), 2.60 - 2.53 (m, 1H), 2.19 (s, 3H), 2.12 - 2.00 (m, 1H), 1.98 - 1.88 (m, 1H). MS (ESI) m / z 542.3 [M+H] +

[0505] Example 70. Synthesis of Compound 71 [ka] Step 1. Procedure for compound 2 azetidin-3-yl (1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate. To a solution of tert-butyl 3-(((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluoroph...

Claims

1. Compounds of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [In the formula, X is selected from H and deuterium; L １ teeth, 【Chemistry 2】 and 5-6 membered heteroaryl; L ２ is a bond and 【Transformation 3】 Selected from: R １ , R ２ , R ３ , and R ４ Each of the groups independently represents hydrogen, halogen, C １～６ Alkoxy, cyano, hydroxy, C ３～６ Cycloalkyl, and C １～６ selected from the group consisting of alkyl; Ring A is C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, wherein C ３～６ Each of the cycloalkyl and 3- to 6-membered heterocyclyl is one or more R ５ optionally substituted with; Each R ５ are independently hydrogen, C １～６ is selected from the group consisting of alkyl, hydroxy, and oxo, wherein C １～６ the alkyl is optionally substituted with one or more halogens; Ring B is C ３～１２ is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and heteroaryl, wherein C ３～１２ Each of cycloalkyl, 3- to 10-membered heterocyclyl, aryl, and heteroaryl may be one or more R ６ optionally substituted with; Each R ６ are independently halogen, cyano, C １～６ Alkoxy, C １～６ Alkyl, —C(O)R ７ , —C(O)NR ７ R ８ , -S(O) ２ R ７ , pyridine, 【Chemistry 4】 wherein each C １～６ Alkyl, C １～６ Alkoxy and pyridine are C １～６ optionally substituted with one or more substituents selected from alkyl and halogen; Each R ７ are independently １～６ Alkyl, phenyl, cyclopropane, N-bonded C ３～９ heterocycloalkyl, N-linked heteroaryl, 【Transformation 5】 wherein R ７ But C １～６ Alkyl, halogen, cyano, trifluoro(methoxy)methane, and C １～６ optionally substituted with one or more substituents selected from the group consisting of alkoxy (e.g., methoxy); R ８ , R ９ , and R １０ each independently represents hydrogen, deuterium, C １～６ Alkyl and deuterated C １～６ Alkyl (e.g., -CD ３ ) selected from; and n is an integer selected from the group consisting of 0, 1, 2, and 3.

2. Ring A is 【Transformation 6】 2. The compound of claim 1 selected from the group consisting of:

3. Ring B is C ３～１２ selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and aryl, wherein C ３～１２ Each of cycloalkyl, 3- to 10-membered heterocyclyl, and aryl may be one or more R ６ 3. The compound of claim 1 or 2, substituted with:

4. Ring B is 【Transformation 7】 3. The compound of claim 1 or 2, selected from the group consisting of:

5. L １ but, 【Transformation 8】 2. The compound of claim 1 selected from the group consisting of:

6. The compound is a compound of formula (IA) 【Chemistry 9】 2. The compound of claim 1, wherein:

7. The compound is a compound of formula (IB) 【Chemistry 10】 2. The compound of claim 1, wherein:

8. The compound is a compound of formula (IC) 【Chemistry 11】 2. The compound of claim 1, wherein:

9. The compound is a compound of formula (ID) 【Chemistry 12】 2. The compound of claim 1, wherein:

10. The compound is a compound of formula (IE) 【Chemistry 13】 2. The compound of claim 1, wherein:

11. The compound is a compound of formula (IF) 【Chemistry 14】 2. The compound of claim 1, wherein:

12. The compound is a compound of formula (IG) 【Chemistry 15】 2. The compound of claim 1, wherein:

13. The compound is a compound of formula (I-H) 【Chemistry 16】 2. The compound of claim 1, wherein:

14. The compound is a compound of formula (II) 【Chemistry 17】 2. The compound of claim 1, wherein:

15. The compound is a compound of formula (IJ) [Chemistry 18] 2. The compound of claim 1, wherein:

16. The compound is a compound of formula (I-K) 【Chemistry 19】 2. The compound of claim 1, wherein:

17. The compound is a compound of formula (IL) 【Chemistry 20】 2. The compound of claim 1, wherein:

18. The compound is a compound of formula (I-I-0) 【Chemistry 21】 2. The compound of claim 1, wherein:

19. The compound is a compound of formula (II-1-2) 【Chemistry 22】 2. The compound of claim 1, wherein:

20. The compound of any one of claims 1 to 19, wherein X is H.

21. L ２ The compound of any one of claims 1 to 20, wherein is a bond.

22. R １ , R ２ , R ３ , and R ４ The compound of any one of claims 1 to 21, wherein is H.

23. R １ is fluoro and R ２ is fluoro and R ３ is H and R ４ The compound of any one of claims 1 to 21, wherein is H.

24. R ９ and R １０ The compound of any one of claims 1 to 23, wherein is H.

25. The compound of any one of claims 1 to 24, wherein n is 3.

26. The compound of any one of claims 1 to 24, wherein n is 1.

27. The compound according to any one of claims 1 to 24, wherein n is 0.

28. R ６ is Cl, F, -CN, -CH ３ , -CF ３ , -CH(CH ３ ) ２ , -OCH ３ , -OC(CH ３ ) ３ , -OCF ３ , —O—Si(CH ３ ) ２ C(CH ３ ) ３ , -C(O)R ７ and R ６ is -C(O)NR ７ R ８ and -S(O) ２ R ７ The compound according to any one of claims 1 to 27,

29. R ７ However, methyl, benzene, cyclopropane, 【Chemistry 23】 is selected from the group consisting of 【Chemistry 24】 29. The compound of any one of claims 1 to 28, wherein each of is optionally substituted with one or two selected from the group consisting of methyl, fluorine, chlorine, cyano, and methoxy.

30. R ８ , R ９ , and R １０ each independently represents hydrogen, CH ３ or CD ３ The compound according to any one of claims 1 to 29,

31. below: 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 【Chemistry 25-6】 【Chemistry 25-7】 【Chemistry 25-8】 【Chemistry 25-9】 【Chemistry 25-10】 【Chemistry 25-11】 【Chemistry 25-12】 【Chemistry 25-13】 [Chemistry 25-14] 【Chemistry 25-15】 [Chemistry 25-16] 【Chemistry 25-17】 [Chemistry 25-18] 【Chemistry 25-19】 【Chemistry 25-20】 【Chemistry 25-21】 [Chemistry 25-22] [Chemistry 25-23] [Chemistry 25-24] 【Chemistry 25-25】 [Chemistry 25-26] [Chemistry 25-27] [Chemistry 25-28] [Chemistry 25-29] [Chemistry 25-30] [Chemistry 25-31] [Chemistry 25-32] [Chemistry 25-33] [Chemistry 25-34] [Chemistry 25-35] [Chemistry 25-36] [Chemistry 25-37] [Chemistry 25-38] [Chemistry 25-39] [Chemistry 25-40] [Chemistry 25-41] [Chemistry 25-42] [Chemistry 25-43] [Chemistry 25-44] [Chemistry 25-45] 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. A method for degrading CDK2 in a subject suffering from cancer, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32.

34. 33. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32.

35. 35. The method of claim 33 or 34, wherein the cancer is breast cancer.

36. 36. The method of claim 35, wherein the breast cancer is triple-negative breast cancer or estrogen receptor-positive breast cancer.

37. 33. A method of treating a solid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32.

38. 33. A method of treating a liquid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32.

39. 39. The method of any one of claims 33 to 38, further comprising administering to the subject an additional therapeutic agent.

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