NEK7 degraders and methods of use

Abstract

The present invention provides compounds of formula (Ia) or (Ib) and methods of using same. [Formula 1] JPEG2025537537001192.jpg49170

Description

[Technical Field]

[0001] The present invention relates to novel compounds that can act as NEK7 degraders and methods of use thereof. [Background technology]

[0002] Inflammasomes are a group of intracellular complexes located in the cytosol that are components of innate immunity responsible for detecting pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Inflammasome multiprotein complexes consist of three parts: a sensor protein, an adaptor, and procaspase-1, which is responsible for producing the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 from their precursors (pro-IL-1β and pro-IL-18, respectively).

[0003] Among all known inflammasomes, the NLRP3 inflammasome plays a central role in innate immunity. It consists of the sensor protein NLRP3, the adaptor proteins apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, and pro-caspase 1. The interaction between these proteins is closely related to the formation of the NLRP3 inflammasome. NLRP3 contains an N-terminal pyrin domain that interacts with the adaptor protein ASC through pyrin-domain interactions; a central adenosine triphosphatase (ATPase) domain known as NACHT, which contains the NBD, helix domain 1 (HD1), winged helix domain (WHD), and helix domain 2 (HD2); and a C-terminal LRR domain. ASC also possesses a caspase recruitment domain that recruits caspase-1 through interactions between the caspase recruitment domains to promote caspase dimerization and activation. Caspase-1 matures the proinflammatory cytokines IL-1β and IL-18 from their precursor forms (pro-IL-1β and pro-IL-18, respectively).

[0004] Inflammasome formation and activation require the synergistic action of two signals. First, initiation signals from TOLL-like receptors (TLRs) result in the induction of proinflammatory transcription factors, particularly NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) or cytokines such as TNF or IL-1β, which upregulate inflammasome components and NEK7. Recently, NEK7 has been identified as a key requirement for NLRP3 inflammasome activation through direct interaction with NLRP3. Human NEK7 is a member of the mammalian NIMA-related kinase (NEK) family and consists of a nonconserved and irregular N-terminal regulatory domain and a conserved C-terminal catalytic domain, i.e., a serine / threonine kinase.

[0005] NEK7 directly binds to the leucine-rich repeat (LRR) domain of NLRP3. This interaction stimulates the assembly and activation of the NLRP3 inflammasome and promotes its oligomerization through cross-linking of adjacent subunits of the NLRP3 protein. Although NLRP3 associates with the catalytic domain of NEK7, the catalytic activity of NEK7 was shown to be dispensable for NLRP3 inflammasome activation.

[0006] NEK7 is expressed in various tissues and is essential for cell division, cell proliferation, and mammalian cell survival. Low activity of NEK7 protein in resting cells is crucial for maintaining homeostasis. However, when homeostasis is disrupted, abnormal NEK7 expression occurs, which is closely related to the progression of neoplasia. NEK7 overexpression promotes the production of abnormal cells, including inflammation-related multinucleated and apoptotic cells. Through the inappropriate release of inflammatory cytokines, the NLRP3 inflammasome is involved in various inflammatory diseases, such as atherosclerosis, type 2 diabetes, metabolic syndrome, multiple sclerosis, Alzheimer's disease, gout, rheumatoid arthritis, and inflammatory bowel disease. The mechanism of NEK7-mediated NLRP3 inflammasome activation strongly suggests that targeting NEK7 may play a promising role in treating inflammation-related diseases. Several pathways are essential for NLRP3 inflammasome activation, including ROS signaling, K+ efflux, Ca2+ signaling, chloride efflux, and lysosomal destabilization. Therefore, numerous inhibitors have been widely used to disrupt these signaling pathways. NEK7-focused compounds can suppress inflammatory responses by regulating NLRP3 with improved specificity and potency. In addition to NLRP3 inflammasome activation, NEK7 also plays an important role in mitotic entry, cell cycle progression, cell division, and mitotic progression. Over the past few years, the potential role of NEK7 in cancer development in various tissues has been demonstrated.

[0007] Although inhibitors can generally block the activity of a protein of interest (POI), targeted degradation appears to be an attractive therapeutic alternative. Protein degradation is primarily regulated by the ubiquitin-proteasome pathway, in which proteins are tagged for degradation by the covalent attachment of multiple ubiquitin molecules. The ubiquitin-proteasome system can be manipulated to achieve targeted protein degradation within cells using chemical and drug approaches. Targeted protein degradation (TPD) rather than inhibition potentially offers advantages such as a reduced drug exposure time required to suppress signaling, and increased completeness and durability of downstream signaling inactivation due to the time required for cells to re-express the POI at the required levels. TPD can also overcome endogenous feedback activation or overexpression of the target protein. Protein degraders could potentially be used as a general method to resolve compensatory upregulation of proteins that contribute to disease, adverse effects, and drug resistance. Therefore, there is a great need to provide NEK7 degraders as a key to downregulating inflammasome activation in the treatment of NLRP3 inflammasome-related diseases and cancer. Summary of the Invention [Means for solving the problem]

[0008] According to a first aspect of the present invention, there is provided a compound of formula (Ia) or (Ib): [ka] During the ceremony, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] is in formula (Ia) [ka] or in formula (Ib) [ka] indicates the point of attachment to; [ka] is the attachment point [ka] is a heterocycloalkyl group having a heteroatom adjacent to [ka] is a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group; [ka] is unsubstituted or contains one or more R 3 is replaced by The one or more R 3 The substituents other than [ka] Not present in; Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 is independently H, unsubstituted alkyl, or cycloalkyl; In formula (Ib), (i) [ka] but, [ka] and when Z is CH2 and n=0, (a) [ka] is one or more R 3 or (b) y is 2; (ii) [ka] but, [ka] Z is CH2 and n=0; [ka] is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) [ka] but, [ka] Z is CH2 and n=0; [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with (a) [ka] Through it [ka] the carbon atom adjacent to the carbon atom bonded to is unsubstituted; (b)R 3 is alkyl or O(alkyl), [ka] is monosubstituted; (c)R 3 is O(alkyl), the substitution is in the meta or para position relative to the heteroatom of said heteroaryl group; (d)R 3 is aryl or -NR 2 C(O)R 1 wherein the substitution is in the meta position relative to the heteroatom of said heteroaryl group; (iv) [ka] but, [ka] Z is C=O and n=0; [ka] But one or more R 3 When R is a 6-membered monocyclic heteroaryl group substituted with 3 is hydroxy, the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group; (v) [ka] but, [ka] Z is CH2 and n=0; [ka] But one or more R 3 is a 10-membered fused bicyclic heteroaryl group substituted with Each R 3 teeth, [ka] present in the ring containing the point of attachment to Each R 3 is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R 3 is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R 3 If is OEt, R 3 is ortho to the heteroatom of the heteroaryl group; R 3 NR 2 If COMe, R 3is in the meta position relative to the heteroatom of the heteroaryl group.

[0009] According to a second aspect of the present invention, there is provided a compound of formula (I) for use in a method of treating an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn in a subject in need thereof: [ka] During the ceremony, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, (i) [ka] (In the formula, [ka] is a heterocycloalkyl group) or (ii) [ka] (In the formula, [ka] is unsubstituted or contains one or more R 3 a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R 3 The substituents other than [ka] Not present in each R 3are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. is a heterocyclic group selected from [ka] but, [ka] where Z is CH2 or C=O and n=0; [ka] but, [ka] and [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with R 3 When is hydroxy or O(alkyl), the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group.

[0010] According to a third aspect of the present invention, there is provided a method for degrading a NEK7 protein, comprising: combining said protein with a compound of formula (I): [ka] (In the formula, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, [ka] indicates the point of attachment to; [ka] is a heterocyclic group) With a compound of formula (I), a method is provided.

[0011] As used herein, the term "alkyl" is intended to include both unsubstituted alkyl groups and alkyl groups substituted with one or more additional groups. The term "alkyl" is intended to include both straight-chain and branched alkyl groups. In some embodiments, the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is an alkyl group selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is C-C 12 Alkyl groups, C1-C 10 In some embodiments, the alkyl group is a straight chain alkyl group. In some embodiments, the alkyl group is an unsubstituted straight chain alkyl group. In some embodiments, the alkyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is a branched alkyl group. In some embodiments, the alkyl group is an unsubstituted branched alkyl group. In some embodiments, the alkyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W, -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0012] In some embodiments of any of the above aspects, all alkyl groups are unsubstituted alkyl groups.

[0013] As used herein, the term "cycloalkyl" is intended to include both unsubstituted cycloalkyl groups and cycloalkyl groups substituted with one or more additional groups. In some embodiments, a cycloalkyl group is an unsubstituted cycloalkyl group. In some embodiments, a cycloalkyl group is an alkyl group selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the cycloalkyl group is C-C 12 It is a cycloalkyl group, a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group.

[0014] In some embodiments of any of the above aspects, all cycloalkyl groups are unsubstituted cycloalkyl groups.

[0015] As used herein, the term "alkenyl" is intended to include both unsubstituted alkenyl groups and alkenyl groups substituted with one or more additional groups. In some embodiments, an alkenyl group is an unsubstituted alkenyl group. In some embodiments, an alkenyl group is an alkyl group such as -OH, -OR, or -O. W , -NH2, -NHRW , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is C-C 12 Alkenyl groups, C2-C 10 In some embodiments, the alkenyl group is a straight-chain alkenyl group. In some embodiments, the alkenyl group is an unsubstituted straight-chain alkenyl group. In some embodiments, the alkenyl group is an -OH, -OR alkenyl group. W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is a branched alkenyl group. In some embodiments, the alkenyl group is an unsubstituted branched alkenyl group. In some embodiments, the alkenyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0016] In some embodiments of any of the above aspects, all alkenyl groups are unsubstituted alkenyl groups.

[0017] As used herein, the term "alkynyl" is intended to include both unsubstituted alkynyl groups and alkynyl groups substituted with one or more additional groups. In some embodiments, an alkynyl group is an unsubstituted alkynyl group. In some embodiments, an alkynyl group is an alkynyl group selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is C-C 12 Alkynyl groups, C2-C 10 In some embodiments, the alkynyl group is a straight-chain alkynyl group. In some embodiments, the alkynyl group is an unsubstituted straight-chain alkynyl group. In some embodiments, the alkynyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is a branched alkynyl group. In some embodiments, the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments, the alkynyl group is an -OH, -OR W , -NH2, -NHR W , -NRW 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0018] In some embodiments of any of the above aspects, all alkynyl groups are unsubstituted alkynyl groups.

[0019] As used herein, the term "aryl" is intended to include both unsubstituted aryl groups and aryl groups substituted with one or more additional groups. In some embodiments, an aryl group is an unsubstituted aryl group. In some embodiments, an aryl group is an aryl group selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the aryl group is C-C 10 It is an aryl group, a C6-C8 aryl group, or a C6 aryl group.

[0020] In some embodiments of any of the above aspects, all aryl groups are unsubstituted aryl groups.

[0021] As used herein, the term "benzyl" is intended to include both unsubstituted benzyl groups and benzyl groups substituted with one or more additional groups. In some embodiments, a benzyl group is an unsubstituted benzyl group. In some embodiments, a benzyl group is selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHRW , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, and each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0022] In some embodiments of any of the above aspects, all benzyl groups are unsubstituted benzyl groups.

[0023] As used herein, the term "heterocyclic" is intended to include monocyclic heteroaryl groups, monocyclic heterocycloalkyl groups, fused bicyclic heteroaryl groups, fused bicyclic heterocycloalkyl groups, and fused bicyclic heterocycloalkyl-aryl groups. The term "heterocyclic" is intended to include both unsubstituted heterocyclic groups and heterocyclic groups substituted with one or more additional groups. In some embodiments, a heterocyclic group is an unsubstituted heterocyclic group. In some embodiments, a heterocyclic group is a heterocyclic group substituted with one or more R 3 and wherein said one or more R 3 No substituents other than 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. In some embodiments, when the heterocyclic group is a heterocycloalkyl group, two R on adjacent atoms of said heterocycloalkyl group are 3In some embodiments, when the heterocyclic group is a heterocycloalkyl group, two R groups on the same carbon atom of the heterocycloalkyl group together form an aryl ring. 3 The groups together with the carbon atom to which they are attached form a C=O group.

[0024] As used herein, the term "heterocycloalkyl" is intended to include monocyclic and fused bicyclic heterocycloalkyl groups. The term "heterocycloalkyl" is intended to include both unsubstituted heterocycloalkyl groups and heterocycloalkyl groups substituted with one or more additional groups. In some embodiments, a heterocycloalkyl group is an unsubstituted heterocyclic group. In some embodiments, a heterocycloalkyl group is one or more R 3 and wherein said one or more R 3 No substituents other than 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. In some embodiments, two R on adjacent atoms of a heterocycloalkyl group are 3 In some embodiments, two R groups on the same carbon atom of a heterocycloalkyl group together with the atom to which they are attached form an aryl ring. 3 Groups taken together with the carbon atom to which they are attached form a C=O group. In some embodiments, heterocycloalkyl groups are 5-10 membered heterocycloalkyl groups (C5-C 10heterocycloalkyl), a 5- to 9-membered heterocycloalkyl group (also called C5-C9 heterocycloalkyl), a 5- to 8-membered heterocycloalkyl group (also called C5-C8 heterocycloalkyl), or a 5- or 6-membered heterocycloalkyl group (also called C5 or C6 heterocycloalkyl).

[0025] As used herein, the term "heteroaryl" is intended to include monocyclic and fused bicyclic heteroaryl groups. The term "heteroaryl" is intended to include both unsubstituted heteroaryl groups and heteroaryl groups substituted with one or more additional groups. In some embodiments, a heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, a heteroaryl group is one or more R 3 and wherein said one or more R 3 No substituents other than 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group (C-C 10In some embodiments, the heteroaryl group is a monocyclic heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 7-membered monocyclic heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered monocyclic heteroaryl group. In some embodiments, the heteroaryl group is a fused bicyclic heteroaryl group. In some embodiments, the heteroaryl group is a 9- or 10-membered fused bicyclic heteroaryl group. In some embodiments, the heteroaryl group is a 10-membered fused bicyclic heteroaryl group.

[0026] In some embodiments of any of the above aspects of the invention, all alkyl, alkenyl, alkynyl, aryl, and benzyl groups in the compound are unsubstituted. [Brief explanation of the drawings]

[0027] [Figure 1] Representative Western blotting membranes showing NEK7 proteolysis induced by inventive compound 2, compound 25, and compound 64. Loading controls: β-actin and vinculin. [Figure 2A] ~ [Figure 2B] Figure 1 shows the levels of IL-1β and IL-18 release by human PBMC-derived macrophages after treatment with Compound 2, Compound 25, and Compound 64 (respectively). Results are normalized to the DMSO control sample. UT - cells not treated with LPS and nigericin; LPS - cells treated with LPS only; LPS+NIG - cells treated with LPS and nigericin but not DMSO; N / A - not applicable (compound unrelated to this application). DETAILED DESCRIPTION OF THE INVENTION

[0028] In a first aspect of the present invention, there is provided a compound of formula (Ia) or (Ib): [ka] During the ceremony, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] is in formula (Ia) [ka] or in formula (Ib) [ka] indicates the point of attachment to; [ka] is the attachment point [ka] is a heterocycloalkyl group having a heteroatom adjacent to [ka] is a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group; [ka] is unsubstituted or contains one or more R 3 is replaced by The one or more R 3 The substituents other than [ka] Not present in; Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 is independently H, unsubstituted alkyl, or cycloalkyl; In formula (Ib), (i) [ka] but, [ka] and when Z is CH2 and n=0, (a) [ka] is one or more R 3 or (b) y is 2; (ii) [ka] but, [ka] Z is CH2 and n=0; [ka] is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) [ka] but, [ka] Z is CH2 and n=0; [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with (a) [ka] Through it [ka] the carbon atom adjacent to the carbon atom bonded to is unsubstituted; (b)R 3 is alkyl or O(alkyl), [ka] is monosubstituted; (c)R 3 is O(alkyl), the substitution is in the meta or para position relative to the heteroatom of said heteroaryl group; (d)R 3 is aryl or -NR 2 C(O)R 1 wherein the substitution is in the meta position relative to the heteroatom of said heteroaryl group; (iv) [ka] but, [ka] Z is C=O and n=0; [ka] But one or more R 3 and R is a 6-membered monocyclic heteroaryl group substituted with 3 is hydroxy, the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group; (v) [ka] but, [ka] Z is CH2 and n=0; [ka] But one or more R 3 is a 10-membered fused bicyclic heteroaryl group substituted with Each R 3 teeth, [ka] present in the ring containing the point of attachment to Each R3 is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R 3 is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R 3 If is OEt, R 3 is ortho to the heteroatom of the heteroaryl group; R 3 NR 2 If COMe, R 3 is in the meta position relative to the heteroatom of the heteroaryl group; The compound of formula (I) is provided.

[0029] In some embodiments, in formula (Ib): [ka] but, [ka] and when Z is CH2 and n=0, [ka] is one or more R 3 is replaced by .

[0030] In some embodiments, in formula (Ib): [ka] but, [ka] Z is C=O or CH2, and n=0; [ka] But one or more R 3 and R is a 6-membered monocyclic heteroaryl group substituted with 3When is hydroxy or O(alkyl), the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group.

[0031] In some embodiments, in formula (Ib): (i) [ka] but, [ka] and when n=0, Z is CH(C 1-2 alkyl) or C=O, (ii) [ka] but, [ka] and when Z is CH2, n is 1, 2, or 3.

[0032] In some embodiments, Z is CH or CH(C 1-2 alkyl).

[0033] In some embodiments, [ka] teeth, [ka] is.

[0034] In some embodiments, [ka] teeth, [ka] is.

[0035] In some embodiments, [ka] teeth, [ka] is.

[0036] In some embodiments, [ka] teeth, [ka] is.

[0037] In some embodiments, [ka] teeth, [ka] is.

[0038] In some embodiments, [ka] teeth, [ka] is.

[0039] In some embodiments, [ka] teeth, [ka] is.

[0040] In some embodiments, [ka] teeth, [ka] is.

[0041] In some embodiments, [ka] teeth, [ka] is.

[0042] In some embodiments, [ka] teeth, [ka] is.

[0043] In some embodiments, [ka] teeth, [ka] is.

[0044] In some embodiments, [ka] teeth, [ka] is.

[0045] In some embodiments, [ka] teeth, [ka] is.

[0046] In some embodiments, [ka] contains 1 heteroatom. In some embodiments, the heteroatom is N, S, or O. In some embodiments, the heteroatom is N. In some embodiments, the heteroatom is O.

[0047] In some embodiments, [ka] contains two heteroatoms, which may be independently selected from N, S, and O.

[0048] In some embodiments, [ka] is a 5- to 10-membered heterocycloalkyl group.

[0049] In some embodiments, [ka] is a 5- or 6-membered heterocycloalkyl group.

[0050] In some embodiments, [ka] is a pyrrolidine group, a piperidine group, or an oxane group.

[0051] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0052] In some embodiments, [ka] teeth, [ka] is.

[0053] In some embodiments, [ka] teeth, [ka] is.

[0054] In some embodiments, [ka] is dioxane, diazinane, morpholine, or thiomorpholine. In some of these embodiments, the dioxane is 1,4-dioxane and the diazinane is 1,2-diazinane or 1,4-diazinane.

[0055] In some embodiments, [ka] teeth, [ka] is.

[0056] In some embodiments, [ka] is Azepan.

[0057] In some embodiments, [ka] teeth, [ka] is.

[0058] In some embodiments, [ka] is unsubstituted. In other embodiments, [ka] is one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl; or two R on adjacent atoms of a heterocycloalkyl group. 3 form an aromatic ring together with the atom to which they are attached; or two R on the same carbon atom of the heterocycloalkyl group. 3 together with the carbon atom to which they are attached form a C=O group.

[0059] In some embodiments, each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R 1 or two R on the same carbon atom of a heterocycloalkyl group; 3 together with the carbon atom to which they are attached form a C=O group.

[0060] In other embodiments, two R on adjacent atoms of a heterocycloalkyl group 3 together with the atoms to which they are attached form an aromatic ring.

[0061] In some embodiments, each R 1 are independently unsubstituted alkyl or aryl, and each R 2 is independently H or unsubstituted alkyl.

[0062] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to r is an integer from 1 to 7, optionally from 1 to 3; s is an integer from 1 to 9, optionally from 1 to 4.

[0063] In some embodiments, [ka] teeth, [ka] is.

[0064] In some embodiments, [ka] teeth, [ka] is.

[0065] In some embodiments, [ka] teeth, [ka] is.

[0066] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to s is an integer from 1 to 9, optionally from 1 to 4.

[0067] In some embodiments, [ka] teeth, [ka] is.

[0068] In some embodiments, [ka] teeth, [ka] is.

[0069] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to R 3 is unsubstituted alkyl, haloalkyl, aryl, benzyl, or -NR 2 C(O)R 1 is.

[0070] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, benzyl, or -NR 2 C(O)R 1 is.

[0071] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, benzyl, or -NR 2 C(O)R 1 In some of these embodiments, R 3 is unsubstituted alkyl or benzyl.

[0072] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, benzyl, —NHC(O)Me, or —NHC(O)Ph.

[0073] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, —NHC(O)Me, or —NHC(O)Ph.

[0074] In some embodiments, [ka] teeth, [ka] and R is F or alkyl. In some of these embodiments, [ka] teeth, [ka] and R is F.

[0075] In some of these embodiments, [ka] teeth, [ka] is.

[0076] In some embodiments, [ka] teeth, [ka] In some of these embodiments, [ka] teeth, [ka] is.

[0077] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, benzyl, —NHC(O)Ph, or —NHC(O)Me; R 3a is unsubstituted alkyl, R 3b is aryl.

[0078] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, benzyl, or -NHC(O)Ph; R 3a is unsubstituted alkyl, R 3b is aryl or unsubstituted alkyl.

[0079] In some embodiments, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, benzyl, or -NHC(O)Ph; R 3a is unsubstituted alkyl, R 3b is aryl.

[0080] In some embodiments, [ka] teeth, [ka] is.

[0081] In some embodiments, [ka] contains 1 heteroatom. In some embodiments, the heteroatom is N, S, or O. In some embodiments, the heteroatom is N. In some embodiments, the heteroatom is O.

[0082] In other embodiments, [ka] contains two heteroatoms, which may be independently selected from N, S, and O.

[0083] In some embodiments, [ka] is a 6-membered monocyclic heteroaryl group.

[0084] In some embodiments, [ka] is a pyridine group.

[0085] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0086] In some embodiments, [ka] is a 10-membered fused bicyclic heteroaryl group.

[0087] In some embodiments, [ka] is a quinoline group or an isoquinoline group.

[0088] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0089] In some embodiments, [ka] is unsubstituted. In other embodiments, [ka] is one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 is independently H, unsubstituted alkyl, or cycloalkyl. In some embodiments, R 3 are independently halogen, unsubstituted alkyl, haloalkyl, hydroxy, OR 1, aryl, benzyl, or -NHC(O)R 1 In some embodiments, each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R 1 is.

[0090] In some embodiments, each R 1 are independently unsubstituted alkyl or aryl, and each R 2 is independently H or unsubstituted alkyl.

[0091] In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] and q is an integer of 1 to 4, optionally 1 to 3.

[0092] In some embodiments, [ka] teeth, [ka] and R 3 is aryl, haloalkyl, hydroxy, OR 1 , or -NR 2 C(O)R 1 is.

[0093] In some embodiments, [ka] teeth, [ka] is.

[0094] In some embodiments, R 3 is aryl, haloalkyl, or -NR 2 C(O)R 1 In some embodiments, R 3 is aryl or -NR 2 C(O)R 1 In other embodiments, R 3 is aryl or haloalkyl.

[0095] In some embodiments, [ka] teeth, [ka] is.

[0096] In some embodiments, [ka] teeth, [ka] is.

[0097] In some embodiments, [ka] teeth, [ka] is.

[0098] In some embodiments, the compound is a compound of formula (Ia): In other embodiments, the compound is a compound of formula (Ib):

[0099] In some embodiments, the compound [Table 1] JPEG2025537537000228.jpg255170 JPEG2025537537000229.jpg255170 JPEG2025537537000230.jpg248170 Selected from JPEG2025537537000231.jpg147170.

[0100] In some embodiments of the first aspect, the compound is selected from compound numbers 33, 35, 37, 40, 54, 56, 57, 58, 69 (isomer 2), 74 (isomer 2), 4(2), 7(2), 23(2), 24(2), and 25(2).

[0101] In some embodiments, the compound is selected from compound numbers 2, 9, 25, 32 (isomer 2), 35, 37, 40, 54, 55 (isomer 2), 56, 64, 69 (isomer 1), 70 (isomer 2), 74 (isomer 2), 4(2), 7(2), 16(2), 23(2), 24(2), and 25(2).

[0102] In some embodiments, the compound is selected from compound numbers 35, 37, 40, 54, 56, 74 (isomer 2), 4(2), 7(2), 23(2), 24(2), and 25(2).

[0103] In some embodiments, the compound is selected from Compound Nos. 56 and 23(2).

[0104] In some embodiments, the compound is selected from Compound Nos. 2, 25, 54, and 64.

[0105] In some embodiments, the compound is selected from Compound Nos. 2, 25, and 64.

[0106] The present invention also provides a pharmaceutical composition comprising a compound according to any of the above embodiments.

[0107] The present invention also provides a compound or a pharmaceutical composition as defined above for use in medicine.

[0108] The invention also provides a compound or pharmaceutical composition as above defined for use in the treatment of an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, an infectious disease, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes related condition, an arthritis related condition, a wound or burn, or cancer.

[0109] In a second aspect of the present invention, there is provided a compound of formula (I) for use in a method of treating an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn in a subject in need thereof. [ka] During the ceremony, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, (i) [ka] (In the formula, [ka] is a heterocycloalkyl group) or (ii) [ka] (In the formula, [ka] is unsubstituted or contains one or more R 3 a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R 3 The substituents other than [ka] Not present in each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. is a heterocyclic group selected from [ka] but, [ka] where Z is CH2 or C=O and n=0; [ka] but, [ka] and [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with R 3 is hydroxy or O(alkyl), the substitution is in the meta or para position relative to the heteroatom of said heteroaryl group; The compound of formula (I) is provided.

[0110] In some embodiments, the disease or condition is an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn.

[0111] In some embodiments, the disease or condition is selected from the group consisting of cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), pyogenic arthritis pyoderma gangrenosum and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and familial cold autoinflammatory syndrome (FCAS). Syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet's disease, antisynthetase syndrome, interleukin 1 receptor antagonist deficiency (DIRA), A20 haploinsufficiency (HA20), lupus nephritis, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, amyotrophic lateral sclerosis, gout, Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal cord injury, atherosclerosis, heart failure, dilated cardiomyopathy (DCM), nonalcoholic steatohepatitis (NASH), cirrhosis, inflammatory bowel disease (IBD),inflammatory bowel disease), ulcerative colitis (UC), or Crohn's disease.

[0112] In a third aspect of the present invention, there is provided a method for degrading NEK7 protein, comprising the step of contacting said protein with a compound of formula (I). [ka] During the ceremony, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, [ka] indicates the point of attachment to; [ka] is a heterocyclic group.

[0113] In some embodiments of the third aspect of the invention, [ka] teeth, (i) [ka] (In the formula, [ka] is a heterocycloalkyl group) or (ii) [ka] (In the formula, [ka] is unsubstituted or contains one or more R 3 a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R 3 The substituents other than [ka] Not present in each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. is.

[0114] In some embodiments of the second or third aspect of the invention, [ka] is the attachment point [ka] is a heterocycloalkyl group having a heteroatom adjacent to

[0115] In some embodiments of the second or third aspect of the invention, (i) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] If (a) [ka] is one or more R 3 or (b) y is 2; (ii) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] and [ka] is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] and [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with (a) [ka] But through that, [ka] the carbon atom adjacent to the carbon atom bonded to is unsubstituted; (b)R 3 is alkyl or O(alkyl), [ka] is monosubstituted; (c)R 3 is O(alkyl), the substitution is in the meta or para position relative to the heteroatom of said heteroaryl group; (d)R 3 is aryl or -NR 2 C(O)R 1 when the substitution is in the meta position relative to the heteroatom of said heteroaryl group; (iv) [ka] but, [ka] Z is C=O and n=0; [ka] but, [ka] and [ka] But one or more R 3 and R is a 6-membered monocyclic heteroaryl group substituted with 3 is hydroxy, the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group; (v) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] and [ka] But one or more R 3 is a 10-membered fused bicyclic heteroaryl group substituted with Each R 3 teeth, [ka] present in the ring containing the point of attachment to Each R 3 is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R 3 is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R 3 If is OEt, R 3 is ortho to the heteroatom of the heteroaryl group; R 3 NR 2 If COMe, R 3 is in the meta position relative to the heteroatom of the heteroaryl group.

[0116] In some embodiments of the second or third aspect of the invention, [ka] but, [ka] Z is C=O or CH2, and n=0; [ka] but, [ka] and [ka] But one or more R 3 and R is a 6-membered monocyclic heteroaryl group substituted with 3 When is hydroxy or O(alkyl), the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group.

[0117] In some embodiments of the second or third aspect of the invention, (i) [ka] but, [ka] and n=0, [ka] but, [ka] If Z is CH(C 1-2 alkyl) or C=O, (ii) [ka] but, [ka] and Z is CH2; [ka] but, [ka] where n is 1, 2, or 3.

[0118] In some embodiments of the second or third aspect of the invention, Z is CH or CH(C1-2 alkyl).

[0119] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0120] In some embodiments, [ka] teeth, [ka] is.

[0121] In some embodiments, [ka] teeth, [ka] is.

[0122] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0123] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0124] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0125] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0126] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0127] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0128] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0129] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0130] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0131] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0132] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0133] In some embodiments of the second or third aspect of the invention, [ka] In some embodiments of the second or third aspect of the invention, [ka] contains two heteroatoms, which may be independently selected from N, S, and O.

[0134] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] is a heterocycloalkyl group.

[0135] In some embodiments of the second or third aspect of the invention, [ka] is a 5- to 10-membered heterocycloalkyl group.

[0136] In some embodiments of the second or third aspect of the invention, [ka] is a 5- or 6-membered heterocycloalkyl group.

[0137] In some embodiments of the second or third aspect of the invention, [ka] is a pyrrolidine group, a piperidine group, or an oxane group.

[0138] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0139] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0140] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0141] In some embodiments of the second or third aspect of the invention, [ka] is dioxane, diazinane, morpholine, or thiomorpholine. In some embodiments, the dioxane is 1,4-dioxane and the diazinane is 1,2-diazinane or 1,4-diazinane.

[0142] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0143] In some embodiments of the second or third aspect of the invention, [ka] is Azepan.

[0144] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0145] In some embodiments of the second or third aspect of the invention, [ka] is unsubstituted. In another embodiment of the second or third aspect of the invention, [ka] is one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1, aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl; or two R on adjacent atoms of a heterocycloalkyl group. 3 form an aromatic ring together with the atom to which they are attached; or two R on the same carbon atom of the heterocycloalkyl group. 3 together with the carbon atom to which they are attached form a C=O group. In some embodiments, each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R 1 or two R on the same carbon atom of a heterocycloalkyl group; 3 together with the carbon atom to which they are attached form a C=O group. In some embodiments, two R on adjacent atoms of a heterocycloalkyl group 3 together with the atoms to which they are attached form an aromatic ring.

[0146] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to r is an integer from 1 to 7, optionally from 1 to 3; s is an integer from 1 to 9, optionally from 1 to 4.

[0147] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0148] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0149] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0150] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to s is an integer from 1 to 9, optionally from 1 to 4.

[0151] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0152] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0153] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to R 3 is unsubstituted alkyl, haloalkyl, aryl, benzyl, or -NR 2 C(O)R 1is.

[0154] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to R 3 is unsubstituted alkyl, aryl, benzyl, or -NR 2 C(O)R 1 is.

[0155] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, benzyl, or -NR 2 C(O)R 1 In some embodiments, R 3 is unsubstituted alkyl or benzyl.

[0156] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, benzyl, —NHC(O)Me, or —NHC(O)Ph.

[0157] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, —NHC(O)Me, or —NHC(O)Ph.

[0158] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R is F or alkyl.

[0159] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R is F.

[0160] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0161] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0162] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0163] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, benzyl, —NHC(O)Ph, or —NHC(O)Me; R 3a is unsubstituted alkyl, R 3b is aryl.

[0164] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, aryl, benzyl, or -NHC(O)Ph; R 3a is unsubstituted alkyl, R 3b is aryl or unsubstituted alkyl.

[0165] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is unsubstituted alkyl, benzyl, or -NHC(O)Ph; R 3a is unsubstituted alkyl, R 3b is aryl.

[0166] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0167] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] is unsubstituted or contains one or more R 3 a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R 3 The substituents other than [ka] Not present in each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 is independently H, unsubstituted alkyl, or cycloalkyl.

[0168] In some embodiments of the second or third aspect of the invention, [ka] is a 6-membered monocyclic heteroaryl group.

[0169] In some embodiments of the second or third aspect of the invention, [ka] is a pyridine group.

[0170] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0171] In some embodiments of the second or third aspect of the invention, [ka] is a 10-membered fused bicyclic heteroaryl group.

[0172] In some embodiments of the second or third aspect of the invention, [ka] is a quinoline group or an isoquinoline group. In some embodiments, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the attachment point to

[0173] In some embodiments of the second or third aspect of the invention, each R 1 are independently unsubstituted alkyl or aryl, and each R 2 is independently H or unsubstituted alkyl.

[0174] In some embodiments of the second or third aspect of the invention, [ka] is non-substituted.

[0175] In other embodiments, [ka] is one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 is independently H, unsubstituted alkyl, or cycloalkyl. In some embodiments, each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, hydroxy, OR 1 , aryl, benzyl, or -NHC(O)R 1 In some embodiments, each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R 1 In some embodiments, each R 1 are independently unsubstituted alkyl or aryl, and each R 2 is independently H or unsubstituted alkyl.

[0176] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] and q is an integer of 1 to 4, optionally 1 to 3.

[0177] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is aryl, haloalkyl, hydroxy, OR 1 , or -NR 2 C(O)R 1 is.

[0178] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0179] In some embodiments of the second or third aspect of the invention, R 3 is aryl, haloalkyl, or -NR 2 C(O)R 1 In some embodiments, R 3 is aryl or -NR 2 C(O)R 1 In some embodiments, R 3 is aryl or haloalkyl.

[0180] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0181] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0182] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and [ka] teeth, [ka] indicates the point of attachment to R 3 is aryl, haloalkyl, or -NR 2 C(O)R 1 is.

[0183] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] and R 3 is aryl or -NR 2 C(O)R 1 is.

[0184] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0185] In some embodiments of the second or third aspect of the invention, [ka] teeth, [ka] is.

[0186] In some embodiments of the first, second, or third aspect of the invention, L is hydrogen.

[0187] In some embodiments of the first, second, or third aspect of the invention, X1 and X2 are O. In other embodiments, X1 is O and X2 is S. In other embodiments, X1 is S and X2 is O. In other embodiments, X1 and X2 are S.

[0188] In some embodiments of the first, second, or third aspects of the invention, Y is S.

[0189] In some embodiments of the first, second, or third aspect of the invention, Z is C=O, CH2, or CHMe. In some embodiments, Z is CH2 or CHMe. In some embodiments, Z is CH2.

[0190] In some embodiments of the first, second, or third aspects of the invention, each R is independently unsubstituted alkyl or halogen. In some embodiments, each R is independently Me or F.

[0191] In some embodiments of the first, second, or third aspects of the invention, n is 0 or 1. In some embodiments, n is 0.

[0192] In some embodiments of the first, second, or third aspects of the invention, m is 0.

[0193] In some embodiments of the first, second or third aspect of the invention, y=1.

[0194] In some embodiments of the second or third aspect of the invention, the compound is [Table 2] JPEG2025537537000453.jpg248170 JPEG2025537537000454.jpg249170 JPEG2025537537000455.jpg248170 Selected from JPEG2025537537000456.jpg115170.

[0195] In some embodiments of the second or third aspect of the invention, the compound is selected from Compound Nos. 33, 35, 37, 40, 54, 56, 57, 58, 69 (isomer 2), 74 (isomer 2), 4(2), 5(2), 6(2), 7(2), 23(2), 24(2), and 25(2).

[0196] In some embodiments of the second or third aspect of the invention, the compound is selected from compound numbers 2, 9, 25, 32 (isomer 2), 35, 37, 40, 54, 55 (isomer 2), 56, 64, 69 (isomer 1), 70 (isomer 2), 74 (isomer 2), 2(2), 4(2), 5(2), 6(2), 7(2), 16(2), 23(2), 24(2), and 25(2).

[0197] In some embodiments of the second or third aspect of the invention, the compound is selected from Compound Nos. 35, 37, 40, 54, 56, 74 (isomer 2), 4(2), 5(2), 6(2), 7(2), 23(2), 24(2), and 25(2).

[0198] In some embodiments of the second or third aspect of the invention, the compound is selected from Compound Nos. 56 and 23(2).

[0199] In some embodiments of the second or third aspect of the invention, the compound is selected from Compound Nos. 2, 25, 54, and 64.

[0200] In some embodiments of the second or third aspect of the invention, the compound is selected from Compound Nos. 2, 25, and 64.

[0201] In some embodiments of the second or third aspect of the invention, the compound is formulated as a pharmaceutical composition.

[0202] [Example]

[0203] Compound synthesis Reagents and solvents were used as received from commercial sources. Proton nuclear magnetic resonance (NMR) spectra were recorded on a 500 MHz or 400 MHz Bruker Avance spectrometer. Spectra are reported in terms of chemical shift (δ [ppm]), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet), coupling constant (J [Hz]), and integration. Chemical shifts are reported in ppm relative to dimethyl sulfoxide-d (δ 2.50) or chloroform-d (δ 7.26) as indicated in the NMR spectral data. Samples were prepared by dissolving dry sample (0.2–2 mg) in the appropriate deuterated solvent (0.7–1 mL).

[0204] LCMS measurements were collected using a Shimadzu Nexera X2 / MS-2020 or Advion Expression CMS coupled to a liquid chromatograph. Unless otherwise noted, all masses reported are the m / z of the protonated parent ion. Samples were dissolved in an appropriate solvent (e.g., DMSO, ACN, water) and injected directly onto the column using an automated sample handler.

[0205] Chemical names were generated using ChemDraw Professional v. 18.2.0.48 from PerkinElmer Informatics, Inc.

[0206] Abbreviations used in the examples below are listed below in alphabetical order: [Table 3] JPEG2025537537000458.jpg247170 JPEG2025537537000459.jpg141170

[0207] General Procedure The synthesis of the compounds can be outlined in the following general procedures set out below.

[0208] Example Method 1: Reduction of the Pyridine Ring [ka] Reaction Scheme 1: Reduction of the pyridine ring To a solution of substituted pyridine (1 equiv.) and PtO (0.1-0.4 equiv.), glacial acetic acid, MeOH, or DMF was added, and the resulting slurry was stirred under a hydrogen atmosphere (1-30 bar) at room temperature for 5-24 h. Solid particles were removed by filtration on a Celite® pad and washed with EtOH. The filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography and / or preparative HPLC.

[0209] Example Method 2: Stille Coupling [ka] Reaction Scheme 2: Stille Coupling The appropriate R2-X (1 equivalent), substituted trialkylstannane (1-2 equivalents), and palladium catalyst (0.05-0.2 equivalents) were purged with argon and dissolved in an appropriate solvent (DMF, toluene, or 1,4-dioxane). The reaction mixture was stirred at 90-120 °C for 5-24 hours. The solution was cooled to ambient temperature, filtered through a Celite® pad, and concentrated under reduced pressure. The crude product was purified by flash column chromatography and / or preparative HPLC.

[0210] Example Method 3: Piperidine-2,6-dione Ring Formation [ka] Reaction Scheme 3: Piperidine-2,6-dione ring formation The appropriate tert-butyl 5-amino-5-oxo-4-(1-oxoisoindolin-2-yl)pentanoate (1 equivalent) was dissolved in ACN and benzenesulfonic acid (1.5-2.5 equivalents) was added. The reaction mixture was stirred under microwave irradiation at 80-140 °C for 30-60 minutes. Volatiles were removed under reduced pressure, and the crude product was purified by flash column chromatography and / or preparative HPLC.

[0211] Example Method 4: Reaction of Methyl o-(haloalkyl)aryl Esters with Amines [ka] Reaction Scheme 4: Reaction of methyl o-(haloalkyl)aryl esters with amines The appropriate methyl o-(haloalkyl)aryl ester (1 equivalent) and amine hydrochloride (1-1.5 equivalents) were suspended in dry DMF or ACN. Base (2-5 equivalents) was added, and the reaction was stirred at 60-140 °C for 5-48 hours. Volatiles were removed in vacuo, water was added, and the solid was stirred for 1-6 hours. The product was filtered, washed with water and EtO, and dried in vacuo. If necessary, the product was purified by flash column chromatography and / or preparative HPLC.

[0212] Example Method 5: Suzuki Coupling [ka] Reaction Scheme 5: Suzuki reaction To a solution of the appropriate arylboronic acid pinacol ester (1-1.5 equiv.) in a dioxane-HO mixture was added a base (K2CO3 or K3PO4, 2-6 equiv.), an aryl bromide (1-1.5 equiv.), and a palladium catalyst (0.05-0.15 equiv.). The reaction mixture was heated at 70-110 °C for 8-48 h. Upon completion, the reaction mixture was diluted with water, extracted with AcOEt, and the organic fraction was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography and / or preparative HPLC.

[0213] Example Method 6: Benzylic Bromination [ka] Reaction Scheme 6: Benzylic Bromination To a solution of the aryl compound (1 equiv.) in an appropriate solvent, NBS (1-2 equiv.) and AIBN (0.05-0.2 equiv.) were added, and the reaction mixture was stirred at 70-100 °C for 8-48 h. After completion, the reaction mixture was cooled, diluted with water, and extracted with AcOEt. The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography.

[0214] Analytical LC, Method A: Column name: Kinetex XB-C18 (50 x 2.1 mm, 2.6 mm, 100 Å), operated at 40 °C and a flow rate of 0.5 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = 0.1% formic acid in acetonitrile. Gradient profile: initial composition 95% A and 5% B, followed by 5% A and 95% B in 4 min, followed by 5% A and 95% B in the next 1 min, followed by a return to 95% A and 5% B in the next 20 s, followed by a hold for 1 min 40 s.

[0215] Analytical LC, Method B: Column name: Arion HILIC Plus (50 x 3.0 mm, 2.2 mm), operated at 40 °C and a flow rate of 0.5 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = 0.1% formic acid in acetonitrile. Gradient profile: initial composition 5% A and 95% B, followed by 5% A and 95% B for 2 min, then 60% A and 40% B for the next 5.5 min, then hold this composition for the next 1.5 min, then 5% A and 95% B for the next 30 s, then 5% A and 95% B for the next 5.5 min.

[0216] Analytical LC, Method C: Column name: Shim-pack Scepter C18 (150 x 3.0 mm, 3.0 mm, 300 Å), operated at 40 °C and a flow rate of 0.5 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = 0.1% formic acid in acetonitrile. Gradient profile: initial composition 95% A and 5% B, followed by 5% A and 95% B in 15 min, then maintaining this composition for the next 3 min, followed by 95% A and 5% B in the next 1 min, followed by 95% A and 5% B in the next 6 min.

[0217] Unless otherwise indicated, any percentages given for solvents used in analytical liquid chromatography (LC) and HPLC procedures are by volume.

[0218] Example A1: Synthesis of 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 2(2)) [ka]

[0219] Step 1: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(pyridin-2-yl)benzoate was synthesized (18% yield) using methyl 2-methyl-4-(pyridin-2-yl)benzoate (20 mg, 0.088 mmol, 1 equiv.) as starting material, AIBN (0.1 equiv.) as initiator, and DMC as solvent.

[0220] Methyl 2-methyl-4-(pyridin-2-yl)benzoate was synthesized according to the procedure described in US Pat. No. 6,335,327. LCMS (ESI+) m / z 306.1, 308.1 [M+H] +

[0221] Step 2: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (82% yield) using methyl 2-(bromomethyl)-4-(pyridin-2-yl)benzoate (20 mg, 0.046 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.5 equiv.) as starting materials, NaOAc (4 equiv.) as base, and ACN as solvent. LCMS(ESI+)m / z 322.0[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.00(s,1H), 8.76~8.68(m,1H), 8.33(s,1H), 8.24(dd,J=8.0,1.5Hz,1H), 8.0 8(dd,J=8.0,1.1Hz,1H), 7.94(td,J=7.7,1.8Hz,1H), 7.83(d,J=7.9Hz,1H), 7.43(ddd,J=7.5,4.8,1.0H z,1H), 5.15(dd,J=13.3,5.1Hz,1H), 4.55(d,J=17.3Hz,1H), 4.43(d,J=17.3Hz,1H), 2.93(ddd,J=17.3 ,13.7,5.4Hz,1H), 2.61~2.56(m,1H), 2.42(td,J=13.2,4.5Hz,1H), 2.04(dtt,J=12.8,5.4,2.7Hz,1H).

[0222] Example A2: Synthesis of 3-(1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 2) [ka]

[0223] Step 1: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (hydrochloride salt) was synthesized (44% yield) using 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.1 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 328.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H), 9.47(s,1H), 9.31(d,J=10.9Hz,1H), 7.81(dd,J=9.2,6.8Hz,2H ), 7.75~7.66(m,1H), 5.13(dd,J=13.4,5.0Hz,1H), 4.49(dd,J=17.3,9.7Hz,1H), 4.35(dd,J=17.6,9.2 Hz,2H), 3.35(d,J=12.5Hz,1H), 3.12~2.99(m,1H), 2.92(ddd,J=18.2,13.7,5.3Hz,1H), 2.60(d,J=17 .7Hz,1H), 2.41(tt,J=13.2,6.9Hz,1H), 2.06~1.97(m,1H), 1.97~1.75(m,5H), 1.65(d,J=12.9Hz,1H).

[0224] Example A3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-2-yl)isoindoline-1,3-dione (Compound 1) [ka]

[0225] Step 1: A vial was charged with dimethyl 4-(pyridin-2-yl)phthalate (125.0 mg, 0.46 mmol, 1 equiv.), diphenylamine (311.9 mg, 1.84 mmol, 4 equiv.), and tris(pentafluorophenyl)borane (23.6 mg, 0.046 mmol, 0.1 equiv.). Dry toluene (5 mL) was added, followed by diphenylsilane (0.428 mL, 2.3 mmol, 5 equiv.), and the reaction mixture was refluxed for 18 h. Water (2 mL) and NaHCO3 (194 mg, 2.3 mmol, 5 equiv.) were added, followed by benzyl chloroformate (0.132 mL, 0.922 mmol, 2 equiv.), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was acidified by the addition of 10% citric acid and extracted with DCM. The organic fraction was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give dimethyl 4-(1-((benzyloxy)carbonyl)piperidin-2-yl)phthalate (71.0 mg, 37% yield).

[0226] Dimethyl 4-(pyridin-2-yl)phthalate was prepared as described in Barlow, HL et al., Org. Lett. 2017, 19, 6662. LCMS (ESI+) 412.1 m / z [M+H] +

[0227] Step 2: Dimethyl 4-(1-((benzyloxy)carbonyl)piperidin-2-yl)phthalate (55.0 mg, 0.134 mmol, 1 equiv) was dissolved in MeOH (5 mL) and 1 M LiOH (3 mL, 3 mmol, 22.4 equiv) was added. The reaction mixture was stirred at room temperature for 18 h, concentrated under reduced pressure, and acidified with 1 M HCl. The product was extracted with DCM, dried over Na2SO4, and concentrated under reduced pressure to give 4-(1-((benzyloxy)carbonyl)piperidin-2-yl)phthalic acid (51 mg, 100% yield), which was used directly in the next step. LCMS (ESI+) m / z 384.1 [M+H] +

[0228] Step 3: 4-(1-((benzyloxy)carbonyl)piperidin-2-yl)phthalic acid (72.0 mg, 0.188 mmol, 1 equiv.) was dissolved in acetic anhydride (1 mL, 10.6 equiv.) and the solution was refluxed for 1 h. Volatiles were removed under reduced pressure to give the crude product, benzyl 2-(1,3-dioxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (68 mg, 99% yield), which was used directly in the next step.

[0229] Step 4: Benzyl 2-(1,3-dioxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (34.0 mg, 0.093 mmol, 1 equiv), 3-aminopiperidine-2,6-dione hydrochloride (16.8 mg, 0.1 mmol, 1.1 equiv), and KOAc (28.3 mg, 0.29 mmol, 3.1 equiv) were dissolved in glacial acetic acid (0.57 mL), and the reaction mixture was stirred at 90° C. for 18 h. Volatiles were removed under reduced pressure, and the crude product was purified by preparative HPLC to give benzyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate (16.9 mg, 38% yield). LCMS(ESI+)m / z 476.0[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H), 7.91(d,J=7.9Hz,1H), 7.75~7.70(m,1H), 7.70~ 7.65(m,1H), 7.40~7.21(m,5H), 5.47(t,J=4.4Hz,1H), 5.22~5.05(m,3H), 4.06(d,J=1 2.8Hz,1H), 2.95~2.83(m,2H), 2.61~2.53(m,2H), 2.11~2.01(m,2H), 1.91(td,J=12.2 ,10.6,5.3Hz,1H), 1.60(d,J=11.6Hz,2H), 1.54~1.41(m,1H), 1.25(d,J=11.9Hz,1H).

[0230] Step 5: Benzyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-1-carboxylate (16.8 mg, 0.035 mmol, 1 equiv.) and palladium on activated carbon (5 mg, 10 wt%) were suspended in EtOH (2 mL) and argon was bubbled through for 15 min. Hydrogen was then bubbled through the reaction mixture at room temperature for 90 min until complete conversion was achieved. Solid particles were filtered off and volatiles were removed under reduced pressure. The crude product was purified by preparative HPLC to give 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-2-yl)isoindoline-1,3-dione (as the formate salt, 10.0 mg, 74% yield). LCMS(ESI+)m / z 342.0[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H), 8.20(s,1H), 7.92(s,1H), 7.87(d,J=1.0Hz,2H), 5.14 (dd,J=12.8,5.4Hz,1H), 3.83(dd,J=11.1,2.6Hz,1H), 3.11(d,J=11.7Hz,1H), 2.89(ddd,J=1 6.8,13.7,5.4Hz,1H), 2.71(td,J=11.8,2.8Hz,1H), 2.64~2.54(m,2H), 2.53(s,1H), 2.11~2 .00(m,1H), 1.86~1.73(m,2H), 1.61(d,J=10.4Hz,1H), 1.56~1.40(m,2H), 1.40~1.30(m,1H).

[0231] Example A4: Synthesis of 3-(1-oxo-5-((R)-piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (Compound 9) [ka]

[0232] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 5-(pyridin-2-yl)isobenzofuran-1(3H)-one was synthesized (84% yield) using 5-bromoisobenzofuran-1(3H)-one (5.0 g, 23.4 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.4 equiv.) as starting materials, Pd(PPh3)4 (0.1 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS (ESI+) m / z 212.1 [M+H] +

[0233] Step 2: To a solution of 5-(pyridin-2-yl)isobenzofuran-1(3H)-one (2.10 g, 9.94 mmol, 1 equiv.) in MeOH (5 mL) was added PtO (0.13 equiv.) and di-tert-butyl dicarbonate (4.33 g, 19.9 mmol, 2 equiv.). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. Upon completion, the reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (2.50 g, 79% yield) as an off-white solid. LCMS (ESI+) m / z 318.3 [M+H] +

[0234] Step 3: To a solution of tert-butyl 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (2.50 g, 7.88 mmol, 1 equiv.) in THF (10 mL) and water (40 mL) was added NaOH (788 mg, 19.7 mmol, 2.5 equiv.) at 0° C. and stirred at room temperature for 1.5 hours. After completion, the reaction mixture was acidified with 10% HCl to pH 5, and the product was extracted with AcOEt. The combined organic fractions were dried over NaSO and concentrated under reduced pressure to give 4-(1-(tert-butoxycarbonyl)piperidin-2-yl)-2-(hydroxymethyl)benzoic acid (2.10 g, 79% yield) as a white solid. LCMS (ESI+) m / z 336.2 [M+H] +

[0235] Step 4: To a solution of 4-(1-(tert-butoxycarbonyl)piperidin-2-yl)-2-(hydroxymethyl)benzoic acid (700 mg, 2.08 mmol, 1 equiv) in MeOH (8 mL) and AcOEt (8 mL) was added trimethylsilyldiazomethane (5.0 mL, 5 equiv) at −10° C. and stirred at that temperature for 30 min. After completion, the reaction was quenched with ice water, extracted with AcOEt, dried over NaSO, and concentrated under reduced pressure to give tert-butyl 2-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (610 mg, crude), which was carried on to the next step without further purification. LCMS (ESI+) m / z 350.6 [M+H] +

[0236] Step 5: To a solution of tert-butyl 2-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (600 mg, 1.71 mmol, 1 equiv.) in THF (15 mL), CBr4 (850 mg, 2.57 mmol, 1.5 equiv.) and PPh3 (810 mg, 3.07 mmol, 1.8 equiv.) were added at 0 °C and stirred at room temperature for 16 h. After completion of the reaction, the solid precipitate was filtered on a sintered funnel, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography to give tert-butyl 2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (500 mg, 71% yield after two steps) as a colorless liquid. LCMS (ESI+) m / z 312.3 [M-BOC+H] +

[0237] Step 6: The enantiomers of tert-butyl 2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate were separated by chiral HPLC (Chiralcel OJ-H, hexane / EtOH 85 / 15 + 0.1% iPrNH) to give tert-butyl (R)-2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate R t 5.05 minutes,

number

number

[0238] Step 7: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, tert-butyl (2R)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate was synthesized (62% yield) using tert-butyl (R)-2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (28.0 mg, 0.068 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.4 equiv.) as starting materials, DIPEA (5 equiv.) as base, and ACN as solvent. LCMS (ESI+) m / z 428.3 [M+H] +

[0239] Step 8: tert-Butyl (2R)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (18.0 mg, 0.042 mmol, 1 equiv.) was dissolved in TFA (5 mL), stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The product was purified by flash column chromatography to give 3-(1-oxo-5-((R)-piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (8.0 mg, 51% yield, formate salt). LCMS(ESI+)m / z 328.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H), 7.75(d,J=7.9Hz,1H), 7.67(s,1H), 7.57(dt,J=7.8,1. 9Hz,1H), 5.13(dd,J=13.3,5.1Hz,1H), 4.48(dd,J=17.3,7.3Hz,1H), 4.35(dd,J=17.3,7.6Hz, 1H), 4.00(d,J=9.4Hz,1H), 3.00~2.80(m,2H), 2.68~2.58(m,1H), 2.42(dd,J=13.1,4.5Hz,1H ), 2.03(dtd,J=12.7,5.4,2.4Hz,1H), 1.86(d,J=10.7Hz,2H), 1.71(s,1H), 1.63~1.48(m,3H).

[0240] Example A5: Synthesis of 3-(1-oxo-5-((S)-piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 10) [ka]

[0241] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, tert-butyl (2S)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate was synthesized (67% yield) using tert-butyl (S)-2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (29.0 mg, 0.07 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.26 equiv.) as starting materials, DIPEA (5 equiv.) as base, and ACN as solvent. LCMS (ESI+) m / z 428.2 [M+H] +

[0242] Step 2: tert-Butyl (2S)-2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (20.0 mg, 0.047 mmol, 1 equiv.) was dissolved in TFA (2 mL), stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The product was purified by flash column chromatography to give 3-(1-oxo-5-((S)-piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (12.0 mg, 69% yield, formate salt). LCMS(ESI+)m / z 328.1[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.00(s,1H), 7.77(d,J=7.8Hz,1H), 7.68(s,1H), 7.58(dt,J=7.9,2.0Hz,1H ), 5.14(dd,J=13.3,5.1Hz,1H), 4.48(dd,J=17.3,7.7Hz,1H), 4.35(dd,J=17.3,7.8Hz,1H), 4.07(d, J=10.4Hz,1H), 2.93(ddt,J=15.0,11.9,6.0Hz,3H), 2.63(ddd,J=17.3,4.4,2.2Hz,1H), 2.47~2.37( m,1H), 2.03(dtd,J=12.8,5.4,2.3Hz,1H), 1.87(t,J=5.1Hz,2H), 1.74(d,J=9.4Hz,1H), 1.60(s,3H).

[0243] Example A6: Synthesis of 3-(1-oxo-5-(pyrrolidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 6) [ka]

[0244] Step 1: To a solution of tert-butyl 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidine-1-carboxylate (130 mg, 0.43 mmol, 1 equiv.) in a mixture of THF, MeOH, and water (3 mL, 1:1:1), NaOH (69.0 mg, 1.71 mmol, 4 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in water (30 mL). The solution was washed with AcOEt and then acidified with 1 M HCl. The product was extracted with AcOEt, and the combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give 4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(hydroxymethyl)benzoic acid (90.0 mg, 65% yield) as a white solid.

[0245] tert-Butyl 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidine-1-carboxylate was prepared as described in Zuo, Z. et al., J. Am. Chem. Soc. 2014, 136, 5257. LCMS (ESI+) m / z 322.4 [M+H] +

[0246] Step 2: To a solution of 4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(hydroxymethyl)benzoic acid (250 mg, 0.78 mmol, 1 equiv.) in MeOH (3 mL) and AcOEt (3 mL) was added trimethylsilyldiazomethane (1.17 mL, 2.33 mmol, 3 equiv., 2 M EtO solution) dropwise at −10° C. The reaction mixture was then stirred at −10° C. for 2 h, quenched by the addition of water, and extracted with AcOEt. The combined organic layers were washed with water, brine, dried over NaSO, and concentrated under reduced pressure to give the crude product tert-butyl 2-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (250 mg, 95% yield), which was used in the next step without further purification.

[0247] Step 3: To a solution of tert-butyl 2-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (1.10 g, 3.284 mmol, 1 equiv.) in THF (20 mL) were added PPh (2.58 g, 9.851 mmol, 3 equiv.) and CBr (3.27 g, 9.851 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 1 h, quenched by the addition of water, and the product was extracted with AcOEt. The combined organic layers were washed with water, brine, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give tert-butyl 2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (310 mg, 23% yield). LCMS (ESI+) m / z 398.1 [M+H]+

[0248] Step 4: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, tert-butyl 2-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (50.0 mg, 0.126 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.2 equiv.) as starting materials, DIPEA (5 equiv.) as base, and ACN as solvent, tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-1-carboxylate was synthesized (62% yield) using this compound. LCMS(ESI+)m / z 413.8[M+H] + 1 H NMR(500MHz,DMSO-d6,353K)δ10.64(s,1H), 7.67(d,J=7.9Hz,1H), 7.40(s,1H), 7.33( d,J=7.5Hz,1H), 5.12~5.01(m,1H), 4.97~4.86(m,1H), 4.45(dd,J=16.8,6.8Hz,1H), 4. 36(dd,J=16.9,7.8Hz,1H), 3.64~3.52(m,2H), 2.95~2.81(m,1H), 2.72~2.61(m,1H), 2. 44~2.26(m,2H), 2.19~2.02(m,1H), 1.93~1.84(m,2H), 1.83~1.74(m,1H), 1.27(s,9H).

[0249] Step 5: To a solution of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-1-carboxylate (20.0 mg, 0.048 mmol, 1 equiv) in 1,4-dioxane (2 mL) and water (0.5 mL) was added concentrated HCl (0.5 mL). The resulting mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and purified by preparative HPLC to give 3-(1-oxo-5-(pyrrolidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (12.0 mg, 67% yield, formate salt). LCMS(ESI+)m / z 313.9[M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 7.68(d,J=7.8Hz,1H), 7.64(s,1H), 7.53(d,J=7.9Hz,1H), 5.11(dd,J=13 .4,5.1Hz,1H), 4.44(dd,J=17.3,3.2Hz,1H), 4.35~4.26(m,2H), 3.11(dt,J=10.1,6.8Hz,1H), 3.06~2.97(m,1H) , 2.92(ddd,J=17.4,13.7,5.4Hz,1H), 2.61(ddd,J=17.2,4.2,2.1Hz,1H), 2.40(qd,J=13.4,4.5Hz,1H), 2.24(dt d,J=12.3,7.7,4.8Hz,1H), 2.01(dtd,J=12.6,5.2,2.1Hz,1H), 1.94~1.77(m,2H), 1.61(dq,J=12.2,8.4Hz,1H).

[0250] Example A7: Synthesis of 3-(4-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 19) [ka]

[0251] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-bromo-4-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (13% yield) using methyl 4-bromo-2-(bromomethyl)-3-methylbenzoate (3.00 g, 9.3 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.1 equivalents) as starting materials, DIPEA (5 equivalents) as base, and DMF as solvent.

[0252] Methyl 4-bromo-2-(bromomethyl)-3-methylbenzoate was prepared as described in WO2018169777. LCMS (ESI+) m / z 337.1 [M+H] +

[0253] Step 2: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(4-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (96% yield) using 3-(5-bromo-4-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70.0 mg, 0.21 mmol, 1 equiv.) and 2-(trimethylstannyl)pyridine (1.5 equiv.) as starting materials, Pd(PPh3)4 (0.05 equiv.) as catalyst, and toluene as solvent. LCMS(ESI+)m / z 336.1[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.00(s,1H), 8.71(ddd,J=4.9,1.8,0.9Hz,1H), 7.93(td,J=7 .7,1.8Hz,1H), 7.65(d,J=7.8Hz,1H), 7.61~7.52(m,2H), 7.43(ddd,J=7.6,4.8,1.1Hz ,1H), 5.17(dd,J=13.3,5.1Hz,1H), 4.51(d,J=17.2Hz,1H), 4.34(d,J=17.2Hz,1H),3. 00~2.88(m,1H), 2.64~2.59(m,1H), 2.48~2.40(m,1H), 2.30(s,3H), 2.08~2.00(m,1H).

[0254] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(4-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (32% yield) using 3-(4-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (38.0 mg, 0.113 mmol, 1 equiv) as the starting material. LCMS(ESI+)m / z 342.1[M+H] + 1H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 7.69(d,J=8.0Hz,1H), 7.57(d,J=7.9Hz,1H), 5.12(dd,J=13.3,5.1Hz,1H), 4.42(d,J=17 .1Hz,1H), 4.25(d,J=17.1Hz,1H), 4.03(dd,J=11.2,2.5Hz,1H), 3.20~3.14(m,1H), 2.92(ddd,J=17.3,13.7,5.4Hz,1H), 2.83(t d,J=11.8,2.9Hz,1H), 2.61(ddd,J=17.3,4.4,2.3Hz,1H), 2.42(qd,J=13.3,4.5Hz,1H), 2.30(s,3H), 2.01(dtd,J=12.7,5.3,2 .3Hz,1H), 1.83(dt,J=10.0,3.2Hz,1H), 1.79~1.70(m,1H), 1.69~1.61(m,1H), 1.60~1.47(m,2H), 1.40(qd,J=12.5,3.7Hz,1H).

[0255] Example A8: Synthesis of 3-(6-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 20) [ka]

[0256] Step 1: 5-Bromo-6-methylisobenzofuran-1(3H)-one (1.00 g, 4.44 mmol, 1 equiv) was dissolved in EtOH (15 mL) and DCE (15 mL) at 0 °C. Thionyl chloride (1 mL, 1.9 equiv) was added and the reaction mixture was refluxed for 16 h. The volatiles were removed under reduced pressure, and the residue was neutralized using NaHCO. The product was extracted into AcOEt, and the organic layer was dried over NaSO and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 4-bromo-2-(chloromethyl)-5-methylbenzoate (800 mg, 61% yield).

[0257] 5-Bromo-6-methylisobenzofuran-1(3H)-one was prepared as described in WO202229138. 1 H NMR (400MHz, CDCl3) δ7.83(s,1H), 7.71(s,1H), 4.96(s,2H), 4.39(q,J=7.1Hz,2H), 2.43(s,3H), 1.41(t,J=7.1Hz,3H).

[0258] Step 2: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-bromo-6-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (59% yield) using ethyl 4-bromo-2-(chloromethyl)-5-methylbenzoate (800 mg, 2.77 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.4 equiv.) as starting materials, DIPEA (3 equiv.) as base, and ACN as solvent. LCMS (ESI+) m / z 335.3 [M+H] +

[0259] Step 3: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(6-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (91% yield) using 3-(5-bromo-6-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55.0 mg, 0.163 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.3 equiv.) as starting materials, Pd(PPh3)4 (0.08 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS (ESI+) m / z 336.0 [M+H] +

[0260] Step 4: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(6-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (69% yield) using 3-(6-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (45.0 mg, 0.134 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 342.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.99~10.94(m,1H), 7.75(s,1H), 7.52(s,1H), 5.09(ddd,J=13.3,5.1,3.3Hz,1H), 4.39(t, J=16.8Hz,1H), 4.26(dd,J=17.0,14.5Hz,1H), 3.90(dt,J=11.0,2.4Hz,1H), 3.15~3.11(m,2H), 2.90(ddd,J=17.3,13 .7,5.4Hz,1H), 2.81~2.74(m,1H), 2.60(ddd,J=17.3,4.5,2.4Hz,1H), 2.42(s,3H), 1.98(dtt,J=12.9,5.4,2.6Hz,1 H), 1.82(d,J=7.2Hz,1H), 1.77~1.70(m,1H), 1.63(d,J=9.1Hz,1H), 1.54~1.45(m,2H), 1.31(dd,J=11.4,5.4Hz,1H).

[0261] Example A9: Synthesis of 3-(7-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 21) [ka]

[0262] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-bromo-7-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (17% yield) using methyl 4-bromo-2-(bromomethyl)-6-methylbenzoate (1.70 g, 5.3 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.2 equivalents) as starting materials, DIPEA (4 equivalents) as base, and ACN as solvent.

[0263] Methyl 4-bromo-2-(bromomethyl)-6-methylbenzoate was prepared as described in Miles, DH et al., ACS Med. Chem. Lett., 2020, 11, 2244. LCMS (ESI+) m / z 337.1 [M+H] +

[0264] Step 2: Using the general procedure outlined in Reaction Scheme 2 above and Example Method 2, 3-(7-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (61% yield) using 3-(5-bromo-7-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (98.0 mg, 0.291 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.2 equiv.) as starting materials, Pd(PPh3)4 (0.05 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS (ESI+) m / z 336.0 [M+H] +

[0265] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(7-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (66% yield) using 3-(7-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (58.0 mg, 0.173 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 342.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.96(s,1H), 7.40(s,1H), 7.27(s,1H), 5.06(dd,J=13.3,5.2Hz,1H), 4.36(dd,J=17 .2,6.8Hz,1H), 4.23(dd,J=17.2,7.0Hz,1H), 3.72(dd,J=10.7,2.6Hz,1H), 3.11(dt,J=10.8,2.5Hz,1H), 2.9 0(ddd,J=17.3,13.7,5.4Hz,1H), 2.72(td,J=11.8,3.0Hz,1H), 2.63~2.55(m,4H), 2.45~2.31(m,1H), 1.98(d td,J=12.7,5.4,2.3Hz,1H), 1.85~1.78(m,1H), 1.78~1.71(m,1H), 1.61(t,J=6.4Hz,1H), 1.51~1.42(m,3H).

[0266] Example A10: Synthesis of 3-(3-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 24(2)) [ka]

[0267] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (80% yield) using methyl 4-bromo-2-(1-bromoethyl)benzoate (70 mg, 0.217 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.5 equiv.) as starting materials, NaOAc (4 equiv.) as base, and ACN as solvent.

[0268] Methyl 4-bromo-2-(1-bromoethyl)benzoate was prepared as described in WO202220342. LCMS (ESI+) m / z 337.2, 339.2 [M+H] +

[0269] Step 2: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(3-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (95% yield) using 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.5 equiv.) as starting materials, Pd(PPh3)4 (0.1 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS(ESI+)m / z 336.1[M+H] + 1H NMR(500MHz,DMSO-d6)δ10.96(d,J=16.6Hz,1H), 8.74(ddd,J=4.8,1.9,0.9Hz,1H), 8.37( dd,J=4.7,1.5Hz,1H), 8.25(ddd,J=7.9,4.2,1.5Hz,1H), 8.12(ddt,J=8.1,2.1,1.1Hz,1H) , 7.97(tt,J=7.8,1.5Hz,1H), 7.79(dd,J=8.0,6.8Hz,1H), 7.45(ddd,J=7.5,4.7,1.0Hz,1 H), 4.92~4.75(m,2H), 2.92~2.59(m,3H), 2.11~2.01(m,1H), 1.53(dd,J=11.7,6.7Hz,3H).

[0270] Example A11: Synthesis of 3-(3-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 25) [ka]

[0271] Step 1: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(3-methyl-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (20% yield) using 3-(3-methyl-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (47.0 mg, 1 equivalent) as the starting material. LCMS(ESI+)m / z 341.9[M+H] + 1H NMR(500MHz,DMSO-d6)δ10.92(s,1H), 7.64~7.58(m,2H), 7.50(ddd,J=13.5,7.8,1.3Hz,1H), 4.73(dd,J=12.8,5.3Hz,1H), 4.64(p,J=6.5Hz,1H), 3.73(dd,J=10.6,2.6Hz,1H), 3.10(d,J= 11.9Hz,1H), 2.87~2.77(m,1H), 2.74~2.64(m,1H), 2.62~2.56(m,1H), 1.98(ddt,J=10.4,5.3 ,2.7Hz,1H), 1.86~1.79(m,2H), 1.78~1.71(m,2H), 1.60(d,J=9.6Hz,1H), 1.51~1.35(m,6H).

[0272] Example A12: Synthesis of 3-(6-fluoro-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 23) [ka]

[0273] Step 1: Using the general procedure outlined in Reaction Scheme 2 above and Example Method 2, 3-(6-fluoro-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (91% yield) using 3-(5-bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (52.0 mg, 0.152 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.2 equiv.) as starting materials, Pd(PPh3)4 (0.057 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS (ESI+) m / z 340.0 [M+H] +

[0274] Step 2: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(6-fluoro-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (23% yield) using 3-(6-fluoro-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (45.0 mg, 0.133 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 346.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 7.81(d,J=5.9Hz,1H), 7.47(d,J=9.1Hz,1H), 5.11(ddd,J=13.3,5.1,2.5Hz, 1H), 4.43(dd,J=17.2,13.2Hz,1H), 4.30(dd,J=17.1,13.3Hz,1H), 3.98(d,J=10.8Hz,1H), 3.14~3.07(m,1H), 2.91 (ddd,J=17.3,13.7,5.4Hz,1H), 2.73(td,J=11.5,2.7Hz,1H), 2.65~2.56(m,1H), 2.45~2.32(m,1H), 2.00(dtt,J=1 2.9,5.3,2.4Hz,1H), 1.86~1.71(m,2H), 1.64~1.57(m,1H), 1.55~1.40(m,2H), 1.35(qdd,J=12.1,9.3,3.3Hz,1H).

[0275] Example A13: Synthesis of 3-(4-fluoro-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 22) [ka]

[0276] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(4-fluoro-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (91% yield) using 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, 0.35 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.2 equiv.) as starting materials, Pd(PPh3)4 (0.1 equiv.) as catalyst, and DMF as solvent. LCMS(ESI+)m / z 340.2[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.02(s,1H), 8.77(ddd,J=4.8,1.8,1.0Hz,1H), 8.08(dd,J=7.8,6.7Hz,1H), 7.9 7(td,J=7.7,1.8Hz,1H), 7.87(ddt,J=7.9,2.2,1.1Hz,1H), 7.71(d,J=7.8Hz,1H), 7.47(ddd,J=7.5,4.8, 1.1Hz,1H), 5.16(dd,J=13.3,5.1Hz,1H), 4.65(d,J=17.4Hz,1H), 4.49(d,J=17.4Hz,1H), 2.93(ddd,J=17 .3,13.6,5.4Hz,1H), 2.63~2.59(m,1H), 2.45(dd,J=13.4,4.4Hz,1H), 2.04(dtd,J=12.6,5.3,2.2Hz,1H).

[0277] Step 2: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(4-fluoro-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (9% yield) using 3-(4-fluoro-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (70.0 mg, 0.21 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 346.0[M+H] + 1H NMR(500MHz,DMSO-d6)δ10.99(s,1H), 7.73(dd,J=7.8,6.1Hz,1H), 7.56(d,J=7.8Hz,1H), 5.10(dd,J=13.3,5.1Hz,1H), 4.53( d,J=17.3Hz,1H), 4.37(d,J=17.3Hz,1H), 3.94(dd,J=11.0,2.5Hz,1H), 3.08(dt,J=11.5,2.6Hz,1H), 2.91(ddd,J=17.3,13.7 ,5.4Hz,1H), 2.68(td,J=11.8,2.7Hz,1H), 2.63~2.57(m,1H), 2.42(td,J=13.4,4.5Hz,1H), 2.00(dtd,J=12.8,5.4,2.4Hz,1H) ), 1.81(t,J=6.2Hz,1H), 1.77~1.70(m,1H), 1.62~1.54(m,1H), 1.46(dddt,J=19.3,16.0,7.5,3.6Hz,2H), 1.38~1.28(m,1H).

[0278] Example A14: Synthesis of 3-(7-fluoro-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 24) [ka]

[0279] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (58% yield) using methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (600 mg, 1.84 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.3 equiv.) as starting materials, DIPEA (3 equiv.) as base, and ACN as solvent. LCMS (ESI+) m / z 341.0 [M+H] +

[0280] Step 2: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(7-fluoro-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (67% yield) using 3-(5-bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.44 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.2 equiv.) as starting materials, Pd(PPh3)4 (0.05 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS (ESI+) m / z 340.0 [M+H] +

[0281] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(7-fluoro-1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (4.4% yield) using 3-(7-fluoro-1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (99.0 mg, 0.292 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 346.0[M+H] + 1H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 7.43(s,1H), 7.26(d,J=10.8Hz,1H), 5.06(dd,J=13.3,5.1Hz,1H), 4.44(dd, J=17.6,5.5Hz,1H), 4.31(dd,J=17.6,6.4Hz,1H), 3.69(dd,J=11.0,2.6Hz,1H), 3.10~3.04(m,1H), 2.90(ddd,J=17. 3,13.6,5.4Hz,1H), 2.70~2.64(m,1H), 2.59(ddd,J=17.4,4.5,2.2Hz,1H), 2.43~2.36(m,1H), 1.99(dtd,J=12.5,5 .4,2.2Hz,1H), 1.80(d,J=10.9Hz,1H), 1.78~1.71(m,1H), 1.61~1.54(m,1H), 1.51~1.38(m,2H), 1.38~1.26(m,1H).

[0282] Example A15: Synthesis of 3-(1-oxo-5-(6-oxopiperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 42) [ka]

[0283] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, methyl 4-(6-methoxypyridin-2-yl)-2-methylbenzoate was synthesized (82% yield) using methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.50 g, 5.43 mmol, 1 equivalent) and 2-bromo-6-methoxypyridine (1.2 equivalents) as starting materials, KCO (3 equivalents) as base, and Pd(PPh) (0.06 equivalents) as catalyst. LCMS (ESI+) m / z 257.7 [M+H] +

[0284] Step 2: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(6-methoxypyridin-2-yl)benzoate was synthesized (76% yield) using methyl 4-(6-methoxypyridin-2-yl)-2-methylbenzoate (1.00 g, 3.89 mmol, 1 equiv.) as starting material, AIBN (0.2 equiv.) as initiator, and DMC as solvent. LCMS (ESI+) m / z 336.0 [M+H] +

[0285] Step 3: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-(6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (62% yield) using methyl 2-(bromomethyl)-4-(6-methoxypyridin-2-yl)benzoate (200 mg, 0.59 mmol, 1 eq) and 3-aminopiperidine-2,6-dione hydrochloride (1.1 eq) as starting materials, TEA (3 eq) as base, and DMF as solvent. LCMS (ESI+) m / z 352.2 [M+H] +

[0286] Step 4: To a solution of 3-(5-(6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.57 mmol, 1 equiv) in DCE (10 mL) was added 1 M BBr (1.7 mL, 1.7 mmol, 3 equiv) dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. Additional BBr (0.57 mL, 0.57 mmol, 1 equiv) was added, and the reaction mixture was refluxed for 16 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to give 3-(5-(6-hydroxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35.0 mg, 18% yield). LCMS (ESI+) m / z 338.2 [M+H] +

[0287] Step 5: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(1-oxo-5-(6-oxopiperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (37% yield) using 3-(5-(6-hydroxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.44 mmol, 1 equiv) as the starting material. LCMS(ESI+)m / z 342.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H), 7.85(d,J=2.0Hz,1H), 7.71(d,J=7.9Hz,1H), 7.52(s,1H), 7.43 (d,J=7.9Hz,1H), 5.11(dd,J=13.3,5.1Hz,1H), 4.65(d,J=7.3Hz,1H), 4.45(dd,J=17.4,4.7Hz,1H),4. 32(dd,J=17.4,5.6Hz,1H), 2.91(ddd,J=17.3,13.6,5.4Hz,1H), 2.65~2.55(m,1H), 2.40(qd,J=13.3, 4.4Hz,1H), 2.29~2.20(m,2H), 2.11~1.94(m,2H), 1.67(p,J=6.6Hz,2H), 1.60(dt,J=13.4,6.8Hz,1H).

[0288] Example A16: Synthesis of 3-(1-oxo-5-(quinolin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 5(2)) [ka]

[0289] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, methyl 2-methyl-4-(quinolin-2-yl)benzoate was synthesized (72% yield) using methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.00 g, 3.62 mmol, 1 equivalent) and 2-bromoquinoline (1.2 equivalents) as starting materials, KCO (3 equivalents) as base, and Pd(PPh) (0.05 equivalents) as catalyst. LCMS (ESI+) m / z 278.8 [M+H] +

[0290] Step 2: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(quinolin-2-yl)benzoate was synthesized (62% yield) using methyl 2-methyl-4-(quinolin-2-yl)benzoate (100 mg, 0.36 mmol, 1 equiv.) as starting material, AIBN (0.2 equiv.) as initiator, and DMC as solvent. LCMS (ESI+) m / z 355.8 [M+H] +

[0291] Step 3: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(1-oxo-5-(quinolin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (24% yield) using methyl 2-(bromomethyl)-4-(quinolin-2-yl)benzoate (1.00 g, 2.8 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.1 equivalents) as starting materials, TEA (3 equivalents) as base, and DMF as solvent. LCMS(ESI+)m / z 372.3[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H), 8.53(d,J=9.2Hz,2H), 8.45(d,J=8.1Hz,1H), 8.26(d,J=8.7Hz ,1H), 8.12(d,J=8.5Hz,1H), 8.04(d,J=8.1Hz,1H), 7.90(d,J=8.0Hz,1H), 7.82(t,J=7.7Hz,1H), 7.6 4(t,J=7.5Hz,1H), 5.17(dd,J=13.3,5.1Hz,1H), 4.60(d,J=17.3Hz,1H), 4.47(d,J=17.3Hz,1H), 2.9 4(ddd,J=17.9,13.4,5.4Hz,1H), 2.66~2.58(m,1H), 2.44(dd,J=14.0,9.6Hz,1H), 2.10~2.01(m,1H).

[0292] Example A17: Synthesis of 3-(5-(isoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 6(2)) [ka]

[0293] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, methyl 4-(isoquinolin-3-yl)-2-methylbenzoate was synthesized (66% yield) using methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (600 mg, 2.17 mmol, 1 equiv.) and 3-bromoisoquinoline (1.2 equiv.) as starting materials, KCO (3 equiv.) as base, and Pd(PPh) (0.05 equiv.) as catalyst. LCMS (ESI+) m / z 278.0 [M+H] +

[0294] Step 2: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(isoquinolin-3-yl)benzoate was synthesized (68% yield) using methyl 4-(isoquinolin-3-yl)-2-methylbenzoate (400 mg, 1.44 mmol, 1 equiv.) as starting material, AIBN (0.2 equiv.) as initiator, and DMC as solvent. LCMS (ESI+) m / z 356.2 [M+H] +

[0295] Step 3: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-(isoquinolin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (44% yield) using methyl 2-(bromomethyl)-4-(isoquinolin-3-yl)benzoate (110 mg, 0.31 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.1 equivalents) as starting materials, TEA (3 equivalents) as base, and DMF as solvent. LCMS(ESI+)m / z 372.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H), 9.46(s,1H), 8.58(s,1H), 8.48(s,1H), 8.39(d,J= 7.9Hz,1H), 8.19(d,J=8.1Hz,1H), 8.07(d,J=8.3Hz,1H), 7.85(dd,J=17.3,8.2Hz,2H), 7. 72(t,J=7.5Hz,1H), 5.17(dd,J=13.2,5.3Hz,1H), 4.58(d,J=17.2Hz,1H), 4.45(d,J=17. 2Hz,1H), 2.92(d,J=11.1Hz,1H), 2.62(d,J=18.1Hz,1H), 2.45~2.32(m,1H), 2.05(s,1H).

[0296] Example A18: Synthesis of 3-(1-oxo-5-(tetrahydro-2H-pyran-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 54) [ka]

[0297] Step 1: A vial was charged with 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (240 mg, 0.743 mmol, 1 equiv.), 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (187 mg, 0.891 mmol, 1.2 equiv.), PdCl(PPh) (104 mg, 0.149 mmol, 0.2 equiv.), KOAc (146 mg, 1.48 mmol, 2 equiv.), 1,4-dioxane (4.2 mL), and water (0.16 mL). The reaction mixture was stirred at 100° C. for 6 hours. The mixture was diluted with ACN / AcOEt and filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was triturated in ACN / AcOEt to give 3-(5-(3,4-dihydro-2H-pyran-6-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (240 mg, 99% yield), which was used directly in the next step. LCMS (ESI+) m / z 327.2 [M+H] +

[0298] Step 2: 3-(5-(3,4-Dihydro-2H-pyran-6-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (132 mg, 0.30 mmol, 1 equiv.) was dissolved in degassed 1-butanol (10 mL) and ACN (1 mL). Platinum on carbon (15 mg, 10 wt.%) was added, and the reaction mixture was stirred under a hydrogen balloon (1 bar) for 48 h. The solid was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-(1-oxo-5-(tetrahydro-2H-pyran-2-yl)isoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 30% yield). LCMS: (ESI+) m / z 329.0 [M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.97(s,1H), 7.67(d,J=7.8Hz,1H), 7.58~7.55(m,1H), 7.46(dt,J=8.1,1.4Hz,1H), 5.10(dd,J=13.3,5 .1Hz,1H), 4.48~4.41(m,2H), 4.31(d,J=17.2Hz,1H), 4.05(ddt,J=11.4,3.7,1.8Hz,1H), 3.56(ddd,J=11.3,9.1,6.3Hz,1H), 2.9 1(ddd,J=17.3,13.7,5.4Hz,1H), 2.60(ddd,J=17.1,4.5,2.2Hz,1H), 2.44~2.37(m,1H), 2.00(dtd,J=12.6,5.3,2.2Hz,1H), 1.8 5(dddd,J=13.0,8.8,6.9,3.8Hz,2H), 1.66(ddtt,J=17.4,13.8,7.1,3.7Hz,1H), 1.57(tq,J=6.0,3.6Hz,2H), 1.46~1.36(m,1H).

[0299] Example A19: Synthesis of 3-(1-oxo-5-(5-phenylpyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 4(2)) [ka]

[0300] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, methyl 2-methyl-4-(5-phenylpyridin-2-yl)benzoate was synthesized (67% yield) using methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500 mg, 1.8 mmol, 1 equiv.) and 2-bromo-5-phenylpyridine (1.2 equiv.) as starting materials, KCO (3 equiv.) as base, and Pd(PPh) (0.06 equiv.) as catalyst. LCMS (ESI+) m / z 304.2 [M+H] +

[0301] Step 2: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(5-phenylpyridin-2-yl)benzoate was synthesized (64% yield) using methyl 2-methyl-4-(5-phenylpyridin-2-yl)benzoate (370 mg, 1.22 mmol, 1 equiv.) as starting material, AIBN (0.2 equiv.) as initiator, and DMC as solvent. LCMS (ESI+) m / z 382.0 [M+H] +

[0302] Step 3: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(1-oxo-5-(5-phenylpyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (52% yield) using methyl 2-(bromomethyl)-4-(5-phenylpyridin-2-yl)benzoate (130 mg, 0.34 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.2 equivalents) as starting materials, TEA (3 equivalents) as base, and ACN as solvent. LCMS(ESI+)m / z 398.1[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H), 9.05(d,J=2.5Hz,1H), 8.40(s,1H), 8.31(d,J=8.1Hz,1 H), 8.25(dd,J=8.5,2.4Hz,1H), 8.18(d,J=8.4Hz,1H), 7.84(dd,J=10.9,7.9Hz,3H), 7.54(t,J =7.5Hz,2H), 7.46(t,J=7.4Hz,1H), 5.16(dd,J=13.3,5.0Hz,1H), 4.57(d,J=17.4Hz,1H), 4.44 (d,J=17.4Hz,1H), 3.01~2.86(m,1H), 2.62(d,J=18.1Hz,1H), 2.46~2.36(m,1H), 2.06(s,1H).

[0303] Example A20: Synthesis of 3-(1-oxo-5-(5-phenylpiperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 32) [ka]

[0304] Step 1: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(1-oxo-5-(5-phenylpyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.50 mmol, 1 equivalent) was used as the starting material to synthesize 3-(1-oxo-5-(5-phenylpiperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 15% yield). The product was isolated by preparative HPLC to give a mixture of two stereoisomers as formate salts (isomer 1: 20.0 mg, 10% yield and isomer 2: 10.0 mg, 5% yield).

[0305] Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Hydrosphere Actus Triart C18 (250 x 20 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 95% A and 5% B, followed by 90% A and 10% B in 3 min, then 65% A and 35% B in the next 22 min, then 5% A and 95% B in the next 23 min, then maintained at this composition for 25 min, followed by a return to the initial composition in 26 min and maintained there for 28 min.

[0306] Isomer 1: Analytical LC, Method A:R t =2.02 minutes. LCMS(ESI+)m / z 404.2[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H), 7.68(d,J=7.9Hz,1H), 7.65(s,1H), 7.57(dd,J=8.1,3.0Hz,1H), 7.51(d,J =7.6Hz,2H), 7.28(t,J=7.5Hz,2H), 7.16(t,J=7.3Hz,1H), 5.10(dd,J=13.3,5.1Hz,1H), 4.45(dd,J=17.2,3.2Hz ,1H), 4.31(dd,J=17.2,3.5Hz,1H), 3.94(dd,J=7.7,3.7Hz,1H), 3.18~3.10(m,1H), 3.07(dd,J=12.6,3.8Hz,1H) , 2.97~2.84(m,2H), 2.65~2.55(m,1H), 2.45~2.34(m,1H), 1.95(ddt,J=22.8,9.1,5.4Hz,2H), 1.87~1.64(m,3H).

[0307] Isomer 2: Analytical LC, Method A:R t =2.08 minutes. LCMS(ESI+)m / z 404.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H), 7.71~7.63(m,2H), 7.55(d,J=7.9Hz,1H), 7.31(td,J=8.2,6.0Hz,4H), 7.2 4~7.18(m,1H), 5.11(dd,J=13.3,5.1Hz,1H), 4.44(dd,J=17.2,4.8Hz,1H), 4.31(dd,J=17.2,5.1Hz,1H), 3.77(dd ,J=11.2,2.6Hz,1H), 3.18~3.11(m,1H), 2.91(ddd,J=17.9,13.5,5.4Hz,1H), 2.82~2.69(m,2H), 2.65~2.55(m,1 H), 2.45~2.34(m,1H), 2.04~1.93(m,1H), 1.90(td,J=6.3,3.0Hz,1H), 1.84~1.66(m,1H), 1.52(q,J=12.3Hz,1H).

[0308] Example A21: Synthesis of N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-3-yl)acetamide (Compound 7(2)) [ka]

[0309] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (460 mg, 2.51 mmol, 1.2 equiv.) and N-(6-bromopyridin-3-yl)acetamide (1 equiv.) as starting materials, KPO (3 equiv., 1 M aqueous solution) as base, and PdCl(dtbpf) (0.03 equiv.) as catalyst, tert-butyl 4-(5-(5-acetamidopyridin-2-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate was synthesized (46% yield) using tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (460 mg, 2.51 mmol, 1.2 equiv.) and N-(6-bromopyridin-3-yl)acetamide (1 equiv.).

[0310] tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate was prepared according to the procedure described in WO2021194914. LCMS (ESI+) m / z 453.0 [M+H] +

[0311] Step 2: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-3-yl)acetamide was synthesized (26% yield) using tert-butyl 4-(5-(5-acetamidopyridin-2-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (90.0 mg, 1 equivalent) as the starting material. LCMS(ESI+)m / z 379.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H), 10.32(s,1H), 8.83(d,J=2.4Hz,1H), 8.27(s,1H), 8. 21~8.15(m,2H), 8.04(d,J=8.7Hz,1H), 7.80(d,J=8.0Hz,1H), 5.14(dd,J=13.3,5.1Hz,1H), 4.53(d,J=17.3Hz,1H), 4.41(d,J=17.3Hz,1H), 2.93(ddd,J=17.2,13.6,5.4Hz,1H), 2.61( ddd,J=17.3,4.5,2.3Hz,1H), 2.41(td,J=13.2,4.5Hz,1H), 2.11(s,3H), 2.07~1.97(m,1H).

[0312] Example A22: Synthesis of N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-3-yl)acetamide (Compound 33) [ka]

[0313] Step 1: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-3-yl)acetamide (250 mg, 0.66 mmol, 1 equivalent) was used as the starting material to synthesize N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-3-yl)acetamide (50 mg, 20% yield). The product was isolated by preparative HPLC to give a mixture of two stereoisomers as the hydrochloride salt (isomer 1: 40.0 mg, 16% yield and isomer 2: 10.0 mg, 4% yield).

[0314] Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Luna Omega C18 (250 x 21.2 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 0.1% w / w aqueous HCl. Mobile phase B = acetonitrile. Gradient profile: initial composition 95% A and 5% B, followed by 95% A and 5% B for 3 min, then 80% A and 20% B for the next 22 min, followed by 5% A and 95% B for the next 23 min, then maintaining this composition for 25 min, followed by a return to the initial composition in 26 min and maintaining it for 30 min.

[0315] Isomer 1: Analytical LC, Method A:R t =1.53 minutes. LCMS(ESI+)m / z 385.2[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H), 8.75(d,J=6.6Hz,1H), 7.89(d,J=6.4Hz,1H), 7.86~7. 72(m,2H), 5.13(dd,J=13.3,5.0Hz,1H), 4.55~4.28(m,3H), 4.10(d,J=6.6Hz,1H), 3.35(d,J= 12.3Hz,2H), 2.93(ddd,J=18.1,13.5,5.3Hz,1H), 2.65~2.56(m,1H), 2.43(dd,J=14.9,4.0H z,1H), 2.20(d,J=13.4Hz,1H), 2.07~1.99(m,1H), 1.88(d,J=22.6Hz,5H), 1.28~0.99(m,1H).

[0316] Opposite sex body 2: Analysis using LC, Method B:R t =6.12 points. LCMS(ESI+) m / z 385.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H), 8.13(d,J=7.3Hz,1H), 7.80(dd,J=11.3,5.7Hz,2H ), 7.68(d,J=7.9Hz,1H), 5.13(dd,J=13.4,5.1Hz,1H), 4.57~4.29(m,3H), 4.11(s,1H), 3 .01~2.74(m,2H), 2.61(d,J=17.7Hz,1H), 2.42(dd,J=13.5,4.3Hz,1H), 1.99(td,J=25.4 ,21.7,13.2Hz,3H), 1.85(s,3H), 1.66(d,J=10.4Hz,2H), 1.16(dd,J=35.5,24.4Hz,1H).

[0317] Example A23: 3-(5-(5-ベンジルピペリジン-2-イル)-1-オキソイソイSynthesis of ンドリン-2-イル)ピペリジン-2,6-ジオン(Compound 35)

change

[0318] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (540 mg, 1.21 mmol, 1.2 equiv.) and 5-benzyl-2-bromopyridine (1 equiv.) as starting materials, KPO (5 equiv.) as base, and PdCl(dtbpf) (0.05 equiv.) as catalyst, tert-butyl 5-amino-4-(5-(5-benzylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (34% yield) using tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (540 mg, 1.21 mmol, 1.2 equiv.) and 5-benzyl-2-bromopyridine (1 equiv.) as starting materials, KPO (5 equiv.) as base, and PdCl(dtbpf) (0.05 equiv.) as catalyst. LCMS (ESI+) m / z 486.2 [M+H] +

[0319] Step 2: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(5-(5-benzylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (23% yield) using tert-butyl 5-amino-4-(5-(5-benzylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (100 mg, 1 equivalent) as the starting material. LCMS (ESI+) m / z 412.3 [M+H] +

[0320] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(5-(5-benzylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140 mg, 0.32 mmol, 1 equivalent) was used as the starting material to synthesize 3-(5-(5-benzylpiperidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (37 mg, 24% yield). The product was isolated by preparative HPLC to give a mixture of two stereoisomers as acetate salts (Isomer 1: 12.0 mg, 8% yield and Isomer 2: 25.0 mg, 16% yield).

[0321] Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Kinetex Evo C18 (250 × 21.2 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 10 mmol / L ammonium acetate in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 90% A and 10% B, followed by 80% A and 20% B in 5 min, then 50% A and 50% B in the next 30 min, then 5% A and 95% B in the next 31 min, then maintained at this composition for 34 min, followed by a return to the initial composition in 35 min and maintained there for 38 min.

[0322] Isomer 1: Analytical LC, Method A:R t =2.17 minutes. LCMS(ESI+)m / z 418.4[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H)、7.63(d,J=7.8Hz,1H)、7.57(s,1H)、7.47(d,J=7.8Hz,1H)、7.29( t,J=7.5Hz,2H), 7.19(d,J=7.1Hz,3H), 5.09(dd,J=13.3,5.0Hz,1H), 4.41(dd,J=17.3,4.9Hz,1H), 4.2 7(dd,J=17.3,5.5Hz,1H), 3.61(d,J=10.5Hz,1H), 2.97(dd,J=11.8,3.7Hz,1H), 2.94~2.83(m,1H), 2.6 4~2.55(m,1H), 2.45~2.29(m,2H), 1.98(dt,J=11.0,5.1Hz,1H), 1.82~1.63(m,4H), 1.38~1.11(m,3H).

[0323] Opposite sex body 2: Analysis using LC, Method A:R t =2.24 points. LCMS(ESI+)m / z 418.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H)、7.68(d,J=6.1Hz,2H)、7.57(d,J=7.9Hz,1H)、7.2 4(ddd,J=26.4,16.9,7.4Hz,5H), 5.11(dd,J=13.4,5.1Hz,1H), 4.45(dd,J=17.1,4.9Hz ,1H), 4.32(dd,J=17.2,4.9Hz,1H), 3.71(d,J=8.9Hz,1H), 2.92(dd,J=13.9,8.6Hz,3H) , 2.61(d,J=17.4Hz,1H), 2.40(dd,J=13.7,4.4Hz,1H), 2.01(s,1H), 1.81~1.46(m,7H).

[0324] Example A24: 3-(5-(5-ブチルピペリジン-2-イル)-1-オキソイソインSynthesis of ドリン-2-イル)ピペリジン-2,6-ジオン(Compound 37)

change

[0325] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.10 g, 2.54 mmol, 1.2 equiv.) and (E)-2-bromo-5-(but-1-en-1-yl)pyridine (450 mg, 2.12 mmol, 1.0 equiv.) as starting materials, KCO (2.5 equiv.) as base, and PdCl(dppf) (0.1 equiv.) as catalyst, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.10 g, 2.54 mmol, 1.2 equiv.) was prepared. (E)-5-amino-4-(5-(5-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (49% yield).

[0326] (E)-2-Bromo-5-(but-1-en-1-yl)pyridine was prepared as described in Huang, BB et al., Molecules 2020, 25, 3859. LCMS (ESI+) m / z 449.9 [M+H] +

[0327] Step 2: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, (E)-3-(5-(5-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (60% yield) using tert-butyl (E)-5-amino-4-(5-(5-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (70 mg, 1 equivalent) as the starting material. LCMS (ESI+) m / z 376.1 [M+H] +

[0328] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(5-(5-butylpiperidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (35% yield, mixture of stereoisomers, acetate salt) using (E)-3-(5-(5-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (160 mg, 1 equivalent) as the starting material. LCMS(ESI+)m / z 384.4[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H), 7.68~7.57(m,2H), 7.51(d,J=8.6Hz,1H), 5.10(dd,J=13.4,5.1Hz,1H), 4.42(dt ,J=17.4,4.5Hz,1H), 4.29(dd,J=17.2,5.6Hz,1H), 3.74~3.64(m,1H), 3.60(dd,J=11.1,2.4Hz,0.5H), 3.08(d,J=11.5 Hz,0.5H), 2.91(ddd,J=18.1,13.5,5.3Hz,1H), 2.81(d,J=3.5Hz,2H), 2.65~2.55(m,1H), 2.39(qd,J=13.9,5.1Hz,1H) , 2.05~1.95(m,1H), 1.71~1.48(m,3H), 1.44(dq,J=12.6,6.4Hz,1H), 1.29(qq,J=11.1,5.8Hz,5H), 0.95~0.81(m,4H). (mixture of stereoisomers)

[0329] Example A25: Synthesis of 3-(5-(6-butylpiperidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 40) [ka]

[0330] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (130 mg, 0.61 mmol, 1 equiv.) and (E)-2-bromo-6-(but-1-en-1-yl)pyridine (1.2 equiv.) as starting materials, KCO (2.5 equiv.) as base, and PdCl(dppf) (0.1 equiv.) as catalyst, tert-butyl (E)-5-amino-4-(5-(6-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (45% yield) using tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (130 mg, 0.61 mmol, 1 equiv.) and (E)-2-bromo-6-(but-1-en-1-yl)pyridine (1.2 equiv.) as starting materials, KCO (2.5 equiv.) as base, and PdCl(dppf) (0.1 equiv.) as catalyst.

[0331] (E)-2-Bromo-6-(but-1-en-1-yl)pyridine was prepared as described in WO2020252240. LCMS (ESI+) m / z 449.9 [M+H] +

[0332] Step 2: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, (E)-3-(5-(6-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (79% yield) using tert-butyl (E)-5-amino-4-(5-(6-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (120 mg, 1 equivalent) as the starting material. LCMS (ESI+) m / z 376.4 [M+H] +

[0333] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(5-(6-butylpiperidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (mixture of stereoisomers, formate salt) was synthesized (66% yield) using (E)-3-(5-(6-(but-1-en-1-yl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 1 equivalent) as the starting material. LCMS(ESI+)m / z 384.4[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.07~10.91(s,1H), 7.67(d,J=7.8Hz,1H), 7.63(s,1H), 7.52(d,J=7.9Hz,1H), 5.1 1(dd,J=13.4,5.0Hz,1H), 4.43(dd,J=17.2,2.9Hz,1H), 4.30(dd,J=17.3,3.5Hz,1H), 3.81(d,J=10.9Hz,1H) , 2.91(ddd,J=18.4,13.4,5.2Hz,1H), 2.73~2.56(m,2H), 2.39(qd,J=13.7,4.4Hz,1H), 2.05~1.93(m,1H), 1 .82(d,J=12.1Hz,1H), 1.71(t,J=14.6Hz,2H), 1.56~1.18(m,8H), 1.09(q,J=12.5Hz,1H), 0.94~0.77(m,3H).

[0334] Example A26: Synthesis of 3-(1-oxo-5-(5-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 16(2)) [ka]

[0335] Step 1: 3-(1-Oxo-5-(tributylstannyl)isoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 0.056 mmol, 1 equiv.), 2-bromo-5-(trifluoromethyl)pyridine (19.1 mmol, 0.084 mmol, 1.1 equiv.), and Pd(PPh3)4 (5.2 mg, 0.005 mmol, 0.08 equiv.) were dissolved in 1,4-dioxane (1.5 mL). The reaction mixture was stirred at 110 °C for 18 h. Additional 2-bromo-5-(trifluoromethyl)pyridine (19.1 mmol, 0.084 mmol, 1.1 equiv.) and Pd(PPh3)4 (5.2 mg, 0.005 mmol, 0.08 equiv.) were added, and the reaction was continued for an additional 18 h. The crude product was purified by preparative HPLC to give 3-(1-oxo-5-(5-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (7.5 mg, 34% yield).

[0336] 3-(1-oxo-5-(tributylstannyl)isoindolin-2-yl)piperidine-2,6-dione was prepared as described in WO2022029573. LCMS(ESI+)m / z 390.0[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H), 9.10(dd,J=2.1,1.1Hz,1H), 8.41(dd,J=1.6,0.8Hz,1H), 8. 38~8.34(m,1H), 8.32(q,J=1.3Hz,1H), 8.32~8.30(m,1H), 7.89(dd,J=8.0,0.7Hz,1H), 5.16(dd,J= 13.3,5.1Hz,1H), 4.58(d,J=17.4Hz,1H), 4.45(d,J=17.4Hz,1H), 2.93(ddd,J=17.2,13.6,5.4Hz, 1H), 2.60(dd,J=4.4,2.3Hz,1H), 2.43(td,J=13.2,4.6Hz,1H), 2.05(dtd,J=12.7,5.4,2.3Hz,1H).

[0337] Example A27: Synthesis of 3-(2-oxo-5-(pyridin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (compound 23(2)) [ka]

[0338] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 5-(pyridin-2-yl)benzo[cd]indol-2(1H)-one was synthesized (98% yield) using 5-bromobenzo[cd]indol-2(1H)-one (200 mg, 0.806 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.3 equiv.) as starting materials, Pd(PPh) (0.08 equiv.) as catalyst, and 1,4-dioxane as solvent.

[0339] 5-Bromobenzo[cd]indol-2(1H)-one was prepared as described in WO2022081927. LCMS (ESI+) m / z 247.1 [M+H] +

[0340] Step 2: 5-(Pyridin-2-yl)benzo[cd]indol-2(1H)-one (120 mg, 0.49 mmol, 1 equiv.) was dissolved in dry DMF (4 mL) and sodium bis(trimethylsilyl)amide (2.4 mL, 1 M THF solution, 2.4 mmol, 5 equiv.) was added in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then a solution of 3-bromopiperidine-2,6-dione (255 mg, 1.33 mmol, 2.5 equiv.) in DMF (2 mL) was added dropwise. The reaction mixture was stirred at 80° C. for 60 hours. The reaction mixture was cooled to −50° C., quenched with solid NH4Cl, the volatiles were removed under reduced pressure, and the crude product was purified by preparative HPLC to give 3-(2-oxo-5-(pyridin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (11.5 mg, 6.6% yield) as a yellow solid. LCMS(ESI+)m / z 358.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.14(s,1H), 8.84(dt,J=4.9,1.5Hz,1H), 8.20(d,J=7.3Hz,1H), 8. 09~8.00(m,2H), 7.96(d,J=8.7Hz,1H), 7.89(dt,J=7.9,1.1Hz,1H), 7.61~7.50(m,2H), 7.21( d,J=7.2Hz,1H), 5.49(dd,J=13.0,5.4Hz,1H), 2.97(ddd,J=16.8,13.5,5.3Hz,1H), 2.80(qd ,J=13.0,4.4Hz,1H), 2.67(ddd,J=16.9,4.3,2.3Hz,1H), 2.14(dtd,J=12.8,5.3,2.2Hz,1H).

[0341] Example A28: Synthesis of 3-(4-oxo-1-(pyridin-2-yl)-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione (compound 31(2)) [ka]

[0342] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(4-oxo-1-(pyridin-2-yl)-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione was synthesized (15% yield) using 3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione (20 mg, 0.06 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.5 equiv.) as starting materials, Pd(PPh)Cl (0.1 equiv.) as catalyst, and 1,4-dioxane as solvent.

[0343] 3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione was prepared as described in US Patent Application Publication No. 2018170948. LCMS(ESI+)m / z 328.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H), 8.59(d,J=4.4Hz,1H), 8.14(s,1H), 7.93~7.84(m,1H), 7.56(d,J=8.0Hz,1H), 7.34(t,J=5.2,7.1Hz,1H), 5.09 (dd,J=5.1,13.2Hz,1H), 4.69(d,J=16.5Hz,1H), 4.50(d,J=16.5Hz,1H), 3 .00~2.86(m,1H), 2.66~2.56(m,1H), 2.46~2.34(m,1H), 2.07~1.99(m,1H).

[0344] Example A29: Synthesis of 3-(6-oxo-2-(pyridin-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (compound 30(2)) [ka]

[0345] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(6-oxo-2-(pyridin-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione was synthesized (28% yield) using 3-(2-bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (54 mg, 0.164 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.5 equiv.) as starting materials, Pd(PPh)Cl (0.12 equiv.) as catalyst, and 1,4-dioxane as solvent.

[0346] 3-(2-Bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione was prepared as described in US Patent Application Publication No. 2018170948. LCMS(ESI+)m / z 328.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H), 8.59(d,J=4.2Hz,1H), 8.05(d,J=7.9Hz,1H), 7.98~7.89(m,2H), 7.39(t,J=5.2,6.6Hz,1H) ), 5.04(dd,J=4.9,13.2Hz,1H), 4.64~4.14(m,2H), 2.98~2.84(m,1H), 2.73~2.55(m,1H), 2.47~2.34(m,1H), 2.06~1.98(m,1H).

[0347] Example A30: Synthesis of 3-(6-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (Compound 73) [ka]

[0348] Step 1: Using the general procedure set forth in Reaction Scheme 5 above and Example Method 5, 3-(2-bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (100 mg, 0.304 mmol, 1 equiv.) and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dione were prepared. Starting from oxaborolane (1.5 equiv.), 3-(2-(3,4-dihydro-2H-pyran-6-yl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione was synthesized in 79% yield using PdCl(dtbpf) (0.1 equiv.) as catalyst and KPO (2.5 equiv.) as base. LCMS (ESI+) m / z 333.2 [M+H] +

[0349] Step 2: 3-(2-(3,4-Dihydro-2H-pyran-6-yl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (70 mg, 0.21 mmol, 1 equiv.) was dissolved in a mixture of THF / AcOEt / DMF (7 mL, 3 / 3 / 1 v / v / v), and 50% Pd / C-Pd(OH) (140 mg, 1 / 1) was added. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 24 h. After completion, the solids were filtered off, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give 3-(6-oxo-2-(tetrahydro-2H-pyran-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (30 mg, 42% yield). LCMS(ESI+)m / z 335.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H), 7.11(s,1H), 4.99(dd,J=5.1,13.4Hz, 1H), 4.68(d,J=10.5Hz,1H), 4.34(d,J=17.9Hz,1H), 4.26~4.16(m,1H), 4.01 (d,J=11.6Hz,1H), 3.63~3.55(m,1H), 2.95~2.81(m,1H), 2.62~2.53(m,1H), 2.42~2.26(m,1H), 2.09~1.91(m,2H), 1.91~1.79(m,1H), 1.75~1.44(m,4H).

[0350] Example A31: Synthesis of 3-(6-oxo-2-(piperidin-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (Compound 72) [ka]

[0351] Step 1: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(6-oxo-2-(piperidin-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (formate) was synthesized (11% yield) using 3-(6-oxo-2-(pyridin-2-yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (70 mg, 1 equivalent) as the starting material. LCMS(ESI+)m / z 334.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H), 8.24(s,1H), 7.09(s,1H), 4.98(dd,J=13.3,5.0Hz,1H ), 4.32(dd,J=17.8,2.6Hz,1H), 4.18(d,J=17.8Hz,1H), 3.94~3.85(m,1H), 2.99(d,J=12.4Hz) , 1H), 2.89 (ddd, J = 18.0, 13.7, 5.7 Hz, 1H), 2.62 (d, J = 14.3 Hz, 1H), 2.42-2.33 (m, 1H), 1.99 (s, 1H), 1.92-1.84 (m, 1H), 1.77 (s, 1H), 1.54 (d, J = 11.6 Hz, 1H), 1.41 (dt, J = 21.8, 12.1 Hz, 2H). (2H overlaps with water signal.)

[0352] Example A32: Synthesis of 3-(4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione (Compound 71) [ka]

[0353] Step 1: Using the general procedure outlined in Reaction Scheme 5 above and Example Method 5, 3-(1-(3,4-dihydro-2H-pyran-6-yl)-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione was synthesized (24% yield) using 3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione (200 mg, 0.61 mmol, 1 equiv.) and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 equiv.) as starting materials, PdCl(dtbpf) (0.1 equiv.) as catalyst, and KPO (2.5 equiv.) as base. LCMS (ESI+) m / z 333.2 [M+H] +

[0354] Step 2: 3-(1-(3,4-Dihydro-2H-pyran-6-yl)-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione (50 mg, 0.15 mmol, 1 equiv.) was dissolved in a mixture of THF / AcOEt / DMF (7 mL, 3 / 3 / 1 v / v / v), and 50% Pd / C-Pd(OH) (100 mg, 1 / 1) was added. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 24 h. After completion, the solids were filtered off, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give 3-(4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione (7.5 mg, 15% yield). LCMS(ESI+)m / z 335.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H), 7.91(s,1H), 5.07~4.97(m,1H), 4.68 ~4.57(m,1H), 4.34(dd,J=4.7,15.6Hz,1H), 4.17(dd,J=4.1,15.6Hz,1H), 4 .01~3.93(m,1H), 3.60~3.49(m,1H), 2.96~2.81(m,1H), 2.60~2.54(m,1H), 2.42~2.33(m,1H), 2.04~1.89(m,2H), 1.90~1.79(m,1H), 1.69~1.46(m,4H).

[0355] Example A33: Synthesis of (2,6-dioxo-3-(1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidin-1-yl)methyl pivalate (Compound 63) [ka]

[0356] Step 1: To a solution of 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.24 mmol, 1 equiv.), CsCO (1.1 equiv.), and TBAI (1 equiv.) in DMF (10 mL) was added chloromethyl pivalate (1.1 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was precipitated from cold water, washed with pentane, and the crude product (2,6-dioxo-3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidin-1-yl)methyl pivalate (510 mg, 94% yield) was used directly in the next step. LCMS (ESI+) m / z 436.4 [M+H] +

[0357] Step 2: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, (2,6-dioxo-3-(1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)piperidin-1-yl)methyl pivalate (formate salt) was synthesized (12% yield) using (2,6-dioxo-3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidin-1-yl)methyl pivalate (200 mg, 1 equivalent) as the starting material. LCMS(ESI+)m / z 442.4[M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H), 7.70(d,J=7.8Hz,1H), 7.65(s,1H), 7.53(d,J=6.6Hz, 1H), 5.62(q,J=9.6Hz,2H), 5.30(dd,J=5.0,13.4Hz,1H), 4.47(dd,J=6.2,17.2Hz,1H), 4.2 6(dd,J=7.2,17.2Hz,1H), 3.84(d,J=9.6Hz,1H), 3.19~3.04(m,2H), 2.88~2.71(m,2H), 2.4 9~2.34(m,1H), 2.11~2.02(m,1H), 1.84~1.74(m,2H), 1.70~1.35(m,4H), 1.28~0.95(m,9H).

[0358] Example A34: Synthesis of 3-(1-oxo-5-(4-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 26(2)) [ka]

[0359] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(1-oxo-5-(4-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (26% yield) was synthesized using 3-(1-oxo-5-(tributylstannyl)isoindolin-2-yl)piperidine-2,6-dione (30 mg, 0.056 mmol, 1 equiv.) and 2-bromo-4-(trifluoromethyl)pyridine hydrochloride (1.5 equiv.) as starting materials, Pd(PPh3)4 (0.08 equiv.) as catalyst, TEA (2 equiv.) as base, and DMF as solvent. LCMS(ESI+)m / z 390.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H), 9.00(dt,J=5.0,0.8Hz,1H), 8.44(ddd,J=13.5,1.7,0.8Hz, 2H), 8.36(dd,J=8.0,1.7Hz,1H), 7.87(dd,J=8.0,0.7Hz,1H), 7.81(ddd,J=5.0,1.7,0.8Hz,1H), 5 .16(dd,J=13.3,5.1Hz,1H), 4.56(d,J=17.3Hz,1H), 4.45(d,J=17.3Hz,1H), 2.93(ddd,J=17.2,13 .6,5.4Hz,1H), 2.60(dd,J=4.4,2.3Hz,1H), 2.47~2.41(m,1H), 2.05(ddt,J=13.2,5.8,3.0Hz,1H).

[0360] Example A35: Synthesis of 3-(2-oxo-6-(pyridin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (compound 28(2)) [ka]

[0361] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 6-(pyridin-2-yl)benzo[cd]indol-2(1H)-one was synthesized (41% yield) using 6-bromobenzo[cd]indol-2(1H)-one (100 mg, 0.4 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.3 equiv.) as starting materials, Pd(PPh) (0.1 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS (ESI+) m / z 247.2 [M+H] +

[0362] Step 2: In a Schlenk flask, 6-(pyridin-2-yl)benzo[cd]indol-2(1H)-one (58 mg, 0.236 mmol, 1 equiv.) was dissolved in dry DMF (3 mL) under an argon atmosphere, and 1 M NaHMDS THF solution (1.2 mL, 1.2 mmol, 5 equiv.) was added. The reaction mixture was stirred at room temperature for 2 hours, and a solution of 3-bromopiperidine-2,6-dione (113.1 mg, 0.59 mmol, 2.5 equiv.) in dry DMF (2 mL) was added dropwise. The reaction mixture was stirred at 80 °C for 48 hours, then cooled to -50 °C and quenched with solid NH4Cl. The crude product was purified by preparative HPLC to give 3-(2-oxo-6-(pyridin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (7 mg, 8% yield) as a yellow solid. LCMS(ESI+)m / z 358.1[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.15(s,1H), 8.78(ddd,J=4.8,1.9,0.9Hz,1H), 8.74(dd,J=8.4,0.6Hz,1H), 8.16( d,J=6.8Hz,1H), 7.98(td,J=7.7,1.9Hz,1H), 7.89(dd,J=8.4,7.0Hz,1H), 7.87~7.81(m,2H), 7.45(ddd,J=7 .5,4.8,1.1Hz,1H), 7.29(d,J=7.5Hz,1H), 5.51(dd,J=13.0,5.4Hz,1H), 2.97(ddd,J=16.8,13.5,5.3Hz,1H ), 2.81(qd,J=13.0,4.3Hz,1H), 2.68(ddd,J=16.9,4.2,2.2Hz,1H), 2.15(ddq,J=10.6,5.6,3.3,2.7Hz,1H).

[0363] Example A36: Synthesis of 3-(2-oxo-6-(piperidin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (compound 59) [ka]

[0364] Step 1: To a solution of tert-butyl piperidine-1-carboxylate (374 mg, 2.02 mmol, 4.4 equiv) in dry THF (5 mL) cooled to −78° C., TMEDA (0.36 mL, 2.42 mmol, 5.26 equiv) was added, followed by 0.9 M sec-BuLi in hexanes (2.7 mL, 2.43 mmol, 5.29 equiv). The reaction mixture was stirred at −78° C. for 1 h, and 1.9 M ZnCl2 in 2-methyltetrahydrofuran (1.4 mL, 2.66 mmol, 5.79 equiv) was added. The mixture was stirred at room temperature for 2 h, and the volatiles were removed under reduced pressure. The residue was dissolved in toluene (5 mL), followed by the addition of 6-bromobenzo[cd]indol-2(1H)-one (114 mg, 0.46 mmol, 1 equiv.), Pd(dba) (0.11 equiv.), and SPhos (0.24 equiv.). The reaction mixture was stirred at 60 °C for 18 h, and the volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography to give tert-butyl 2-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidine-1-carboxylate (29 mg, 18% yield). LCMS (ESI+) m / z 353.1 [M+H] +

[0365] Step 2: tert-Butyl 2-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidine-1-carboxylate (28 mg, 0.079 mmol, 1 equiv.) was dissolved in dry DMF (2 mL) and 1 M NaHMDS in THF (0.397 mL, 0.397 mmol, 5 equiv.) was added. The reaction mixture was stirred at room temperature for 2 hours, and a solution of 3-bromopiperidine-2,6-dione (38.1 mg, 0.199 mmol, 2.5 equiv.) in dry DMF (2 mL) was added dropwise. The reaction mixture was stirred at 80°C for 48 hours, then cooled to -50°C and quenched with solid NH4Cl. The crude product was purified by flash column chromatography to give tert-butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidine-1-carboxylate as a yellow solid.

[0366] Step 3: tert-Butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidine-1-carboxylate was dissolved in TFA (2 mL) and stirred at room temperature for 1 h. Volatiles were removed under reduced pressure to give 3-(2-oxo-6-(piperidin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (trifluoroacetate) (6.7 mg, 17% yield over two steps). LCMS(ESI+)m / z 364.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ11.14(d,J=3.2Hz,1H), 9.00(d,J=11.0Hz,1H), 8.72(d,J=11.4Hz,1H), 8.58(dd ,J=8.4,1.6Hz,1H), 8.19(dd,J=7.0,1.2Hz,1H), 7.96(dd,J=8.4,7.0Hz,1H), 7.72(dd,J=7.6,5.2Hz,1H ), 7.29 (dd, J = 7.6, 5.2 Hz, 1H), 5.49 (dt, J = 12.3, 5.8 Hz, 1H), 5.07 (t, J = 11.2 Hz, 1H), 3.04-2.90 (m, 1H), 2.79 (qd, J = 13.1, 4.3 Hz, 1H), 2.73-2.64 (m, 1H), 2.11 (dtd, J = 12.4, 5.3, 2.0 Hz, 1H), 2.07-1.71 (m, 6H). (2H overlaps with water signal.)

[0367] Example A37: Synthesis of 3-(2-oxo-5-(piperidin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione trifluoroacetate (Compound 66) [ka]

[0368] Step 1: To a solution of tert-butyl piperidine-1-carboxylate (65 mg, 0.351 mmol, 5 equiv.) in dry THF (1.4 mL) cooled to −78° C., TMEDA (0.052 mL, 0.351 mmol, 5 equiv.) was added, followed by 1.4 M sec-BuLi in hexanes (0.3 mL, 0.42 mmol, 6 equiv.). The reaction mixture was stirred at −78° C. for 1 h, and then 1.9 M ZnCl2 in 2-methyltetrahydrofuran (0.222 mL, 0.421 mmol, 6 equiv.) was added. The mixture was further stirred at room temperature for 2 h, and the volatiles were removed under reduced pressure. The residue was purged with argon, dissolved in dry toluene (1.4 mL), and 3-(5-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (36 mg, 0.07 mmol, 1 equiv.), Pd(dba) (0.1 equiv.), and SPhos (0.2 equiv.) were added. The reaction mixture was stirred at 70 °C for 18 h. tert-Butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidine-1-carboxylate was purified by preparative HPLC to give tert-butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidine-1-carboxylate as a yellow solid.

[0369] Step 2: tert-Butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidine-1-carboxylate was dissolved in TFA (1 mL) and stirred at room temperature for 1 h. Volatiles were removed under reduced pressure to give 3-(2-oxo-5-(piperidin-2-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (trifluoroacetate) (4.5 mg, 13% yield over two steps). LCMS(ESI+)m / z 364.2[M+H] + 1H NMR(500MHz,DMSO-d6)δ11.13(d,J=2.0Hz,1H), 9.21(d,J=10.7Hz,1H), 8.97(d,J=11.1Hz,1H), 8.26 (dd,J=7.3,1.5Hz,1H), 8.01(d,J=7.4Hz,1H), 7.96(d,J=8.8Hz,1H), 7.65(ddd,J=8.6,7.2,2.5Hz,1H ), 7.24(t,J=6.9Hz,1H), 5.47(dt,J=12.5,6.1Hz,1H), 5.18(t,J=10.2Hz,1H), 3.52~3.47(m,2H), 3. 01~2.89(m,1H), 2.84~2.71(m,1H), 2.15~2.02(m,2H), 1.92(d,J=13.4Hz,4H), 1.25(d,J=3.4Hz,2H).

[0370] Example A38: Synthesis of 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)azepane-2,7-dione (compound 29(2)) [ka]

[0371] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 5-bromo-2-(2-oxoazepan-3-yl)isoindolin-1-one was synthesized (72% yield) using methyl 4-bromo-2-(bromomethyl)benzoate (1.00 g, 3.25 mmol, 1 equiv.) and 3-aminoazepan-2-one hydrochloride (1.5 equiv.) as starting materials, NaOAc (4 equiv.) as base, and ACN as solvent. LCMS (ESI+) m / z 322.9 [M+H] +

[0372] Step 2: A solution of 5-bromo-2-(2-oxoazepan-3-yl)isoindolin-1-one (410 mg, 1.269 mmol, 1 equiv) and Dess-Martin periodinane (2 equiv) in a mixture of ACN (25 mL), DMSO (1.2 mL), and water (0.2 mL) was stirred at 80° C. for 18 h. Volatiles were removed under reduced pressure, and the crude product was purified by flash column chromatography to give 3-(5-bromo-1-oxoisoindolin-2-yl)azepane-2,7-dione (48 mg, 11% yield). LCMS (ESI+) m / z 336.9 [M+H] +

[0373] Step 3: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)azepane-2,7-dione was synthesized (30% yield) using 3-(5-bromo-1-oxoisoindolin-2-yl)azepane-2,7-dione (10 mg, 0.03 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (1.3 equiv.) as starting materials, Pd(PPh3)4 (0.1 equiv.) as catalyst, and 1,4-dioxane as solvent. LCMS(ESI+)m / z 336.1[M+H] + 1H NMR(500MHz,DMSO-d6)δ10.72(s,1H), 8.72(ddd,J=4.8,1.9,0.9Hz,1H), 8.34(d,J=1.4Hz,1H), 8.23(dd,J=8.0,1.5Hz ,1H), 8.07(dt,J=8.0,1.1Hz,1H), 7.95(td,J=7.7,1.8Hz,1H), 7.83(d,J=8.0Hz,1H), 7.43(ddd,J=7.5,4.8,1.1Hz,1H ), 5.28(dd,J=12.5,5.3Hz,1H), 4.62(d,J=2.8Hz,2H), 3.10(ddd,J=16.7,13.1,3.7Hz,1H), 2.62~2.56(m,1H), 2.31(d td,J=12.7,8.0,4.0Hz,1H), 2.15(dtd,J=13.2,8.2,5.4Hz,1H), 2.10~1.98(m,1H), 1.84(tdd,J=13.0,8.0,5.1Hz,1H).

[0374] Example A39: Synthesis of 3-(1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)azepane-2,7-dione (compound 65) [ka]

[0375] Step 1: To a solution of tert-butyl piperidine-1-carboxylate (53 mg, 0.309 mmol, 5 equiv.) in THF (1.2 mL) cooled to −78° C., TMEDA (0.046 mL, 0.309 mmol, 5 equiv.) was added, followed by 1.6 M sec-BuLi in hexanes (0.232 mL, 0.371 mmol, 6 equiv.). The reaction mixture was stirred at −78° C. for 1 h, and 1.9 M ZnCl2 in 2-methyltetrahydrofuran (0.195 mL, 0.371 mmol, 6 equiv.) was added. The mixture was further stirred at room temperature for 2 h, and the volatiles were removed under reduced pressure. The residue was dissolved in toluene (1.2 mL), and 5-bromo-2-(2-oxoazepan-3-yl)isoindolin-1-one (20 mg, 0.062 mmol, 1 equiv.), Pd(dba) (0.1 equiv.), and SPhos (0.2 equiv.) were added. The reaction mixture was stirred at 70 °C for 18 h and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give tert-butyl 2-(1-oxo-2-(2-oxoazepan-3-yl)isoindolin-5-yl)piperidine-1-carboxylate (17 mg, 64% yield). LCMS (ESI+) m / z 428.0 [M+H] +

[0376] Step 2: A solution of tert-butyl 2-(1-oxo-2-(2-oxoazepan-3-yl)isoindolin-5-yl)piperidine-1-carboxylate (17 mg, 0.04 mmol, 1 equiv.) and Dess-Martin periodinane (2 equiv.) in a mixture of ACN (10 mL), DMSO (0.5 mL), and water (0.1 mL) was stirred at 80° C. for 18 h. The volatiles were removed under reduced pressure and tert-butyl 2-(2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate was purified by preparative TLC to give tert-butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidine-1-carboxylate.

[0377] Step 3: tert-Butyl 2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidine-1-carboxylate was dissolved in TFA (1 mL) and stirred at room temperature for 1 h. Volatiles were removed under reduced pressure to give 3-(1-oxo-5-(piperidin-2-yl)isoindolin-2-yl)azepane-2,7-dione (trifluoroacetate) (10 mg, 55% yield over two steps). LCMS(ESI+)m / z 342.2[M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.73(d,J=1.7Hz,1H), 9.12~8.98(m,1H), 8.78(d,J=11.0Hz,1H), 7.85(dd,J=7.9,1.9Hz,1 H), 7.75(t,J=2.1Hz,1H), 7.64(ddd,J=8.0,3.8,1.5Hz,1H), 5.27(dd,J=12.5,5.3Hz,1H), 4.60~4.56(m,2H), 4.41( t,J=11.3Hz,1H), 3.41(d,J=12.7Hz,2H), 3.11(ddd,J=16.5,11.1,3.7Hz,2H), 2.61(ddt,J=16.4,4.9,2.6Hz,1H), 2 .37~2.27(m,1H), 2.14(ddq,J=15.2,7.7,4.9,3.8Hz,1H), 2.03~1.97(m,1H), 1.96~1.82(m,4H), 1.78~1.64(m,2H).

[0378] Example A40: Synthesis of 3-(5-(4-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 27(2)) [ka]

[0379] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.25 g, 4.68 mmol, 1 equiv.) and 2-bromo-4-methoxypyridine (1.2 equiv.) was used to synthesize methyl 4-(4-methoxypyridin-2-yl)-2-methylbenzoate (91% yield) using Pd(PPh) (0.05 equiv.) as catalyst and KCO (3 equiv.) as base. LCMS (ESI+) m / z 258.2 [M+H] +

[0380] Step 2: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(4-methoxypyridin-2-yl)benzoate was synthesized (60% yield) using methyl 4-(4-methoxypyridin-2-yl)-2-methylbenzoate (2.66 g, 10.34 mmol, 1 equiv.) as starting material, AIBN (0.2 equiv.) as initiator, and DMC as solvent. LCMS (ESI+) m / z 336.2, 338.2 [M+H] +

[0381] Step 3: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-(4-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (10% yield) using methyl 2-(bromomethyl)-4-(4-methoxypyridin-2-yl)benzoate (100 mg, 0.29 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.1 equivalents) as starting materials, TEA (3 equivalents) as base, and DMF as solvent. LCMS(ESI+)m / z 352.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H), 8.52(d,J=5.72Hz,1H), 8.34(s,1H), 8.25(d,J=7.96,1H), 7.81(d,J=7.92Hz,1H), 7.60(s,1H), 7. 01(m,1H), 5.14(m,1H), 4.54(d,J=17.3Hz,1H), 4.42(d,J=17.2Hz,1H), 3.93(s,3H), 2.90(m,1H), 2.63(m,1H), 2.44(m,1H), 2.05(m,1H).

[0382] Example A41: Synthesis of 3-(5-(5-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 25(2)) [ka]

[0383] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.25 g, 4.68 mmol, 1 equiv.) and 2-bromo-5-methoxypyridine (1.2 equiv.) was used to synthesize methyl 4-(5-methoxypyridin-2-yl)-2-methylbenzoate (83% yield) using Pd(PPh) (0.05 equiv.) as catalyst and KCO (3 equiv.) as base. LCMS (ESI+) m / z 258.2 [M+H] +

[0384] Step 2: Using the general procedure shown in Reaction Scheme 6 above and Example Method 6, methyl 2-(bromomethyl)-4-(5-methoxypyridin-2-yl)benzoate was synthesized (69% yield) using methyl 4-(5-methoxypyridin-2-yl)-2-methylbenzoate (1.00 g, 3.89 mmol, 1 equiv.) as starting material, AIBN (0.2 equiv.) as initiator, and DCE as solvent. LCMS (ESI+) m / z 336.2 [M+H] +

[0385] Step 3: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 3-(5-(5-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (42% yield) using methyl 2-(bromomethyl)-4-(5-methoxypyridin-2-yl)benzoate (900 mg, 2.68 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (1.1 equivalents) as starting materials, TEA (3 equivalents) as base, and DMF as solvent. LCMS(ESI+)m / z 352.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H), 8.45(d,J=3.1Hz,1H), 8.25(s,1H), 8. 17(d,J=8.12Hz,1H), 8.04(d,J=8.8Hz,1H), 7.79(d,J=8.04Hz,1H), 7.53(m, 1H), 5.14(dd,J=13.2Hz,J=4.88Hz,1H),4.53(d,J=17.3Hz,1H),4.40(d,J=1 7.3Hz,1H), 3.90(s,3H), 2.90(m,1H), 2.62(m,1H), 2.54(m,1H), 2.03(m,1H).

[0386] Example A42: Synthesis of 3-(3-methyl-1-oxo-5-(tetrahydro-2H-pyran-2-yl)isoindolin-2-yl)piperidine-2,6-dione (Compound 64) [ka]

[0387] Step 1: 3-(5-Bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.59 mmol, 1 equiv.), copper(I) iodide (0.2 equiv.), sodium iodide (2 equiv.), and N,N'-dimethylethane-1,2-diamine (0.4 equiv.) were suspended in dioxane (6 mL) in a vial and purged with argon for 5 minutes. The reaction vial was sealed, and the reaction mixture was stirred at 125 °C for 48 hours. Upon completion, 3-(5-iodo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (67 mg, 0.17 mmol, 29% yield) was purified by flash column chromatography. LCMS (ESI+) m / z 385.0 [M+H] +

[0388] Step 2: A vial was charged with 3-(5-iodo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33 mg, 0.077 mmol, 1 equiv.), tributyl(tetrahydro-2H-pyran-2-yl)stannane (2 equiv.), bis(dibenzylideneacetone)palladium(0) (0.05 equiv.), bis(3,5-bis(trifluoromethyl)phenyl)(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (0.1 equiv.), potassium fluoride (2 equiv.), copper(I) chloride (2 equiv.), and tBuOH (1 mL). The slurry was purged with argon for 10 min, the vial was sealed, and the reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was filtered, the volatiles were removed under reduced pressure, and the crude product was purified by preparative HPLC to give 3-(3-methyl-1-oxo-5-(tetrahydro-2H-pyran-2-yl)isoindolin-2-yl)piperidine-2,6-dione as a white solid (1.8 mg, 6.6% yield). LCMS(ESI+)m / z 343.2[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ10.91(d,J=16.5Hz,1H), 7.63~7.55(m,2H), 7.44(td,J=8.2,6.0Hz,1H), 4.7 8~4.70(m,1H), 4.70~4.61(m,1H), 4.49~4.41(m,1H), 4.06(d,J=11.5Hz,1H), 3.56(ddd,J=14.5,7.8, 4.9Hz,1H), 2.79(dddd,J=37.7,18.1,14.1,5.8Hz,1H), 2.66~2.53(m,2H), 1.99(pt,J=7.7,3.4Hz,1 H), 1.93~1.81(m,2H), 1.66(dt,J=15.9,10.6Hz,1H), 1.57(qt,J=6.6,3.7Hz,2H), 1.47~1.39(m,4H).

[0389] Example A43: Synthesis of 3-(1-oxo-5-(6-(trifluoromethyl)piperidin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (Compound 60) [ka]

[0390] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, 3-(1-oxo-5-(6-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione was synthesized (77% yield) using 3-(1-oxo-5-(tributylstannyl)isoindolin-2-yl)piperidine-2,6-dione (40 mg, 0.075 mmol, 1 equiv.) and 2-bromo-6-(trifluoromethyl)pyridine (1.5 equiv.) as starting materials, Pd(PPh3)4 (0.08 equiv.) as catalyst, and DMF as solvent. LCMS (ESI+) m / z 390.0 [M+H] +

[0391] Step 2: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(1-oxo-5-(6-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (23 mg, 0.059 mmol, 1 equiv.) was synthesized starting from 3-(1-oxo-5-(6-(trifluoromethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (21% yield) using ethanol as the solvent and adding 4M HCl in 1,4-dioxane (0.1 mL, 0.4 mmol, 6.8 equiv.). LCMS(ESI+)m / z 396.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ10.97(s,1H), 7.67(d,J=7.8Hz,1H), 7.61(s,1H), 7.50(d,J=7.8Hz,1H), 5.10(dd,J=13.3,5.1H z,1H), 4.44(dd,J=17.3,2.4Hz,1H), 4.31(d,J=17.1Hz,1H), 3.82(d,J=11.2Hz,1H), 3.43(dd,J=7.4,4.1Hz,1H), 2.91( ddd,J=17.3,13.6,5.5Hz,1H), 2.76(s,1H), 2.60(ddd,J=17.4,4.5,2.4Hz,1H), 2.40(td,J=13.5,4.6Hz,1H), 1.99(ddt ,J=10.5,5.3,2.6Hz,1H), 1.90(d,J=13.2Hz,1H), 1.78(dd,J=28.5,12.5Hz,2H), 1.62~1.50(m,1H), 1.44~1.25(m,2H).

[0392] Example A44: Synthesis of 3-(1-oxo-5-(thiomorpholin-3-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 57) [ka]

[0393] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (1500 mg, 3.79 mmol, 1 equiv.) and tributyl(1-ethoxyvinyl)stannane (1.2 equiv.) as starting materials, Pd(PPh3)2Cl2 (0.06 equiv.) as catalyst, and 1,4-dioxane as solvent, tert-butyl 5-amino-4-(5-(1-ethoxyvinyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (68% yield) using tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (1500 mg, 3.79 mmol, 1 equiv.) and tributyl(1-ethoxyvinyl)stannane (1.2 equiv.) as starting materials, Pd(PPh3)2Cl2 (0.06 equiv.) as catalyst, and 1,4-dioxane as solvent.

[0394] tert-Butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate was prepared according to the procedure described in WO2021194914. LCMS (ESI+) m / z 389.2 [M+H] +

[0395] Step 2: To a solution of tert-butyl 5-amino-4-(5-(1-ethoxyvinyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 g, 2.6 mmol, 1 equiv.) in DCM (20 mL) was added a solution of bromine (0.28 mL, 5.41 mmol, 2.08 equiv.) in DCM at 0 °C and stirred at the same temperature for 20 min. Ice-cold water was added, and the product was extracted with EtO. The organic fraction was dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography to give tert-butyl 5-amino-4-(5-(2-bromoacetyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (210 mg, 18% yield). LCMS (ESI+) m / z 439.1 [M+H] +

[0396] Step 3: To a solution of KOH (56 mg, 1 mmol, 1.8 equiv) in MeOH (10 mL) was added 2-aminoethanethiol hydrochloride (63 mg, 0.55 mmol, 1.1 equiv) at 0 °C. tert-Butyl 5-amino-4-(5-(2-bromoacetyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (220 mg, 0.5 mmol, 1 equiv) was added in one portion, and the reaction mixture was stirred for 1 h. The reaction mixture was acidified with 4 M HCl in 1,4-dioxane (0.2 mL) and stirred for 1 h. NaBH4 (38 mg, 1 mmol, 1.8 equiv) was added in small portions, and the reaction mixture was stirred for an additional 40 min. The volatiles were removed in vacuo and the crude product tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(thiomorpholin-3-yl)isoindolin-2-yl)pentanoate was used directly in the next step. LCMS (ESI+) m / z 420.2 [M+H] +

[0397] Step 4: To a solution of crude tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(thiomorpholin-3-yl)isoindolin-2-yl)pentanoate (250 mg) and TEA (0.44 mL, 3.15 mmol) in DCM (15 mL) was added di-tert-butyl dicarbonate (0.25 mL, 1.15 mmol), and the reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give tert-butyl 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)thiomorpholin-4-carboxylate (80 mg, 31% yield over two steps). LCMS (ESI+) m / z 520.2 [M+H] +

[0398] Step 5: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(1-oxo-5-(thiomorpholin-3-yl)isoindolin-2-yl)piperidine-2,6-dione (trifluoroacetate) was synthesized (15% yield) using tert-butyl 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)thiomorpholine-4-carboxylate (100 mg, 0.19 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 346.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H), 8.16(s,1H), 7.73~7.59(m,2H), 7.53(d,J=7.9Hz,1H), 5.09(dd,J=13.4,5.1Hz,1H), 4.43(dd,J=17.3,5.3Hz ,1H), 4.30(dd,J=17.3,5.8Hz,1H), 3.95(d,J=10.3Hz,1H), 3.03~2.84(m ,2H), 2.80~2.55(m,3H), 2.46~2.30(m,2H), 1.99(dd,J=12.4,6.3Hz,1H). (3H overlaps with water signal)

[0399] Example A45: Synthesis of 3-(5-(5-isopropylpiperidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 55) [ka]

[0400] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-amino-4-(5-(5-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (97% yield) starting from 2-bromo-5-isopropylpyridine (280 mg, 1.41 mmol, 1 equiv.) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.2 equiv.), Pd(dppf)Cl2 as catalyst (0.1 equiv.), and K2CO3 (2.5 equiv.) as base. LCMS (ESI+) m / z 438.0 [M+H] +

[0401] Step 2: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(5-(5-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (25% yield) using tert-butyl 5-amino-4-(5-(5-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (97 mg, 0.22 mmol, 1 equiv) as the starting material. LCMS (ESI+) m / z 364.3 [M+H] +

[0402] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, 3-(5-(5-isopropylpiperidin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (mixture of stereoisomers, acetate salt) was synthesized using 3-(5-(5-isopropylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.55 mmol, 1 equivalent) as the starting material. The product was isolated by preparative HPLC to give a mixture of two stereoisomers as acetate salts (Isomer 1: 12.0 mg, 6% yield and Isomer 2: 5.0 mg, 2% yield).

[0403] Isomer 1: Preparative HPLC method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: YMC-Actus Triart C18 (250 × 20 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 10 mmol / L ammonium acetate in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 90% A and 10% B, followed by 90% A and 10% B for 5 min, then 50% A and 50% B for the next 30 min, followed by 5% A and 95% B for the next 31 min, then maintaining this composition for 33 min, followed by a return to the initial composition at 34 min and maintaining it for 36 min. Analytical LC, Method A:R t =1.94 minutes. LCMS(ESI+)m / z 370.3[M+H] + 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H), 7.65(d,J=7.9Hz,1H), 7.62(s,1H), 7.51(d,J=7.9Hz,1H), 5.10(dd,J=13.3,5.1Hz,1H), 4.42(dd,J=17.2,4.7Hz,1H), 4.29(dd,J=17.2,5.0Hz,1H), 3.73(t,J=6.0Hz,1H), 3.02~2.96(m,1H), 2.91(ddd,J=17.2,13.7, 5.5Hz,1H), 2.72(dd,J=12.0,3.1Hz,1H), 2.60(ddd,J=17.3,4.6,2.3Hz,1H), 2.46~2.33(m,1H), 2.10~1.94(m,2H), 1.89(s,3H) ), 1.76(d,J=6.4Hz,1H), 1.57(h,J=7.4,6.1Hz,3H), 1.09(dt,J=10.1,3.5Hz,1H), 0.92(d,J=6.6Hz,3H), 0.87(d,J=6.7Hz,3H).

[0404] Isomer 2: Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Ascentis RP-Amide C18 (150 × 21.2 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 10 mmol / L ammonium acetate in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 90% A and 10% B, followed by 85% A and 15% B in 3 min, then 45% A and 55% B in the next 20 min, then 5% A and 95% B in the next 21 min, then maintained at this composition for 24 min, followed by a return to the initial composition in 25 min and maintained there for 28 min. Analytical LC, Method C:R t =6.57 minutes. LCMS(ESI+)m / z 370.4[M+H] + 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H), 7.64(d,J=7.9Hz,1H), 7.59(s,1H), 7.49(d,J=7.9Hz,1H), 5.1 0(dd,J=13.4,5.0Hz,1H), 4.42(dd,J=17.2,4.8Hz,1H), 4.29(dd,J=17.2,5.1Hz,1H), 3.58(dd,J=10. 9,2.6Hz,1H), 3.16~3.05(m,1H), 2.91(ddd,J=17.9,13.6,5.3Hz,1H), 2.65~2.55(m,1H), 2.43~2.34 (m,2H), 2.04~1.94(m,1H), 1.89(s,3H), 1.87~1.77(m,2H), 1.46~1.12(m,4H), 0.89(d,J=6.7Hz,6H).

[0405] Example A46: Synthesis of N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-3-yl)benzamide (Compound 56) [ka]

[0406] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-amino-4-(5-(5-benzamidopyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (60% yield) starting from N-(6-bromopyridin-3-yl)benzamide (320 mg, 1.15 mmol, 1 equiv.) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.1 equiv.), Pd(dppf)Cl2 as catalyst (0.1 equiv.), and K2CO3 (2.5 equiv.) as base. LCMS (ESI+) m / z 515.1 [M+H] +

[0407] Step 2: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-3-yl)benzamide was synthesized (51% yield) using tert-butyl 5-amino-4-(5-(5-benzamidopyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (100 mg, 0.19 mmol, 1 equiv.) as the starting material. LCMS (ESI+) m / z 441.3 [M+H] +

[0408] Step 3: Using the general procedure shown in Reaction Scheme 1 above and Example Method 1, N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-3-yl)benzamide (formate salt) was synthesized (6% yield) using N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-3-yl)benzamide (170 mg, 0.39 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 447.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H), 8.34~8.18(m,1H), 8.11(d,J=6.7Hz,1H), 7.86(d ,J=7.3Hz,2H), 7.69(d,J=8.5Hz,2H), 7.58(d,J=7.2Hz,1H), 7.56~7.43(m,3H), 5.15~5 .05(m,1H), 4.44(d,J=17.2Hz,1H), 4.31(d,J=17.0Hz,1H), 4.10~3.98(m,1H), 3.82~3. 70(m,1H), 3.15~2.82(m,4H), 2.65~2.56(m,1H), 2.47~2.34(m,1H), 2.05~1.60(m,4H).

[0409] Example A47: Synthesis of 3-(5-(morpholin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 61) [ka]

[0410] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (500 mg, 1.2 mmol, 1 equiv.) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.1 equiv.) as starting materials, Pd(PtBu) was used as catalyst and KPO (2 equiv.) as base to prepare tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate. 5-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate was synthesized (yield 30%). LCMS (ESI+) m / z 502.2 [M+H] +

[0411] Step 2: A solution of tert-butyl 5-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (200 mg, 0.4 mmol, 1 equiv.) and Pd(OH) (180 mg) in methanol (20 mL) was stirred under a hydrogen atmosphere (50 psi) at room temperature for 3 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to give tert-butyl 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)morpholine-4-carboxylate (160 mg, 79% yield). LCMS (ESI+) m / z 504.3 [M+H] +

[0412] Step 3: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(5-(morpholin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (acetate salt) was synthesized (36% yield) using tert-butyl 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)morpholine-4-carboxylate (80 mg, 0.16 mmol, 1 equiv.) as the starting material. LCMS(ESI-)m / z 328.3[MH] - 1H NMR(400MHz,DMSO-d6)δ7.67(d,J=8.2Hz,2H), 7.58~7.50(m,1H), 5.11(dd,J=13.3,5.1Hz,1 H), 4.43(dd,J=17.3,5.4Hz,1H), 4.29(dd,J=17.3,6.3Hz,1H), 3.91(dd,J=10.0,3.1Hz,1H), 3.80~3.68(m,2H), 3.46(td,J=10.4,4.3Hz,1H), 3.16(td,J=10.3,4.2Hz,1H), 2.97~2.83(m ,3H), 2.59(ddd,J=17.3,4.4,2.2Hz,1H), 2.47~2.31(m,1H), 2.03~1.95(m,1H), 1.87(s,3H).

[0413] Example A48: Synthesis of 3-(5-(azepan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 62) [ka]

[0414] Step 1: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, tert-butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (500 mg, 1.12 mmol, 1 equiv.) and tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (1.1 equiv.) as starting materials, Pd(PtBu) was used as catalyst, and KPO (2 equiv.) was used as base to prepare tert-butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (500 mg, 1.12 mmol, 1 equiv.). 7-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate was synthesized (yield 61%). LCMS (ESI+) m / z 514.0 [M+H] +

[0415] Step 2: A solution of tert-butyl 7-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate (300 mg, 0.58 mmol, 1 equiv.) and Pd(OH) (300 mg) in methanol (15 mL) was stirred under a hydrogen atmosphere (balloon) at room temperature for 16 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to give tert-butyl 2-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)azepane-1-carboxylate (210 mg, 70% yield). LCMS (ESI+) m / z 516.2 [M+H] +

[0416] Step 3: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(5-(azepan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (acetate salt) was synthesized (62% yield) using tert-butyl 2-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)azepane-1-carboxylate (100 mg, 0.19 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 342.4[M+H] + 1H NMR(400MHz,DMSO-d6)δ7.63(d,J=8.0Hz,1H), 7.57(s,1H), 7.47(d,J=8.0Hz, 1H), 5.10(dd,J=13.1,5.1Hz,1H), 4.42(d,J=16.1Hz,1H), 4.28(d,J=17.3Hz,1 H), 3.86 (d, J = 8.4 Hz, 1H), 3.01 to 2.83 (m, 2H), 2.77 (s, 1H), 2.70 to 2.55 (m, 2H), 2.35 (d, J = 20.4 Hz, 1H), 1.95 (d, J = 16.8 Hz, 2H), 1.87 (s, 3H), 1.72 to 1.46 (m, 6H). (2H overlaps with water signal.)

[0417] Example A49: Synthesis of 3-(5-(4-methylpiperazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 67) [ka]

[0418] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 1.26 mmol, 1 equiv.) and 2-(tributylstannyl)pyrazine (1.2 equiv.) as starting materials, Pd(PPh3)4 (0.11 equiv.) as catalyst, and DMF as solvent, tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(pyrazin-2-yl)isoindolin-2-yl)pentanoate was synthesized (64% yield) using DMF as solvent. LCMS (ESI+) m / z 397.4 [M+H] +

[0419] Step 2: To a solution of tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(pyrazin-2-yl)isoindolin-2-yl)pentanoate (280 mg, 0.7 mmol, 1 equiv) in ACN (4 mL) was added methyl iodide (2.1 mL, 34 mmol, 48 equiv) and the reaction mixture was stirred for 16 h at 40° C. Upon completion, the volatiles were removed under reduced pressure and the crude product was triturated with pentane to afford 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-1-methylpyrazin-1-ium iodide (280 mg) as an off-white solid. LCMS (ESI+) m / z 411.2 [M] +

[0420] Step 3: Using the general procedure shown in Reaction Scheme 1 and Example Method 1, tert-butyl 5-amino-4-(5-(4-methylpiperazin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized using 3-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-1-methylpyrazin-1-ium iodide (182 mg, 0.34 mmol, 1 equiv.) as the starting material and methanol as the solvent. Upon completion, the solution was filtered and concentrated. The crude product was used directly in the next step. LCMS (ESI+) m / z 417.2 [M+H] +

[0421] Step 4: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(5-(4-methylpiperazin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (formate) was synthesized (5% yield after 3 steps) using tert-butyl 5-amino-4-(5-(4-methylpiperazin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (280 mg, 0.67 mmol, 1 equiv.) as the starting material. LCMS(ESI+)m / z 343.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H), 8.21(s,1H), 7.69~7.61(m,2H), 7.53(dd,J=7.8,1.4Hz,1H), 5. 11(dd,J=13.3,5.1Hz,1H), 4.43(dd,J=17.2,5.4Hz,1H), 4.29(dd,J=17.2,6.4Hz,1H), 3.85(dd,J=10. 1,2.8Hz,1H), 2.98~2.78(m,3H), 2.78~2.72(m,1H), 2.72~2.64(m,1H), 2.59(ddd,J=17.4,4.5,2.3Hz, 1H), 2.46~2.34(m,1H), 2.17(s,3H), 1.97(td,J=11.4,10.8,3.8Hz,2H), 1.78(td,J=10.4,4.8Hz,1H).

[0422] Example A50: Synthesis of 3-(5-(1,4-dioxan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 68) [ka]

[0423] Step 1: Using the general procedure shown in Reaction Scheme 2 above and Example Method 2, tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (530 mg, 1.33 mmol, 1 equiv.) and tributyl(5,6-dihydro-1,4-dioxin-2-yl)stannane (2 equiv.) as starting materials, Pd(PPh)Cl (0.14 equiv.) as catalyst, and DMF as solvent, tert-butyl 5-amino-4-(5-(5,6-dihydro-1,4-dioxin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was synthesized (63% yield) using tert-butyl 5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (530 mg, 1.33 mmol, 1 equiv.) and tributyl(5,6-dihydro-1,4-dioxin-2-yl)stannane (2 equiv.) as starting materials, Pd(PPh)Cl (0.14 equiv.) as catalyst, and DMF as solvent. LCMS (ESI+) m / z 403.2 [M+H] +

[0424] Step 2: A solution of tert-butyl 5-amino-4-(5-(5,6-dihydro-1,4-dioxin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (537 mg, 1.34 mmol) and 10% Pd / C (537 mg) in MeOH (5 mL) was stirred under a hydrogen atmosphere (balloon) at room temperature for 4 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to give tert-butyl 4-(5-(1,4-dioxan-2-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (375 mg, 69% yield). LCMS (ESI+) m / z 405.2 [M+H] +

[0425] Step 3: Using the general procedure shown in Reaction Scheme 3 above and Example Method 3, 3-(5-(1,4-dioxan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was synthesized (45% yield) using tert-butyl 4-(5-(1,4-dioxan-2-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (200 mg, 0.49 mmol, 1 equiv) as the starting material. LCMS(ESI+)m / z 331.1[M+H] + 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H), 7.70(d,J=7.8Hz,1H), 7.61(s,1H), 7.51(d, J=7.5Hz,1H), 5.11(dd,J=5.1,13.3Hz,1H), 4.72(d,J=8.4Hz,1H), 4.45(d,J=17.0 Hz,1H), 4.32(d,J=17.6Hz,1H), 3.96~3.83(m,2H), 3.85~3.73(m,2H), 3.66~3.55( m,1H), 3.03~2.81(m,1H), 2.68~2.53(m,1H), 2.44~2.34(m,2H), 2.04~1.95(m,1H).

[0426] Example A51: Synthesis of 3-(1-oxo-5-(tetrahydropyridazin-1(2H)-yl)isoindolin-2-yl)piperidine-2,6-dione (compound 58) [ka]

[0427] Step 1: Using the general procedure shown in Reaction Scheme 4 above and Example Method 4, 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromoisoindolin-1-one was synthesized (38% yield) using methyl 4-bromo-2-(bromomethyl)benzoate (650 mg, 3.25 mmol, 1.3 equiv.) and 2,6-bis(benzyloxy)pyridin-3-amine (500 mg, 1.63 mmol, 1 equiv.) as starting materials, TEA (3 equiv.) as base, and DMF as solvent. LCMS (ESI+) m / z 501.0, 502.9 [M+H] +

[0428] Step 2: A solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromoisoindolin-1-one (250 mg, 0.49 mmol, 1 equiv.), CsCO (2.5 equiv.), Pd(dba) (0.06 equiv.), XantPhos (0.1 equiv.), and tert-butyl tetrahydropyridazine-1(2H)-carboxylate (1.2 equiv.) in 1,4-dioxane (9 mL) was stirred at 100° C. for 16 h. Upon completion, the reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous NaSO, concentrated under reduced pressure, and the crude product was purified by flash column chromatography and evaporated to give tert-butyl 2-(2-(2,6-bis(benzyloxy)pyridin-3-yl)-1-oxoisoindolin-5-yl)tetrahydropyridazine-1(2H)-carboxylate (180 mg, 59% yield). LCMS (ESI+) m / z 607.3 [M+H] +

[0429] Step 3: A solution of tert-butyl 2-(2-(2,6-bis(benzyloxy)pyridin-3-yl)-1-oxoisoindolin-5-yl)tetrahydropyridazine-1(2H)-carboxylate (160 mg, 0.26 mmol, 1 equiv.), 10% Pd / C (80 mg), and Pd(OH) (80 mg) in DMF (5 mL) was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by preparative HPLC to give crude tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)tetrahydropyridazine-1(2H)-carboxylate. LCMS (ESI+) m / z 429.3 [M+H] +

[0430] Step 4: A solution of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)tetrahydropyridazine-1(2H)-carboxylate (85 mg, 0.2 mmol, 1 equiv) and TFA (10 equiv) in DCM (2 mL) was stirred at 0° C. for 2 h. Volatiles were removed under reduced pressure and the crude product was purified by preparative HPLC to give 3-(1-oxo-5-(tetrahydropyridazin-1(2H)-yl)isoindolin-2-yl)piperidine-2,6-dione (trifluoroacetate) (35 mg, 54% yield). LCMS(ESI+)m / z 329.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H), 7.62(d,J=8.2Hz,1H), 7.32~7.21(m,2H), 5.07(dd,J=5.0,13.3Hz,1H), 4.37(d,J=17.1Hz,1H), 4.24(d,J=17) .0Hz,1H), 3.52(t,J=5.3Hz,2H), 3.23~2.98(m,2H), 2.98~2.84(m,1H), 2. 64~2.54(m,1H), 2.46~2.33(m,1H), 2.03~1.93(m,1H), 1.84~1.59(m,4H). (1H overlaps with water signal)

[0431] Example A52: Synthesis of 3-(5-(6-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 69) [ka]

[0432] Step 1: To a solution of KHMDS (4.48 mmol, 1.4 equiv.) in THF (5 mL) cooled to −78 °C, a solution of 6-butyltetrahydro-2H-pyran-2-one (500 mg, 3.2 mmol, 1 equiv.) and phenyltriflimide (1.40 g, 3.85 mmol, 1.2 equiv.) in THF (3 mL) was added dropwise, and the reaction mixture was stirred for 1 h. Upon completion, NH₄Cl solution was added, and the product was extracted with hexane. The organic fraction was dried over Na₂SO₄ and concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give 2-butyl-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate (250 mg, 27% yield). GCMS (ESI+) m / z 288.1 [M] +

[0433] Step 2: To a stirred solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromoisoindolin-1-one (100 mg, 0.2 mmol, 1 equiv.) in 1,4-dioxane (2.5 mL) was added bis(pinacolato)diboron (76 mg, 0.3 mmol, 1.5 equiv.) under argon, and the mixture was degassed with argon for 20 min. PdCl(dppf)·DCM complex (0.1 equiv.) and KOAc (3 equiv.) were added, and the reaction mixture was stirred at 60 °C for 16 h. Upon completion, volatiles were removed under reduced pressure, and the crude product was purified by flash column chromatography to give 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (109 mg, 99% yield). LCMS (ESI+) m / z 549.3 [M+H] +

[0434] Step 3: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(2-butyl-3,4-dihydro-2H-pyran-6-yl)isoindolin-1-one was synthesized (68% yield) using 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (200 mg, 0.365 mmol, 1 equiv.) and 2-butyl-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate (2 equiv.) as starting materials, PdCl(dtbpf) (0.1 equiv.) as catalyst, and KPO (2.5 equiv.) as base. LCMS (ESI+) m / z 561.4 [M+H] +

[0435] Step 4: A solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(2-butyl-3,4-dihydro-2H-pyran-6-yl)isoindolin-1-one (100 mg, 0.178 mmol, 1 equiv.) and 10% Pd / C (80 mg) in a THF / AcOEt mixture (10 mL, 1 / 1, v / v) was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by preparative HPLC to give 3-(5-(5-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a mixture of two stereoisomers: Isomer 1 (2 mg, 3% yield) and Isomer 2 (13 mg, 19% yield).

[0436] Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Hydrosphere C18 (250 x 20 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 70% A and 30% B, followed by 50% A and 50% B in 3 min, then 20% A and 80% B in the next 20 min, then 5% A and 95% B in the next 21 min, then maintained at this composition for 22 min, followed by a return to the initial composition in 23 min and maintained there for 25 min.

[0437] Isomer 1: 3-(5-((2R,6S)-6-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-((2S,6R)-6-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Analytical LC, Method A:R t =3.36 minutes. LCMS(ESI+)m / z 385.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H), 7.69(d,J=7.9Hz,1H), 7.58(s,1H), 7.49(d,J=7.8Hz ,1H), 5.11(dd,J=4.9,13.2Hz,1H), 4.82(s,1H), 4.45(dd,J=7.4,17.1Hz,1H), 4.32(dd,J=6 .0,17.2Hz,1H), 3.74~3.67(m,1H), 2.98~2.84(m,1H), 2.65~2.55(m,1H), 2.39(dd,J=4.5,1 3.2Hz,1H), 2.10~1.94(m,1H), 1.94~1.51(m,6H), 1.48~1.19(m,6H), 0.87(t,J=6.9Hz,3H).

[0438] Isomer 2: 3-(5-((2R,6R)-6-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-((2S,6S)-6-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Analytical LC, Method A:R t =3.58 minutes. LCMS(ESI+)m / z 385.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H), 7.68(d,J=7.8Hz,1H), 7.55(s,1H), 7.46(d,J= 8.0Hz,1H), 5.11(dd,J=3.8,13.6Hz,1H), 4.52~4.40(m,2H), 4.38~4.26(m,1H), 3.55 ~3.41(m,1H), 2.98~2.84(m,1H), 2.65~2.55(m,1H), 2.43~2.34(m,1H), 2.05~1.94(m ,1H), 1.91~1.80(m,2H), 1.72~1.60(m,2H), 1.59~1.12(m,8H), 0.87(t,J=7.0Hz,3H).

[0439] Example A53: Synthesis of 3-(5-(5-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 70) [ka]

[0440] Step 1: To a solution of KHMDS (2.9 mmol, 1.5 equiv.) in THF (8 mL) cooled to −78° C., a solution of 5-butyltetrahydro-2H-pyran-2-one (300 mg, 1.92 mmol, 1 equiv.) and phenyltriflimide (823 mg, 2.3 mmol, 1.2 equiv.) in THF (3 mL) was added dropwise, and the reaction mixture was stirred for 1 h. Upon completion, NH4Cl solution was added, and the product was extracted with hexane. The organic fraction was dried over Na2SO4 and concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give 3-butyl-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate (270 mg, 49% yield).

[0441] 5-Butyltetrahydro-2H-pyran-2-one was prepared as described in Wang, S. et al., J. Org. Chem. 2003, 68, 6222. GCMS (ESI+) m / z 288.1 [M] +

[0442] Step 2: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(3-butyl-3,4-dihydro-2H-pyran-6-yl)isoindolin-1-one was synthesized (68% yield) using 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (200 mg, 0.365 mmol, 1 equiv.) and 3-butyl-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate (2 equiv.) as starting materials, PdCl(dtbpf) (0.1 equiv.) as catalyst, and KPO (2.5 equiv.) as base. LCMS (ESI+) m / z 560.9 [M+H] +

[0443] Step 3: A solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(3-butyl-3,4-dihydro-2H-pyran-6-yl)isoindolin-1-one (80 mg, 0.143 mmol, 1 equiv.) and 10% Pd / C (80 mg) in a THF / AcOEt mixture (5 mL, 1 / 1, v / v) was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by preparative HPLC to give 3-(5-(5-butyltetrahydro-2H-pyran-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a mixture of two stereoisomers: Isomer 1 (7 mg, 0.018 mmol, 12% yield) and Isomer 2 (7 mg, 0.018 mmol, 12% yield).

[0444] Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Hydrosphere C18 (250 x 20 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 70% A and 30% B, followed by 50% A and 50% B in 3 min, then 20% A and 80% B in the next 20 min, then 5% A and 95% B in the next 21 min, then maintained at this composition for 22 min, followed by a return to the initial composition in 23 min and maintained there for 25 min.

[0445] Isomer 1: Analytical LC, Method A:R t =3.46 minutes. LCMS(ESI+)m / z 385.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.16~10.79(m,1H), 7.68(d,J=7.8Hz,1H), 7.56(s,1H), 7.46(d ,J=7.9Hz,1H), 5.11(dd,J=5.0,13.2Hz,1H), 4.48~4.40(m,2H), 4.36~4.26(m,1H), 3.85~ 3.78(m,1H), 3.73~3.65(m,1H), 2.97~2.85(m,1H), 2.64~2.55(m,1H), 2.43~2.35(m,1H) , 1.93(dd,J=12.0,71.0Hz,2H), 1.77~1.40(m,6H), 1.37~1.25(m,4H), 0.99~0.84(m,3H).

[0446] Isomer 2: Analytical LC, Method A:R t =3.50 minutes. LCMS(ESI+)m / z 385.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H), 7.67(d,J=7.4Hz,1H), 7.56(s,1H), 7. 46(d,J=7.8Hz,1H), 5.26~5.04(m,1H), 4.48~4.24(m,3H), 4.15~3.93(m,1H) , 3.23~3.12(m,1H), 3.03~2.79(m,1H), 2.75~2.55(m,1H), 2.43~2.34(m,1H) , 2.12~1.83(m,4H), 1.77~1.37(m,2H), 1.39~1.03(m,6H), 0.95~0.76(m,3H).

[0447] Example A54: Synthesis of 3-(1-oxo-5-(5-phenyltetrahydro-2H-pyran-2-yl)isoindolin-2-yl)piperidine-2,6-dione (Compound 74) [ka]

[0448] Step 1: To a solution of KHMDS (1.82 mL, 1.8 mmol, 1.5 equiv.) in THF (7 mL) cooled to −78 °C, a solution of 5-phenyltetrahydro-2H-pyran-2-one (214 mg, 1.214 mmol, 1 equiv.) and phenyltriflimide (520 mg, 1.45 mmol, 1.2 equiv.) in THF (3 mL) was added dropwise, and the reaction mixture was stirred for 1 h. Upon completion, NH₄Cl solution was added, and the product was extracted with hexane. The organic fraction was dried over Na₂SO₄ and concentrated under reduced pressure, and the crude product was purified by flash column chromatography to give 3-phenyl-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate (200 mg, 53% yield).

[0449] 5-Phenyltetrahydro-2H-pyran-2-one was synthesized according to the procedure described by Ishii, Y. et al., J. Org. Chem. 1986, 51, 2034. GCMS (ESI+) m / z 176.2 [M] +

[0450] Step 2: Using the general procedure shown in Reaction Scheme 5 above and Example Method 5, 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(3-phenyl-3,4-dihydro-2H-pyran-6-yl)isoindolin-1-one was synthesized (37% yield) using 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (240 mg, 0.438 mmol, 1 equiv.) and 3-phenyl-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate (2 equiv.) as starting materials, PdCl(dtbpf) (0.1 equiv.) as catalyst, and KPO (2.5 equiv.) as base. LCMS (ESI+) m / z 580.9 [M+H] +

[0451] Step 3: A solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(3-phenyl-3,4-dihydro-2H-pyran-6-yl)isoindolin-1-one (80 mg, 0.138 mmol, 1 equiv.) and 10% Pd / C (80 mg) in a THF / AcOEt mixture (5 mL, 1 / 1, v / v) was stirred under a hydrogen atmosphere (balloon) at room temperature for 8 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by preparative HPLC to give 3-(1-oxo-5-(5-phenyltetrahydro-2H-pyran-2-yl)isoindolin-2-yl)piperidine-2,6-dione as a mixture of two stereoisomers: Isomer 1 (4 mg, 0.01 mmol, 7% yield) and Isomer 2 (5 mg, 0.012 mmol, 8% yield).

[0452] Preparative HPLC Method: Preparative HPLC was performed on a Waters automated purification instrument. Column name: Hydrosphere C18 (250 x 20 mm, 5 μm), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase A = 0.1% formic acid in water. Mobile phase B = acetonitrile. Gradient profile: initial composition 70% A and 30% B, followed by 60% A and 40% B in 3 min, then 25% A and 75% B in the next 20 min, then 5% A and 95% B in the next 21 min, then maintained at this composition for 22 min, followed by a return to the initial composition in 23 min and maintained there for 25 min.

[0453] Isomer 1: Analytical LC, Method A:R t =3.11 minutes. LCMS(ESI+)m / z 405.3[M+H] + 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H)、7.70(d,J=7.8Hz,1H)、7.59(s,1H)、7.51(dd,J=7.8,11.4Hz,3 H), 7.33(t,J=7.6Hz,2H), 7.21(t,J=7.4Hz,1H), 5.11(dd,J=5.1,13.2Hz,1H), 4.66(d,J=8.4Hz,1H) , 4.51~4.41(m,1H), 4.37~4.24(m,2H), 3.99(dd,J=3.3,11.9Hz,1H), 2.98~2.84(m,2H), 2.58(d,J=3 2.0Hz,1H), 2.46~2.34(m,1H), 2.28~2.16(m,1H), 1.98(m,2H), 1.74(d,J=13.3Hz,1H), 1.59(s,1H).

[0454] Opposite sex body 2: Analysis using LC, Method A:R t =3.17 points. LCMS(ESI+)m / z 405.3[M+H] + 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H), 7.70(d,J=7.9Hz,1H), 7.63(s,1H), 7.52(d,J=8.0Hz,1H), 7.39~7.30(m,4H), 7.29~7.19(m,1H), 5.12(dd,J=13.2,5.0Hz,1H), 4.60(d,J=11.2Hz,1H), 4.46( d,J=17.2Hz,1H), 4.33(d,J=17.3Hz,1H), 4.06(dd,J=11.1,4.3Hz,1H), 3.60(t,J=11.2Hz,1H), 3. 00~2.83(m,2H), 2.65~2.53(m,1H), 2.45~2.34(m,1H), 2.01(q,J=12.9Hz,4H), 1.75~1.53(m,1H).

[0455] Biophysical research The ternary complex forms アッセイ The effect of the molecular adhesive compounds of the present invention on the formation of the ternary complex composed of [NEK7]-[compound of formula (I)]-[CRBN / DDB1] was investigated in two ways: by an AlphaLISA dose-response assay or an HTRF ternary complex assay.

[0456] AlphaLISA dose-response assay: Two protein solutions were prepared: - 200 nM biotinylated NEK7, 40 μg / ml AlphaScreen streptavidin-coated donor beads in HBS (10 mM HEPES, 150 mM NaCL, pH 7.4) buffer containing 0.1% Tween-20 and 1 mM DTT, - 200 nM 6XHis-CRBN / Strep-DDB1, 40 μg / ml AlphaLISA anti-6xHis acceptor beads in HBS buffer containing 0.1% Tween-20 and 1 mM DTT.

[0457] The prepared solution was incubated at room temperature for 30 minutes, and then the solution containing the donor beads and the solution containing the acceptor beads were mixed.

[0458] Test compounds were dispensed into white 384-well AlphaPlate 384 SW plates. DMSO was filled into all wells to a final DMSO content of 2%. Wells containing DMSO alone served as background. 10 μl of a solution containing donor and acceptor beads was then added to the wells.

[0459] The plate was sealed with clear film and shaken for 60 seconds at room temperature using a VibroTurbulator at level 3. The plate was then spun down briefly (10 seconds, 1000 rcf, room temperature) and incubated at 25°C for 30 minutes.

[0460] Readings were taken on a PerkinElmer Enspire multimode plate reader (AlphaLISA method: 384-well low volume, filter sets: λexc=680 nm, λem=615 nm).

[0461] The results were analyzed as follows: 1) The average emission of the background signal was calculated and used as a negative control; 2) The average measured maximum emission of compound 2 was calculated and used as an internal positive control; 3) raw luminescence values ​​were normalized to positive and negative controls; 4) The normalized response to Compound 2 was determined.

[0462] As shown in Table 1, the compounds of the present invention have the ability to induce the formation of a [NEK7]-[compound of formula (I)]-[CRBN / DDB1] complex.

[0463] HTRF ternary complex assay: The effect of the molecular adhesive compound of the present invention on the formation of a ternary complex composed of [NEK7]-[compound of formula (I)]-[CRBN / DDB1] was examined.

[0464] A mixed solution of protein and reagent was prepared: A solution of 24 nM NEK7, 52.8 nM 6XHis-CRBN / Strep-DDB1, 3 nM streptavidin-Eu cryptate (acceptor), and 6.67 nM anti-6Xhis-d2 (donor) in PPI europium detection buffer (Cisbio) containing 1 mM DTT was prepared.

[0465] Test compounds for dose response were dispensed into white 384-well low volume plates (Greiner, 784075). DMSO was filled into all wells to give a final DMSO content of 0.5%. Wells containing DMSO alone were used as background.

[0466] The plate was sealed with clear film and shaken at level 3 using a VibroTurbulator for 60 seconds.

[0467] The plate was then spun down briefly (10 seconds, 1000 rcf) and incubated at 25°C for 180 minutes.

[0468] Readings were performed on a plate reader (Pherastar, BMG Labtech) in time-resolved fluorescence mode. Filter set: TR 337 665 620.

[0469] The results were analyzed as follows: 1) The mean fluorescence of the background signal was calculated and used as a negative control; 2) raw fluorescence values ​​of test compounds were normalized to the negative control; 3) The saturation curve was fitted to the specific binding by the Hill slope model; 4) The EC50 and pEC50 values ​​were determined.

[0470] As shown in Table 1, the compounds of the present invention have the ability to induce the formation of a [NEK7]-[compound of formula (I)]-[CRBN / DDB1] complex. [Table 4] JPEG2025537537000523.jpg255169 JPEG2025537537000524.jpg67170AlphaLISA ternary complex level description: A - Normalized activity >80% B - normalized activity >20% and <80% C - normalized activity >10% and <20% D - Normalized activity <10% Description of HTRF activity: +++++ - pEC50 >7.0 ++++ - 7.0 > pEC50 > 6.5 +++ - 6.5 > pEC50 > 6.0 ++ - 6.0 > pEC50 > 5.5 + - 5.5 > pEC50

[0471] Biological Testing Methodology cell culture Human PBMC-derived macrophages Macrophages were differentiated from human PBMCs isolated from buffy coats from healthy donors.

[0472] The buffy coat was diluted 1:1 (v / v) with DPBS (Sigma-Aldrich) in a Falcon tube. After reconstitution, the suspension was carefully layered on Histopaque-1077 solution (Sigma-Aldrich) and centrifuged (760 × g, room temperature, 20 min; brake off). PBMCs were collected and washed with DPBS (three times at 350 × g, room temperature, 8 min, and once at 200 × g, room temperature, 10 min; brake on). Subsequently, the cells were resuspended in an appropriate volume of RPMI 1640 medium (Gibco) supplemented with 10% heat-inactivated FBS (Gibco) and 1% 100x penicillin-streptomycin solution (BioWest). Cell viability was measured using trypan blue solution (Sigma-Aldrich).

[0473] 10 x 10 per well 6 PBMCs were seeded onto 6-well plates in complete medium supplemented with 10 ng / ml M-CSF growth factor (R&D Systems). Differentiation was carried out for 1 week with medium replacement every 2–3 days. Differentiation of PBMCs into mature macrophages was confirmed by microscopic evaluation and FACS surface staining for the markers CD11b, CD14, and CD16 (BD Pharmingen). Differentiated macrophages were subjected to the NLRP3 inflammasome activation assay.

[0474] HEK293 NEK7-HiBiT cell line HEK293 NEK7-HiBiT cells were generated using the CRISPR-Cas9 system. HEK293 cells were transformed with the pSpCas9-BB-2A-Puro v2.0 plasmid carrying a gRNA targeting the N-terminus of NEK7 and an ssODN template containing a HiBiT tag sequence with flanking homologous sequences. The Neon transfection system (Thermo Fisher Scientific) was used for electroporation. HEK293 NEK7-HiBiT cells were cultured in DMEM Glutamax (Gibco) supplemented with 10% heat-inactivated FBS (Gibco). After transfection, the medium was changed to DMEM Glutamax containing 10% heat-inactivated FBS and 1% penicillin-streptomycin (Biowest) supplemented with puromycin (2 μg / ml; Invivogen) for clonal selection. Limiting dilution cloning in 96-well plates was performed to isolate single-cell clones for further validation and analysis. Once single-cell clones reached confluency, a HiBiT cytolytic assay (Promega) was performed to identify HiBiT-positive clones. Clones selected for further study were confirmed and validated using genotyping and HiBiT blotting (Promega).

[0475] Selected clones of HEK293 NEK7-HiBiT cells were maintained in DMEM-Glutamax medium supplemented with 10% heat-inactivated FBS (Gibco) and 1% 100x penicillin-streptomycin solution (Biowest) at 37°C and 5% CO2 and subcultured every 2–3 days.

[0476] Nano-Glo HiBiT cytolysis assay For the Nano-Glo HiBiT cytolysis assay, HEK293 NEK7-HiBiT cells were plated in 384-well plates (Greiner Bio-One) at 2 × 10 cells per well in 40 μL of growth medium. 3Cells were seeded in triplicate at a density of 100 μg / well. Compound or DMSO was added to the treated plates using an Echo555 liquid handler and incubated at 37°C, 5% CO2 for 24 hours. After incubation, 40 μL of Nano-Glo HiBiT cell lysis reagent (prepared according to the manufacturer's protocol) was added to the 40 μL of cell culture medium present in each well. The plate contents were mixed briefly (460 rpm) on an orbital shaker to ensure cell lysis. The plate was left at room temperature, protected from light, for an additional 10 minutes to allow the luminescence signal to stabilize. The luminescence signal was measured using a CLARIOstar multimode plate reader. Focus and gain were adjusted for DMSO-treated cells. Results were calculated as % NEK7-HiBiT relative to the DMSO control for three technical replicates.

[0477] NLRP3 inflammasome activation assay Human PBMC-derived macrophages were pretreated with specific concentrations of exemplary compounds for 24 hours. Dilutions of test compounds in DMSO were prepared. Cells were then primed with 1 μg / ml LPS (Invivogen) for 3 hours, and the NLRP3 inflammasome was activated with 5 μM nigericin solution (Invivogen) for 1 hour. The supernatant was centrifuged and saved for ELISA assay, and cell lysates were prepared for Western blotting analysis.

[0478] Measurement of IL-1β and IL-18 IL-1β and IL-18 levels were quantified using an ELISA assay (R&D Systems) according to the manufacturer's protocol. 96-well plates were coated overnight with the appropriate capture antibody. Plates were blocked and incubated for a minimum of 1 hour at room temperature. Samples or standards were added and incubated for 2 hours at room temperature. Next, biotinylated anti-human IL-1β or IL-18 detection antibodies were added for 2 hours at room temperature. Streptavidin-HRP solution was added for a 20-minute incubation. Substrate solution was then added for 20 minutes. Washing procedures were performed between each step. The reaction was stopped, and optical density was determined using a CLARIOstar multimode plate reader set at 450 nm with wavelength correction set at 570 nm. Analysis was performed using GraphPad Prism software and an Excel spreadsheet.

[0479] Western blotting Cell lysates from human PBMC-derived macrophages were prepared by direct cell lysis in 40 μl of RIPA cell lysis buffer (50 mM Tris·HCl pH 7.4, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 0.1% SDS, and 1 mM EDTA) supplemented with protease and phosphatase inhibitors (Complete EDTA-Free Protease Inhibitor Cocktail, Roche; Halt™ Phosphatase Inhibitor Cocktail, Thermo Scientific). Subsequently, the cell lysates were snap-frozen in liquid nitrogen and stored at -20°C. After thawing, the cell lysates were centrifuged at 19,000 × g for 15 min at 4°C for supernatant collection. Protein concentration in each sample was determined by the BCA method (Pierce BCA Protein Assay Kit, Thermo Fisher Scientific). Absorbance was measured at 562 nm using a CLARIOstar multimode plate reader. SDS-PAGE samples were prepared by mixing cell lysates with 5x SB and RIPA buffers, and samples were denatured by incubation at 95°C for 5 min.

[0480] Protein samples were resolved on a 4-20% TGX Stain-Free™ protein gel (Bio-Rad) and transferred to a nitrocellulose membrane (Bio-Rad) using the Trans-Blot® Turbo system (Bio-Rad). The membrane was blocked in 5% non-fat non-fat milk (NFM) in TBS-T (10 mM Tris, 150 mM NaCl, 0.1% Tween-20) for 1 h at room temperature (RT). The membrane was then incubated with dilutions of anti-NEK7 primary antibody (o / n, 4°C) and loading control β-actin (1 h, RT) in TBS-T containing 5% NFM, followed by incubation with dilutions of the appropriate horseradish peroxidase (HRP)-conjugated secondary antibody in TBS-T containing 5% NFM for 1 h at room temperature. Between antibody incubations, the membrane was washed in TBS-T. Membranes were developed using SuperSignal West Pico PLUS chemiluminescent substrate (ThermoScientific). Images of the membranes were captured using a ChemiDoc imager. Analysis was performed with Image Lab software. NEK7 protein densitometry was normalized to loading controls and calculated relative to cells treated with DMSO controls.

[0481] result NEK7-HiBiT degradation assay HEK293 NEK7-HiBiT cells were treated with compounds (concentrations of 0.1 μM, 1 μM, and 10 μM) or DMSO for 24 hours. After incubation with compounds, NEK7-HiBiT degradation was measured as luminescence signal using a CLARIOstar multimode plate reader.

[0482] As shown in Table 2 below, most compounds of the present invention degraded the NEK7-HiBiT protein. Additionally, compounds were identified that reduced NEK7-HiBiT protein levels by 50% or more at 0.1 μM. [Table 5] JPEG2025537537000526.jpg255169 JPEG2025537537000527.jpg67170A -NEK7-HiBiT protein level ≤25% B - NEK7-HiBiT protein levels >25% and ≤50% C -NEK7-HiBiT protein levels >50% and <75% D -NEK7-HiBiT protein level ≥75%

[0483] NEK7 proteolysis confirmed by Western blotting Furthermore, the NEK7-HiBiT degradation results were confirmed for selected compounds in human PBMC-derived macrophages. Table 3 and Figure 1 show the results of NEK7 protein levels in these cells treated with specific concentrations of exemplary compounds or DMSO for 24 hours prior to NLRP3 inflammasome activation.

[0484] As shown in Table 3 and Figure 1, the compounds of the present invention induced dose-dependent degradation of NEK7 protein in macrophages derived from human PBMC cells. [Table 6] JPEG2025537537000529.jpg89170A - NEK7 protein content ≦10% B - NEK7 protein content >10% and ≤40% C - NEK7 protein content >40% and <75% D - NEK7 protein amount ≥ 75%

[0485] Measurement of IL-1β and IL-18 levels To assess the effect of compounds on inflammasome activation (measured as release of IL-1β and IL-18), human PBMC-derived macrophages were treated with individual compounds for 24 hours prior to inflammasome activation. As shown in Table 4 and Figures 2A and 2B, a dose-dependent decrease in cytokine levels was observed after 24 hours of pretreatment with exemplary compounds. [Table 7] JPEG2025537537000531.jpg85170A - Released cytokine levels ≦25% B - Level of released cytokines >25% and ≤50% C - Level of released cytokines >50% and <75% D - released cytokine levels ≥ 75%

[0486] Further embodiments 1. Formula (Ia) or (Ib): [ka] (In the formula, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] is in formula (Ia) [ka] or in formula (Ib) [ka] indicates the point of attachment to; [ka] is a heterocycloalkyl group, [ka] is a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group; [ka] is unsubstituted or contains one or more R 3 is replaced by The one or more R 3 The substituents other than [ka] Not present in; Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 is independently H, unsubstituted alkyl, or cycloalkyl; In formula (Ib), (i) [ka] but, [ka] and when Z is CH2 and n=0, [ka] is one or more R 3 is replaced by; (ii) [ka] but, [ka] Z is CH2 and n=0; [ka] is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) [ka] but, [ka] Z is CH2 and n=0; [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with (a) [ka] Through it [ka] the carbon atom adjacent to the carbon atom bonded to is unsubstituted; (b)R 3 is alkyl or O(alkyl), [ka] is monosubstituted; (c)R 3 is O(alkyl), the substitution is at the meta or para position relative to the heteroatom of said heteroaryl group; (d)R 3 is aryl or -NR2C(O)R1, the substitution is in the meta position relative to the heteroatom of said heteroaryl group; (iv) [ka] but, [ka] Z is CH2 and n=0; [ka] But one or more R 3 is a 10-membered fused bicyclic heteroaryl group substituted with Each R 3 teeth, [ka] present in the ring containing the point of attachment to Each R 3 is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R 3is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R 3 If is OEt, R 3 is ortho to the heteroatom of the heteroaryl group; R 3 If is NR2COMe, R 3 is in the meta position relative to the heteroatom of the heteroaryl group Compound.

[0487] 2. In formula (Ib), (i) [ka] but, [ka] and when n=0, Z is CH(C 1-2 alkyl) or C=O, (ii) [ka] but, [ka] and n is 1, 2, or 3 when Z is CH2.

[0488] 3.Z is CH2 or CH(C 1-2 The compound according to any one of the above 1 to 2, wherein R is 1 or 2, and ....

[0489] 4. [ka] but, [ka] The compound according to any one of the above 1 to 3,

[0490] 5. [ka] but, [ka] 5. The compound according to any one of the above 1 to 4,

[0491] 6. [ka] but, [ka] 6. The compound according to claim 5, wherein

[0492] 7. [ka] but, [ka] 5. The compound according to any one of the above 1 to 4,

[0493] 8. [ka] but, [ka] 8. The compound according to claim 7, wherein

[0494] 9. [ka] 9. The compound according to any one of the above 1 to 8, wherein contains one heteroatom.

[0495] 10. [ka] 9. The compound according to any one of the above 1 to 8, wherein contains two heteroatoms.

[0496] 11. [ka] 11. The compound according to any one of the above 1 to 10, wherein is a 5- to 10-membered heterocycloalkyl group.

[0497] 12. [ka] 12. The compound according to claim 11, wherein is a 5- or 6-membered heterocycloalkyl group.

[0498] 13. [ka] 13. The compound according to claim 12, wherein is a pyrrolidine group, a piperidine group, or an oxane group.

[0499] 14. [ka] but, [ka] and [ka] but, [ka] 14. The compound according to claim 13, showing the point of attachment to

[0500] 15. [ka] but, [ka] 15. The compound according to claim 14, wherein

[0501] 16. [ka] but, [ka] 16. The compound according to claim 14 or 15,

[0502] 17. [ka] 17. The compound according to any one of the above 1 to 16, wherein is unsubstituted.

[0503] 18. [ka] There are one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl; or two R on adjacent atoms of a heterocycloalkyl group 3 together with the atom to which they are attached form an aromatic ring; or two R on the same carbon atom of the heterocycloalkyl group. 3 and form a C═O group together with the carbon atom to which they are attached.

[0504] 19.Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R1 or two R on the same carbon atom of a heterocycloalkyl group; 3 together with the carbon atom to which they are attached form a C=O group.

[0505] 20. Two Rs on adjacent atoms of a heterocycloalkyl group 3 19. The compound according to claim 18, wherein, together with the atoms to which they are attached, form an aromatic ring.

[0506] twenty one. [ka] but, [ka] and [ka] but, [ka] indicates the point of attachment to r is an integer from 1 to 7, optionally from 1 to 3; 21. The compound according to claim 19 or 20, wherein s is an integer of 1 to 9, optionally 1 to 4.

[0507] twenty two. [ka] but, [ka] 22. The compound according to claim 21, wherein

[0508] twenty three. [ka] but, [ka] 23. The compound according to claim 22, wherein

[0509] twenty four. [ka] but, [ka] and [ka] but, [ka] indicates the point of attachment to R3 is unsubstituted alkyl, aryl, benzyl, or -NR 2 C(O)R 1 14. The compound according to claim 13, wherein

[0510] twenty five. [ka] but, [ka] and R3 is unsubstituted alkyl, benzyl, or -NR 2 C(O)R 1 25. The compound according to claim 24, wherein

[0511] 26.R 3 26. The compound according to claim 25, wherein is unsubstituted alkyl or benzyl.

[0512] 27. [ka] but, [ka] and R3 is aryl; [ka] but, [ka] and 25. The compound according to claim 24, wherein R is F or alkyl.

[0513] 28. [ka] but, [ka] 28. The compound according to claim 27, wherein

[0514] 29. [ka] but, [ka] 16. The compound according to claim 15, wherein

[0515] 3032. [ka] 30. The compound according to any one of the above 1 to 29, wherein contains one heteroatom.

[0516] 31. [ka] 30. The compound according to any one of the above 1 to 29, wherein contains two heteroatoms.

[0517] 32. [ka] The compound according to any one of the above 1 to 31, wherein is a 6-membered monocyclic heteroaryl group.

[0518] 33. [ka] 33. The compound according to claim 32, wherein is a pyridine group.

[0519] 34. [ka] but, [ka] and [ka] but, [ka] 34. The compound of claim 33, showing the point of attachment to

[0520] 35. [ka] 32. The compound according to any one of the above 1 to 31, wherein is a 10-membered fused bicyclic heteroaryl group.

[0521] 36. [ka] 36. The compound according to claim 35, wherein is a quinoline group or an isoquinoline group.

[0522] 37. [ka] but, [ka] and [ka] but, [ka] 37. The compound of claim 36, showing the point of attachment to

[0523] 38. [ka] 38. The compound according to any one of the above 1 to 37, wherein is unsubstituted.

[0524] 39. [ka] There are one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 38. The compound according to any one of the above 1 to 37, wherein are independently H, unsubstituted alkyl, or cycloalkyl.

[0525] 40.Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R 1 40. The compound according to claim 39, wherein

[0526] 41.Each R 1 is independently unsubstituted alkyl or aryl, and each R 2 41. The compound according to any one of the above 1 to 40, wherein are independently H or unsubstituted alkyl.

[0527] 42. [ka] but, [ka] and [ka] but, [ka] 42. The compound according to claim 40 or 41, wherein q is an integer of 1 to 4, optionally 1 to 3, and indicates a point of attachment to:

[0528] 43. [ka] but, [ka] 43. The compound according to claim 42, wherein

[0529] 44. [ka] but, [ka] 30. The compound according to any one of the above 1 to 29, wherein

[0530] 45. [ka] but, [ka] and [ka] but, [ka] indicates the point of attachment to R3 is aryl, haloalkyl, or -NR 2 C(O)R 1 33. The compound according to claim 32, wherein

[0531] 46. ​​R3 is aryl or -NR 2 C(O)R 1 46. ​​The compound according to claim 45, wherein

[0532] 47. The compound according to claim 45, wherein R3 is aryl or haloalkyl.

[0533] 48. The compound according to any one of the above 1 to 47, wherein L is hydrogen.

[0534] 49. The compound according to any one of the above 1 to 48, wherein X1 and X2 are O.

[0535] 50. The compound according to any one of the above 1 to 48, wherein X1 is O and X2 is S.

[0536] 51. The compound according to any one of the above 1 to 48, wherein X1 is S and X2 is O.

[0537] 52. The compound according to any one of the above 1 to 48, wherein X1 and X2 are S.

[0538] 53. The compound according to any one of the above 1 to 52, wherein Y is S.

[0539] 54. The compound according to any one of the above 1 to 53, wherein Z is C=O, CH2, or CHMe.

[0540] 55. The compound according to any one of the above 1 to 53, wherein Z is CH2 or CHMe.

[0541] 56. The compound according to claim 55, wherein Z is CH2.

[0542] 57. The compound according to any one of 1-56 above, wherein each R is independently unsubstituted alkyl or halogen.

[0543] 58. The compound according to any one of 1 to 57 above, wherein each R is independently Me or F.

[0544] 59. The compound according to any one of the above 1 to 58, wherein n is 0 or 1.

[0545] 60. The compound according to claim 59, wherein n is 0.

[0546] 61. The compound according to any one of the above 1 to 60, wherein m is 0.

[0547] 62. The compound according to any one of the above 1 to 61, wherein y=1.

[0548] 63. The compound according to any one of 1 to 62 above, which is a compound of formula (Ia).

[0549] 64. The compound according to any one of 1 to 62 above, which is a compound of formula (Ib).

[0550] 65. [Table 8] JPEG2025537537000640.jpg250170 JPEG2025537537000641.jpg73170.

[0551] 66. A pharmaceutical composition comprising a compound according to any one of 1 to 65 above.

[0552] 67. A compound according to any one of 1 to 65 above, or a pharmaceutical composition according to 66 above, for use in medicine.

[0553] 68. A compound according to any one of claims 1 to 65, or a pharmaceutical composition according to claim 66, for use in the treatment of an inflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, an infectious disease, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, a wound or burn, or cancer.

[0554] 69. A compound of formula (I): for use in a method of treating an inflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft-versus-host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn in a subject in need thereof. [ka] (In the formula, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, [ka] teeth, indicates the point of attachment to; [ka] is a heterocyclic group) Compound.

[0555] 70. The compound for use according to claim 69, wherein the disease or condition is an inflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft-versus-host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn.

[0556] 71. The disease or condition is cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), suppurative sterile arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), hyperimmunoglobulin D-related periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAS) 71. The compound for use according to claim 69 or 70, wherein the compound is selected from the group consisting of juvenile idiopathic arthritis (PS), systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA), A20 haploinsufficiency (HA20), lupus nephritis, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, amyotrophic lateral sclerosis, and gout.

[0557] 72. A method for degrading NEK7 protein, comprising combining the protein with a compound of formula (I): [ka] (In the formula, y is 0, 1, or 2; X1 and X2 are each independently O or S; L is H, —C(O)alkyl, or —CH2(O)COR′; [ka] teeth, [ka] and During the ceremony, Each Z is independently C=O, CH2, or CH(C 1-2 alkyl); Y is S, O, or NH; each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH2, -NHR', or -NR'2; each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; [ka] teeth, [ka] indicates the point of attachment to; [ka] teeth, [ka] indicates the point of attachment to; [ka] is a heterocyclic group) with a compound of formula (I).

[0558] 73. [ka] but, (i) [ka] (In the formula, [ka] is a heterocycloalkyl group) or (ii) [ka] (In the formula, [ka] is unsubstituted or contains one or more R3 a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R 3 The substituents other than [ka] Not present in each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl. 72. The compound for use according to any one of 69 to 71, or the method according to 72,

[0559] 74.(i) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] If [ka] There are one or more R 3 is replaced by; (ii) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] and [ka] is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] and [ka] But one or more R 3 is a 6-membered monocyclic heteroaryl group substituted with (a) [ka] Through it [ka] the carbon atom adjacent to the carbon atom bonded to is unsubstituted; (b)R 3is alkyl or O(alkyl), [ka] is monosubstituted; (c)R 3 is O(alkyl), the substitution is in the meta or para position relative to the heteroatom of said heteroaryl group; (d)R 3 is aryl or -NR2C(O)R1, the substitution is in the meta position relative to the heteroatom of said heteroaryl group; (iv) [ka] but, [ka] Z is CH2 and n=0; [ka] but, [ka] and [ka] But one or more R 3 is a 10-membered fused bicyclic heteroaryl group substituted with Each R 3 but, [ka] present in the ring containing the point of attachment to Each R 3 is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R 3 is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R 3 If is OEt, R 3is ortho to the heteroatom of the heteroaryl group; R 3 If is NR2COMe, R 3 74. The compound or method for use according to claim 73, wherein is in the meta position relative to the heteroatom of the heteroaryl group.

[0560] 75. (i) [ka] but, [ka] and n=0, [ka] but, [ka] If Z is CH(C 1-2 alkyl) or C=O, (ii) [ka] but, [ka] and Z is CH2; [ka] but, [ka] 75. The compound or method for use according to claim 74, wherein n is 1, 2, or 3.

[0561] 76.Z is CH2 or CH(C 1-2 76. The compound or method for use according to any one of 69 to 75, wherein the aryl group is alkyl.

[0562] 77. A compound or method for use according to claim 76, wherein Z is CH2.

[0563] 78. [ka] but, [ka] 78. The compound or method for use according to any one of 69 to 77,

[0564] 79. [ka] but, [ka] 79. The compound or method for use according to any one of 69 to 78,

[0565] 80. [ka] but, [ka] 79. The compound or method for use according to claim 79, wherein

[0566] 81. [ka] but, [ka] 79. The compound or method for use according to any one of 69 to 78,

[0567] 82. [ka] but, [ka] 82. The compound or method for use according to claim 81, wherein

[0568] 83. [ka] 83. The compound or method for use according to any one of 69 to 82, wherein contains one heteroatom.

[0569] 84. [ka] 83. The compound or method for use according to any one of 69 to 82, wherein contains two heteroatoms.

[0570] 85. [ka] but, [ka] and [ka] 85. The compound or method for use according to any one of 69 to 84, wherein is a heterocycloalkyl group.

[0571] 86. [ka] 86. The compound or method for use according to 85 above, wherein is a 5- to 10-membered heterocycloalkyl group.

[0572] 87. [ka] 87. The compound or method for use according to claim 86, wherein is a 5- or 6-membered heterocycloalkyl group.

[0573] 88. [ka] 88. The compound or method for use according to claim 87, wherein is a pyrrolidine group, a piperidine group, or an oxane group.

[0574] 89. [ka] but, [ka] and [ka] but, [ka] 89. A compound or method for use according to claim 88, showing the point of attachment to

[0575] 90. [ka] but, [ka] 89. The compound or method for use according to claim 89, wherein

[0576] 91. [ka] but, [ka] 90. The compound or method for use according to claim 90, wherein

[0577] 92. [ka] 91. The compound or method for use according to any one of 73 to 90, wherein is unsubstituted.

[0578] 93. [ka] There are one or more R 3 and each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 are independently H, unsubstituted alkyl, or cycloalkyl; or two R on adjacent atoms of a heterocycloalkyl group 3 together with the atom to which they are attached form an aromatic ring; or two R on the same carbon atom of the heterocycloalkyl group. 3 91. The compound or method for use according to any one of 73 to 90, wherein, together with the carbon atom to which they are attached, form a C═O group.

[0579] 94.Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R; or two R on the same carbon atom of a heterocycloalkyl group 3 94. The compound or method for use according to claim 93, wherein together with the carbon atom to which they are attached form a C=O group.

[0580] 95. Two Rs on adjacent atoms of a heterocycloalkyl group 395. The compound or method for use according to claim 93 or 94, wherein, together with the atom to which they are attached, form an aromatic ring.

[0581] 96. [ka] but, [ka] and [ka] but, [ka] indicates the point of attachment to r is an integer from 1 to 7, optionally from 1 to 3; 95. The compound or method for use according to claim 93 or 94, wherein s is an integer of 1 to 9, optionally 1 to 4.

[0582] 97. [ka] but, [ka] 97. The compound or method for use according to claim 96, wherein

[0583] 98. [ka] but, [ka] and [ka] but, [ka] 98. A compound or method for use according to claim 97, showing a point of attachment to

[0584] 99. [ka] but, [ka] and [ka] but, [ka] indicates the point of attachment to R3 is unsubstituted alkyl, aryl, benzyl, or -NR 2 C(O)R 1 89. The compound according to claim 88,

[0585] 100. [ka] but, [ka] and R3 is unsubstituted alkyl, benzyl, or -NR 2 C(O)R 1 99. A compound or method for use according to claim 99, wherein

[0586] 101.R 3 101. The compound or method for use according to claim 100, wherein is unsubstituted alkyl or benzyl.

[0587] 102. [ka] but, [ka] and R3 is aryl; [ka] but, [ka] and 99. The compound or method for use according to claim 99, wherein R is F or alkyl.

[0588] 103. [ka] but, [ka] 103. The compound or method for use according to claim 102, wherein

[0589] 104. [ka] but, [ka] 90. The compound or method for use according to claim 90, wherein

[0590] 105. [ka] but, [ka] and [ka] is unsubstituted or contains one or more R 3 a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R 3Substituents other than [ka] Not present in each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 85. The compound or method for use according to any one of 69 to 84, wherein are independently H, unsubstituted alkyl, or cycloalkyl.

[0591] 106. [ka] 106. The compound or method for use according to claim 105, wherein is a 6-membered monocyclic heteroaryl group.

[0592] 107. [ka] 107. The compound or method for use according to claim 106, wherein is a pyridine group.

[0593] 108. [ka] but, [ka] and [ka] but, [ka] 108. A compound or method for use according to claim 107, showing a point of attachment to

[0594] 109. [ka] 106. The compound or method for use according to claim 105, wherein is a 10-membered fused bicyclic heteroaryl group.

[0595] 110. [ka] 110. The compound or method for use according to claim 109, wherein is a quinoline group or an isoquinoline group.

[0596] 111. [ka] but, [ka] and [ka] but, [ka] 111. A compound or method for use according to claim 110, showing a point of attachment to

[0597] 112. [ka] 112. The compound or method for use according to any one of the preceding paragraphs 73 to 111, wherein is unsubstituted.

[0598] 113. [ka] There are one or more R 3 and each R 3are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR 1 , aryl, benzyl, -C(O)R 1 , or -NR 2 C(O)R 1 and each R 1 is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R 2 112. The compound or method for use according to any one of 73 to 111, wherein are independently H, unsubstituted alkyl, or cycloalkyl.

[0599] 114.Each R 3 are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R 1 114. The compound or method for use according to claim 113, wherein

[0600] 115.Each R 1 is independently unsubstituted alkyl or aryl, and each R 2 115. The compound or method for use according to any one of claims 73 to 114, wherein are independently H or unsubstituted alkyl.

[0601] 116. [ka] but, [ka] and [ka] but, [ka] 116. The compound or method for use according to any one of claims 113 to 115, wherein q represents a point of attachment to

[0602] 117. [ka] but, [ka] 117. The compound or method for use according to claim 116, wherein

[0603] 118. [ka] but, [ka] 106. The compound or method for use according to claim 105, wherein

[0604] 119. [ka] but, [ka] and [ka] but, [ka] indicates the point of attachment to R3 is aryl, haloalkyl, or -NR 2 C(O)R 1 106. The compound or method for use according to claim 105, wherein

[0605] 120. [ka] but, [ka] and R3 is aryl or -NR 2 C(O)R 1120. The compound or method for use according to claim 119, wherein

[0606] 121. [ka] but, [ka] 121. The compound or method for use according to claim 120, wherein R3 is aryl or haloalkyl.

[0607] 122. A compound or method for use according to any one of 69 to 121, wherein L is hydrogen.

[0608] 123. The compound or method for use according to any one of 69 to 122, wherein X1 and X2 are O.

[0609] 124. The compound or method for use according to any one of 69 to 122, wherein X1 is O and X2 is S.

[0610] 125. The compound or method for use according to any one of the preceding 69 to 122, wherein X1 is S and X2 is O.

[0611] 126. The compound or method for use according to any one of 69 to 122, wherein X1 and X2 are S.

[0612] 127. A compound or method for use according to any one of 69 to 126, wherein Y is S.

[0613] 128. A compound or method for use according to any one of 69 to 74 and 75 to 127, wherein Z is C=O, CH2, or CHMe.

[0614] 129. A compound or method for use according to any one of 69 to 127, wherein Z is CH2 or CHMe.

[0615] 130. A compound or method for use according to claim 129, wherein Z is CH2.

[0616] 131. The compound or method for use according to any one of 69 to 130 above, wherein each R is independently unsubstituted alkyl or halogen.

[0617] 132. The compound or method for use according to claim 131, wherein each R is independently Me or F.

[0618] 133. A compound or method for use according to any one of 69 to 132, wherein n is 0 or 1.

[0619] 134. A compound or method for use according to claim 133, wherein n is 0.

[0620] 135. A compound or method for use according to any one of 69 to 134, wherein m is 0.

[0621] 136. A compound or method for use according to any one of 69 to 135, wherein y=1.

[0622] 137. Compound [Table 9] 69. A compound for use according to claim 69, or a method according to claim 72, selected from JPEG2025537537000783.jpg240170.

[0623] 138. The compound or method for use according to any one of 69 to 137, wherein the compound is formulated as a pharmaceutical composition.

Claims

1. Formula (Ia) or (Ib): 【Chemistry 1】 (In the formula, y is 0, 1, or 2; X １ and X ２ are each independently O or S; L is H, —C(O)alkyl, or —CH ２ (O)COR'; 【Chemistry 2】 teeth, 【Transformation 3】 and During the ceremony, Each Z is independently C=O, CH ２ , or CH(C １－２ alkyl); Y is S, O, or NH; Each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH ２ , —NHR′, or —NR′ ２ and each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; 【Chemistry 4】 teeth, 【Transformation 5】 indicates the point of attachment to 【Transformation 6】 is in formula (Ia) 【Transformation 7】 or in formula (Ib) 【Transformation 8】 indicates the point of attachment to 【Chemistry 9】 is the attachment point 【Chemistry 10】 is a heterocycloalkyl group having a heteroatom adjacent to 【Chemistry 11】 is a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group; 【Chemistry 12】 is unsubstituted or is substituted with one or more R ３ is replaced by The one or more R ３ The substituents other than 【Chemistry 13】 Not present in Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ is independently H, unsubstituted alkyl, or cycloalkyl; In formula (Ib), (i) 【Chemistry 14】 but, 【Chemistry 15】 and Z is CH ２ and when n=0, (a) 【Chemistry 16】 is one or more R ３ or (b) y is 2; (ii) 【Chemistry 17】 but, [Chemistry 18] and Z is CH ２ and n=0; 【Chemistry 19】 is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) 【Chemistry 20】 but, 【Chemistry 21】 and Z is CH ２ and n=0; 【Chemistry 22】 is one or more R ３ is a 6-membered monocyclic heteroaryl group substituted with (a) 【Chemistry 23】 Through it 【Chemistry 24】 the carbon atom adjacent to the carbon atom bonded to (b) R ３ is alkyl or O(alkyl), 【Chemistry 25】 is monosubstituted; (c) R ３ is O(alkyl), said substitution is at the meta or para position relative to the heteroatom of said heteroaryl group; (d) R ３ is aryl or —NR ２ C(O)R １ wherein the substitution is in the meta position relative to the heteroatom of the heteroaryl group; (iv) 【Chemistry 26】 but, 【Chemistry 27】 Z is C=O and n=0; 【Chemistry 28】 is one or more R ３ When R is a 6-membered monocyclic heteroaryl group substituted with ３ is hydroxy, the substitution is at the meta or para position relative to the heteroatom of the heteroaryl group; (v) 【Chemistry 29】 but, 【Transformation 30】 and Z is CH ２ and n=0; 【Chemistry 31】 is one or more R ３ is a 10-membered fused bicyclic heteroaryl group substituted with Each R ３ teeth, 【Chemistry 32】 present in the ring containing the point of attachment to Each R ３ is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R ３ is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R ３ When is OEt, R ３ is ortho to the heteroatom of the heteroaryl group; R ３ NR ２ If COMe, then R ３ is in the meta position relative to the heteroatom of the heteroaryl group. Compound.

2. In formula (Ib), 【Transformation 33】 but, 【Transformation 34】 and Z is CH ２ and when n=0, 【Chemistry 35】 One or more R ３ 2. The compound of claim 1 , substituted with:

3. In formula (Ib), 【Transformation 36】 but, 【Chemistry 37】 and Z is C=O or CH ２ and n=0; 【Transformation 38】 is one or more R ３ When R is a 6-membered monocyclic heteroaryl group substituted with ３ 3. The compound of claim 1 or 2, wherein when is hydroxy or O(alkyl), the substitution is in the meta or para position relative to the heteroatom of the heteroaryl group.

4. In formula (Ib), (i) 【Chemistry 39】 but, 【Chemistry 40】 and when n=0, Z is CH(C １－２ alkyl) or C═O; (ii) 【Chemistry 41】 but, 【Chemistry 42】 and Z is CH ２ The compound of any one of claims 1 to 3, wherein n is 1, 2, or 3.

5. Z is CH ２ or CH(C １－２ The compound according to any one of claims 1 to 4, wherein the aryl group is aryl, ... 【Request Item 6】 【Chemistry 43】 but, 【Chemistry 44】 The compound according to any one of claims 1 to 5, 【Request Item 7】 【Chemistry 45】 but, 【Chemistry 46】 The compound according to any one of claims 1 to 6, 【Request Item 8】 【Chemistry 47】 but, 【Chemistry 48】 8. The compound of claim 7, wherein: 【Request Item 9】 【Chemistry 49】 but, [Transformation 50] The compound according to any one of claims 1 to 6, 【Request Item 10】 【Chemistry 51】 but, 【Chemistry 52】 10. The compound of claim 9, wherein: 【Request Item 11】 【Chemistry 53】 but, 【Chemistry 54】 The compound according to any one of claims 1 to 5, 【Request Item 12】 【Chemistry 55】 but, 【Transformation 56】 12. The compound of claim 11, wherein: 【Request Item 13】 【Chemistry 57】 but, 【Transformation 58】 The compound according to any one of claims 1 to 5, 【Request Item 14】 【Chemistry 59】 but, 【Transformation 60】 14. The compound of claim 13, wherein: 【Request Item 15】 【Chemistry 61】 but, 【Transformation 62】 15. The compound of claim 14, wherein: 【Request Item 16】 【Chemistry 63】 but, 【Chemistry 64】 14. The compound of claim 13, wherein: 【Request Item 17】 【Chemistry 65】 but, 【Chemical Formula 66】 17. The compound of claim 16, wherein: 【Request Item 18】 【Chemistry 67】 The compound of any one of claims 1 to 17, wherein contains one heteroatom. 【Request Item 19】 【Chemistry 68】 The compound of any one of claims 1 to 17, wherein contains two heteroatoms. 【Request Item 20】 【Chemistry 69】 The compound according to any one of claims 1 to 19, wherein is a 5- to 10-membered heterocycloalkyl group. 【Request Item 21】 【Chemistry 70】 21. The compound of claim 20, wherein is a 5- or 6-membered heterocycloalkyl group. 【Request Item 22】 【Chemistry 71】 22. The compound of claim 21, wherein is a pyrrolidine group, a piperidine group, or an oxane group. 【Request Item 23】 【Chemistry 72】 but, 【Transformation 73】 and 【Chemistry 74】 but, 【Chemistry 75】 23. The compound of claim 22, wherein the compound indicates a point of attachment to 【Request Item 24】 【Chemistry 76】 but, 【Chemical 77】 24. The compound of claim 23, wherein: 【Request Item 25】 【Chemistry 78】 but, 【Chemistry 79】 24. The compound of claim 22 or 23, wherein: 【Request Item 26】 【Chemistry 80】 22. The compound of claim 21, wherein is dioxane, diazinane, morpholine, or thiomorpholine.

27. 27. The compound of claim 26, wherein the dioxane is 1,4-dioxane and the diazinane is 1,2-diazinane or 1,4-diazinane. 【Request Item 28】 【Chemistry 81】 but, 【Chemistry 82】 28. The compound of claim 26 or 27, wherein: 【Request Item 29】 【Chemistry 83】 21. The compound of claim 20, wherein is azepane. 【Request Item 30】 【Chemistry 84】 but, 【Chemical 85】 30. The compound of claim 29, wherein: 【Request Item 31】 【Chemistry 86】 The compound of any one of claims 1 to 30, wherein is unsubstituted. 【Request Item 32】 【Chemistry 87】 One or more R ３ and each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ are independently H, unsubstituted alkyl, or cycloalkyl; or two R on adjacent atoms of a heterocycloalkyl group. ３ form an aromatic ring together with the atom to which they are attached; or two R on the same carbon atom of the heterocycloalkyl group. ３ and the carbon atom to which they are attached form a C=O group.

33. Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R １ or two R on the same carbon atom of a heterocycloalkyl group; ３ together with the carbon atom to which they are attached form a C=O group.

34. Two R on adjacent atoms of the heterocycloalkyl group ３ 34. The compound of claim 33, wherein together with the atoms to which they are attached form an aromatic ring. 【Request Item 35】 【Transformation 88】 but, 【Chemical 89】 and [Chemical 90] but, 【Chemistry 91】 indicates the point of attachment to r is an integer from 1 to 7, optionally from 1 to 3; 35. The compound of claim 33 or 34, wherein s is an integer from 1 to 9, optionally from 1 to 4. 【Request Item 36】 【Chemistry 92】 but, 【Chemistry 93】 36. The compound of claim 35, wherein: 【Request Item 37】 【Chemistry 94】 but, 【Chemical 95】 37. The compound of claim 36, wherein: 【Request Item 38】 【Chemistry 96】 but, 【Chemistry 97】 38. The compound of claim 37, wherein: 【Request Item 39】 【Chemistry 98】 but, 【Chem.99】 and 【Chemistry 100】 but, 【Chemistry 101】 indicates the point of attachment to 35. The compound of claim 33 or 34, wherein s is an integer from 1 to 9, optionally from 1 to 4. 【Request Item 40】 【Chemistry 102】 but, 【Chemistry 103】 40. The compound of claim 39, wherein: 【Request Item 41】 【Chemistry 104】 but, 【Chemistry 105】 41. The compound of claim 40, wherein: 【Request Item 42】 【Chemistry 106】 but, 【Chemistry 107】 and 【Chemistry 108】 but, 【Chemistry 109】 indicates the point of attachment to R ３ is unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NR ２ C(O)R １ 23. The compound of claim 22, wherein: 【Request Item 43】 【Chemistry 110】 but, 【Chemistry 111】 and R ３ is unsubstituted alkyl, aryl, benzyl, or —NR ２ C(O)R １ 43. The compound of claim 42, wherein: 【Request Item 44】 【Chemistry 112】 but, 【Chemistry 113】 and R ３ is unsubstituted alkyl, benzyl, or —NR ２ C(O)R １ 44. The compound of claim 43, wherein:

45. R ３ 45. The compound of claim 44, wherein is unsubstituted alkyl or benzyl. 【Request Item 46】 【Chemistry 114】 but, 【Chemical 115】 and R ３ 21. The compound of claim 20, wherein is unsubstituted alkyl, aryl, benzyl, -NHC(O)Me, or -NHC(O)Ph. 【Request Item 47】 【Chemistry 116】 but, 【Chemistry 117】 and R ３ 47. The compound of claim 46, wherein is unsubstituted alkyl, aryl, -NHC(O)Me, or -NHC(O)Ph. 【Request Item 48】 【Chemistry 118】 but, 【Chemical 119】 and 48. The compound of any one of claims 1 to 47, wherein R is F or alkyl. 【Request Item 49】 【Chemistry 120】 but, 【Chemistry 121】 and 49. The compound of claim 48, wherein R is F. 【Request Item 50】 【Chemistry 122】 but, 【Chemical 123】 50. The compound of claim 49, wherein: 【Request Item 51】 【Chemistry 124】 but, 【Chemistry 125】 51. The compound of claim 50, wherein: 【Request Item 52】 【Chemistry 126】 but, 【Chemistry 127】 52. The compound of claim 51, wherein: 【Request Item 53】 【Chemistry 128】 but, 【Chemistry 129】 and R ３ is unsubstituted alkyl, benzyl, —NHC(O)Ph, or —NHC(O)Me; R ３ａ is unsubstituted alkyl; R ３ｂ 53. The compound of claim 52, wherein is aryl. 【Request Item 54】 【Chemistry 130】 but, 【Chemistry 131】 and R ３ is unsubstituted alkyl, aryl, benzyl, or —NHC(O)Ph; R ３ａ is unsubstituted alkyl; R ３ｂ 53. The compound of claim 51 or 52, wherein is aryl or unsubstituted alkyl. 【Request Item 55】 【Chemistry 132】 but, 【Chemistry 133】 and R ３ is unsubstituted alkyl, benzyl, or —NHC(O)Ph; R ３ａ is unsubstituted alkyl; R ３ｂ 55. The compound of claim 54, wherein is aryl. 【Request Item 56】 【Chemistry 134】 but, 【Chemistry 135】 The compound according to any one of claims 43 and 48 to 52, 【Request Item 57】 【Chemistry 136】 57. The compound of any one of claims 1 to 56, wherein contains one heteroatom. 【Request Item 58】 【Chemistry 137】 57. The compound of any one of claims 1 to 56, wherein contains two heteroatoms. 【Request Item 59】 【Chemistry 138】 The compound of any one of claims 1 to 58, wherein is a 6-membered monocyclic heteroaryl group. 【Request Item 60】 【Chemistry 139】 60. The compound of claim 59, wherein is a pyridine group. 【Request Item 61】 【Chemistry 140】 but, 【Chemistry 141】 and 【Chemistry 142】 but, 【Chemistry 143】 61. The compound of claim 60, wherein the compound indicates a point of attachment to 【Request Item 62】 【Chemistry 144】 The compound of any one of claims 1 to 58, wherein is a 10-membered fused bicyclic heteroaryl group. 【Request Item 63】 【Chemistry 145】 63. The compound of claim 62, wherein is a quinoline group or an isoquinoline group. 【Request Item 64】 【Chemistry 146】 but, 【Chemistry 147】 and 【Chemistry 148】 but, 【Chemistry 149】 64. The compound of claim 63, wherein the compound indicates a point of attachment to 【Request Item 65】 【Chemistry 150】 65. The compound of any one of claims 1 to 64, wherein is unsubstituted. 【Request Item 66】 【Chemistry 151】 One or more R ３ and each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ 65. The compound of any of claims 1-64, wherein is independently H, unsubstituted alkyl, or cycloalkyl.

67. Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, hydroxy, OR １ , aryl, benzyl, or —NHC(O)R １ 67. The compound of claim 66, wherein:

68. Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R １ 68. The compound of claim 67, wherein:

69. Each R １ is independently unsubstituted alkyl or aryl, and each R ２ 69. The compound of any of claims 1-68, wherein is independently H or unsubstituted alkyl. 【Request Item 70】 【Chemistry 152】 but, 【Chemistry 153】 and 【Chemistry 154】 but, 【Chemistry 155】 and q is an integer from 1 to 4, optionally 1 to 3. 【Request Item 71】 【Chemistry 156】 but, 【Chemistry 157】 and R ３ is aryl, haloalkyl, hydroxy, OR １ , or -NR ２ C(O)R １ 71. The compound of claim 70, wherein: 【Request Item 72】 【Chemistry 158】 but, 【Chemistry 159】 72. The compound of claim 70 or 71, wherein:

73. R ３ is aryl, haloalkyl, or —NR ２ C(O)R １ The compound according to any one of claims 70 to 72,

74. R ３ is aryl or —NR ２ C(O)R １ 74. The compound of claim 73, wherein:

75. R ３ 74. The compound of claim 73, wherein is aryl or haloalkyl. 【Request Item 76】 【Chemistry 160】 but, 【Chemistry 161】 The compound according to any one of claims 1 to 56, 【Request Item 77】 【Chemistry 162】 but, 【Chemistry 163】 77. The compound of claim 76, wherein: 【Request Item 78】 【Chemistry 164】 but, 【Chemistry 165】 78. The compound of claim 77, wherein:

79. 79. The compound of any one of claims 1 to 78, which is a compound of formula (Ia):

80. 79. The compound of any one of claims 1 to 78, which is a compound of formula (Ib): 【Request Item 81】 【Table 1】 2. The compound of claim 1 selected from: 【Request Item 82】 【Table 2】 82. The compound of claim 81, selected from: 【Request Item 83】 【Table 3】 82. The compound of claim 81, selected from: 【Request Item 84】 【Table 4】 82. The compound of claim 81, selected from: 【Request Item 85】 【Table 5】 82. The compound of claim 81, selected from: 【Request Item 86】 【Table 6】 82. The compound of claim 81, selected from: 【Request Item 87】 【Table 7】 87. The compound of claim 86, selected from:

88. A pharmaceutical composition comprising a compound according to any one of claims 1 to 87.

89. A compound according to any one of claims 1 to 87, or a pharmaceutical composition according to claim 88, for use in medicine.

90. 90. A compound according to any of claims 1 to 87, or a pharmaceutical composition according to claim 88, for use in the treatment of an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, an infectious disease, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes related condition, an arthritis related condition, a wound or burn, or cancer.

91. 1. A compound of formula (I): for use in a method of treating an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a gastrointestinal disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a skin disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn in a subject in need thereof. 【Chemistry 166】 (In the formula, y is 0, 1, or 2; X １ and X ２ are each independently O or S; L is H, —C(O)alkyl, or —CH ２ (O)COR'; 【Chemistry 167】 teeth, 【Chemical 168】 and During the ceremony, Each Z is independently C=O, CH ２ , or CH(C １－２ alkyl); Y is S, O, or NH; Each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH ２ , —NHR′, or —NR′ ２ and each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; 【Chemistry 169】 teeth, 【Chemistry 170】 indicates the point of attachment to 【Chemistry 171】 teeth, 【Chemistry 172】 indicates the point of attachment to 【Chemistry 173】 teeth, (i) 【Chemistry 174】 (In the formula, 【Chemistry 175】 is a heterocycloalkyl group) or (ii) 【Chemistry 176】 (In the formula, 【Chemistry 177】 is unsubstituted or is substituted with one or more R ３ a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R ３ The substituents other than 【Chemistry 178】 not present in each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ are independently H, unsubstituted alkyl, or cycloalkyl. is a heterocyclic group selected from 【Chemistry 179】 but, 【Transformation 180】 and Z is CH ２ or C=O and n=0; 【Chemistry 181】 but, 【Chemistry 182】 and 【Chemistry 183】 is one or more R ３ is a 6-membered monocyclic heteroaryl group substituted with R ３ is hydroxy or O(alkyl), the substitution is in the meta or para position relative to the heteroatom of the heteroaryl group. Compound.

92. 92. The compound for use according to claim 91, wherein the disease or condition is an inflammatory disease or condition, an autoinflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, a cardiovascular disease or condition, a renal disease or condition, a disease or condition of the central nervous system (CNS), a disease or condition of the endocrine system, a metabolic disease or condition, a liver disease or condition, an eye disease or condition, a lymphatic system disease or condition, a psychiatric disease or condition, graft versus host disease or condition, allodynia, pain, a diabetes-related condition, an arthritis-related condition, or a wound or burn.

93. The disease or condition may be cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), pyogenic aseptic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), hyperimmunoglobulin D-related periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Schnitzler syndrome, Sweet's syndrome, or Becker's syndrome.

93. The compound for use according to claim 91 or 92, wherein the disease to be treated is selected from the group consisting of: Chronic Kidney Disease, Antisynthetase Syndrome, Interleukin-1 Receptor Antagonist Deficiency (DIRA), A20 Haploinsufficiency (HA20), Lupus Nephritis, Pulmonary Arterial Hypertension, Idiopathic Pulmonary Fibrosis, Amyotrophic Lateral Sclerosis, Rheumatoid Arthritis, Gout, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Spinal Cord Injury, Atherosclerosis, Heart Failure, Dilated Cardiomyopathy (DCM), Non-Alcoholic Steatohepatitis (NASH), Cirrhosis, Inflammatory Bowel Disease (IBD), Ulcerative Colitis (UC), or Crohn's Disease.

94. A method for degrading NEK7 protein, comprising combining said protein with a compound of formula (I): 【Chemistry 184】 (In the formula, y is 0, 1, or 2; X １ and X ２ are each independently O or S; L is H, —C(O)alkyl, or —CH ２ (O)COR'; 【Chemistry 185】 teeth, 【Chemistry 186】 and During the ceremony, Each Z is independently C=O, CH ２ , or CH(C １－２ alkyl); Y is S, O, or NH; Each R is independently halogen, alkyl, haloalkyl, hydroxy, alkoxy, -NH ２ , —NHR′, or —NR′ ２ and each R' is independently alkyl or aryl; each n is independently 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; 【Chemistry 187】 teeth, 【Chemical 188】 indicates the point of attachment to 【Chemical 189】 teeth, 【Chemistry 190】 indicates the point of attachment to 【Chemistry 191】 is a heterocyclic group) with a compound of formula (I). [Request Item 95] [Chemistry 192] but, (i) 【Chemistry 193】 (In the formula, 【Chemistry 194】 is a heterocycloalkyl group) or (ii) 【Chemistry 195】 (In the formula, 【Chemistry 196】 is unsubstituted or is substituted with one or more R ３ a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R ３ The substituents other than 【Chemistry 197】 not present in each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ are independently H, unsubstituted alkyl, or cycloalkyl.

95. The method of claim 94, wherein: [Request Item 96] [Chemistry 198] But the connection point 【Chemistry 199】 96. The compound for use according to any one of claims 91 to 93, or the method according to claim 94 or 95, wherein R is a heterocycloalkyl group having a heteroatom adjacent to R.

97. (i) 【Chemistry 200】 but, 【Chemical Engineering 201】 and Z is CH ２ and n=0; 【Chemical Engineering 202】 but, 【Chemical 203】 If (a) 【Chemical 204】 One or more R ３ or (b) y is 2; (ii) 【Chemical 205】 but, 【Chemical 206】 and Z is CH ２ and n=0; 【Chemical 207】 but, 【Chemical 208】 and 【Chemical Engineering 209】 is a 6-membered monocyclic heteroaryl group having two heteroatoms, the two heteroatoms are not adjacent to each other, (iii) 【Chemical 210】 but, 【Chemistry 211】 and Z is CH ２ and n=0; 【Chemical Engineering 212】 but, 【Chemistry 213】 and 【Chemical 214】 is one or more R ３ is a 6-membered monocyclic heteroaryl group substituted with (a) 【Chemical 215】 Through it 【Chemical 216】 the carbon atom adjacent to the carbon atom bonded to (b) R ３ is alkyl or O(alkyl), 【Chemical 217】 is monosubstituted; (c) R ３ is O(alkyl), said substitution is in the meta or para position relative to the heteroatom of said heteroaryl group; (d) R ３ is aryl or —NR ２ C(O)R １ wherein the substitution is in the meta position relative to the heteroatom of the heteroaryl group; (iv) 【Chemical 218】 but, 【Chemical 219】 Z is C=O and n=0; 【Chemical 220】 but, 【Chemistry 221】 and 【Chemistry 222】 is one or more R ３ When R is a 6-membered monocyclic heteroaryl group substituted with ３ is hydroxy, the substitution is at the meta or para position relative to the heteroatom of the heteroaryl group; (v) 【Chemistry 223】 but, 【Chemistry 224】 and Z is CH ２ and n=0; 【Chemical 225】 but, 【Chemistry 226】 and 【Chemistry 227】 is one or more R ３ is a 10-membered fused bicyclic heteroaryl group substituted with Each R ３ but, 【Chemistry 228】 present in the ring containing the point of attachment to Each R ３ is in the ortho or meta position relative to the heteroatom of the heteroaryl group; R ３ is not Cl, methyl, iPr, cyclopropane, unsubstituted phenyl, hydroxy, or OMe; R ３ When is OEt, R ３ is ortho to the heteroatom of the heteroaryl group; R ３ NR ２ If COMe, then R ３ 97. The compound or method for use of any of claims 91-96, wherein is in the meta position relative to the heteroatom of the heteroaryl group. 【Request Item 98】 【Chemistry 229】 but, 【Chemistry 230】 and Z is C=O or CH ２ and n=0; 【Chemistry 231】 but, 【Chemistry 232】 and 【Chemical 233】 is one or more R ３ When R is a 6-membered monocyclic heteroaryl group substituted with ３ 98. The compound or method for use of claim 97, wherein when is hydroxy or O(alkyl), the substitution is in the meta or para position relative to the heteroatom of the heteroaryl group.

99. (i) 【Chemistry 234】 but, 【Chemical 235】 and n=0; 【Chemistry 236】 but, 【Chemistry 237】 When Z is CH(C １－２ alkyl) or C═O; (ii) 【Chemical 238】 but, 【Chemistry 239】 and Z is CH ２ and 【Chemistry 240】 but, 【Chemistry 241】 99. The compound or method for use of claim 97 or 98, wherein when

100. Z is CH ２ or CH(C １－２ 100. The compound or method for use according to any of claims 91 to 99, wherein the aryl group is aryl, ... 【Request Item 101】 【Chemistry 242】 but, 【Chemistry 243】 101. The compound or method for use according to any of claims 91 to 100, wherein 【Request Item 102】 【Chemistry 244】 but, 【Chemistry 245】 102. The compound or method for use according to any one of claims 91 to 101, wherein 【Request Item 103】 【Chemistry 246】 but, 【Chemistry 247】 103. The compound or method for use according to claim 102, wherein 【Request Item 104】 【Chemistry 248】 but, 【Chemistry 249】 102. The compound or method for use according to any one of claims 91 to 101, wherein 【Request Item 105】 【Chemistry 250】 but, 【Chemistry 251】 105. The compound or method for use according to claim 104, wherein: 【Request Item 106】 【Chemistry 252】 but, 【Chemistry 253】 101. The compound or method for use according to any of claims 91 to 100, wherein 【Request Item 107】 【Chemistry 254】 but, 【Chemistry 255】 107. The compound or method for use according to claim 106, wherein: [Request Item 108] [Chemistry 256] but, 【Chemistry 257】 101. The compound or method for use according to any of claims 91 to 100, wherein 【Request Item 109】 【Chemistry 258】 but, 【Chemistry 259】 109. The compound or method for use according to claim 108, wherein 【Request Item 110】 【Chemistry 260】 but, 【Chemistry 261】 110. The compound or method for use of claim 109, wherein 【Request Item 111】 【Chemistry 262】 but, 【Chemical 263】 109. The compound or method for use according to claim 108, wherein 【Request Item 112】 【Chemistry 264】 but, 【Chemical 265】 102. The compound or method for use according to claim 101, wherein: 【Request Item 113】 【Chemistry 266】 113. The compound or method for use according to any of claims 91 to 112, wherein contains one heteroatom. 【Request Item 114】 【Chemistry 267】 113. The compound or method for use according to any of claims 91 to 112, wherein contains two heteroatoms. 【Request Item 115】 【Chemistry 268】 but, 【Chemistry 269】 and 【Chemistry 270】 115. The compound or method for use according to any of claims 91 to 114, wherein is a heterocycloalkyl group. 【Request Item 116】 【Chemistry 271】 116. The compound or method for use according to any one of claims 91 to 93 and 95 to 115, wherein is a 5 to 10 membered heterocycloalkyl group. 【Request Item 117】 【Chemistry 272】 117. The compound or method for use of claim 116, wherein is a 5- or 6-membered heterocycloalkyl group. 【Request Item 118】 【Chemistry 273】 118. The compound or method for use of claim 117, wherein is a pyrrolidine group, a piperidine group, or an oxane group. 【Request Item 119】 【Chemistry 274】 but, 【Chemistry 275】 and 【Chemistry 276】 but, 【Chemistry 277】 119. The compound or method for use of claim 118, wherein the compound or method indicates a point of attachment to [Request Item 120] [Chemistry 278] but, 【Chemistry 279】 120. The compound or method for use of claim 119, wherein: 【Request Item 121】 【Chemistry 280】 but, 【Chemistry 281】 121. The compound or method for use of claim 120, wherein 【Request Item 122】 【Chemistry 282】 118. The compound or method for use of claim 117, wherein is dioxane, diazinan, morpholine, or thiomorpholine.

123. 123. The compound or method for use according to claim 122, wherein the dioxane is 1,4-dioxane and the diazinane is 1,2-diazinane or 1,4-diazinane. 【Request Item 124】 【Chemistry 283】 but, 【Chemistry 284】 124. The compound or method for use according to claim 122 or 123, wherein 【Request Item 125】 【Chemistry 285】 125. The compound or method for use of claim 124, wherein is azepane. 【Request Item 126】 【Chemistry 286】 but, 【Chemistry 287】 117. The compound or method for use of claim 116, wherein: 【Request Item 127】 【Chemistry 288】 127. The compound or method for use according to any of claims 91 to 126, wherein is unsubstituted. [Request Item 128] [Chemistry 289] One or more R ３ and each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ are independently H, unsubstituted alkyl, or cycloalkyl; or two R on adjacent atoms of a heterocycloalkyl group. ３ form an aromatic ring together with the atom to which they are attached; or two R on the same carbon atom of the heterocycloalkyl group. ３ together with the carbon atom to which they are attached form a C=O group.

129. Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R １ or two R on the same carbon atom of a heterocycloalkyl group; ３ together with the carbon atom to which they are attached form a C=O group.

130. Two R on adjacent atoms of the heterocycloalkyl group ３ 130. The compound or method for use of claim 128 or 129, wherein, together with the atoms to which they are attached, form an aromatic ring. 【Request Item 131】 【Chemistry 290】 but, 【Chemistry 291】 and 【Chemistry 292】 but, 【Chemistry 293】 indicates the point of attachment to r is an integer from 1 to 7, optionally from 1 to 3; 130. The compound or method for use of claim 128 or 129, wherein s is an integer from 1 to 9, optionally from 1 to 4. 【Request Item 132】 【Chemistry 294】 but, 【Chemistry 295】 132. The compound or method for use of claim 131, wherein: 【Request Item 133】 【Chemistry 296】 but, 【Chemistry 297】 133. The compound of claim 132, wherein: 【Request Item 134】 【Chemistry 298】 but, 【Chemistry 299】 and 【Chemical 300】 but, 【Chemical 301】 134. The compound or method for use of claim 133, wherein the compound or method indicates a point of attachment to 【Request Item 135】 【Chemical 302】 but, 【Chemical 303】 and 【Chemical 304】 but, 【Chemical 305】 indicates the point of attachment to 119. The compound of claim 118, wherein s is an integer from 1 to 9, optionally from 1 to 4. 【Request Item 136】 【Chemistry 306】 but, 【Chemical 307】 136. The compound of claim 135, wherein: 【Request Item 137】 【Chemistry 308】 but, 【Chemical 309】 137. The compound of claim 136, wherein: 【Request Item 138】 【Chemistry 310】 but, 【Chemical 311】 and 【Chemical 312】 but, 【Chemistry 313】 indicates the point of attachment to R ３ is unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NR ２ C(O)R １ 118. The compound of claim 117, wherein: 【Request Item 139】 【Chemistry 314】 but, 【Chemical Industry 315】 and R ３ is unsubstituted alkyl, aryl, benzyl, or —NR ２ C(O)R １ 139. The compound of claim 138, wherein: 【Request Item 140】 【Chemistry 316】 but, 【Chemical 317】 and R ３ is unsubstituted alkyl, benzyl, or —NR ２ C(O)R １ 140. The compound or method for use of claim 139, wherein

141. R ３ 141. The compound or method for use of claim 140, wherein is unsubstituted alkyl or benzyl. 【Request Item 142】 【Chemistry 318】 but, 【Chemical 319】 and R ３ 140. The compound or method for use of claim 139, wherein is unsubstituted alkyl, aryl, benzyl, -NHC(O)Me, or -NHC(O)Ph. 【Request Item 143】 【Chemistry 320】 but, 【Chemistry 321】 and R ３ 143. The compound or method for use of claim 142, wherein is unsubstituted alkyl, aryl, -NHC(O)Me, or -NHC(O)Ph. 【Request Item 144】 【Chemistry 322】 but, 【Chemical 323】 and 144. The compound or method for use according to any of claims 91 to 143, wherein R is F or alkyl. 【Request Item 145】 【Chemistry 324】 but, 【Chemical 325】 and 145. The compound or method for use of claim 144, wherein R is F. 【Request Item 146】 【Chemistry 326】 but, 【Chemistry 327】 146. The compound or method for use of claim 145, wherein: 【Request Item 147】 【Chemistry 328】 but, 【Chemistry 329】 147. The compound or method for use of claim 146, wherein: 【Request Item 148】 【Chemistry 330】 but, 【Chemistry 331】 148. The compound or method for use of claim 147, wherein: 【Request Item 149】 【Chemistry 332】 but, 【Chemical 333】 and R ３ is unsubstituted alkyl, benzyl, —NHC(O)Ph, or —NHC(O)Me; R ３ａ is unsubstituted alkyl; R ３ｂ 149. The compound or method for use of claim 148, wherein is aryl. [Request Item 150] [Chemistry 334] but, 【Chemistry 335】 and R ３ is unsubstituted alkyl, aryl, benzyl, or —NHC(O)Ph; R ３ａ is unsubstituted alkyl; R ３ｂ 149. The compound or method for use of claim 147 or 148, wherein is aryl or unsubstituted alkyl. 【Request Item 151】 【Chemistry 336】 but, 【Chemistry 337】 and R ３ is unsubstituted alkyl, benzyl, or —NHC(O)Ph; R ３ａ is unsubstituted alkyl; R ３ｂ 151. The compound or method for use of claim 150, wherein is aryl. 【Request Item 152】 【Chemistry 338】 but, 【Chemistry 339】 149. The compound or method for use according to any one of claims 139 and 144 to 148, wherein 【Request Item 153】 【Chemistry 340】 but, 【Chemistry 341】 and 【Chemistry 342】 is unsubstituted or is substituted with one or more R ３ a 6-membered monocyclic heteroaryl group or a 10-membered fused bicyclic heteroaryl group substituted with one or more of R ３ Substituents other than 【Transformation 343】 not present in each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ 115. The compound or method for use of any of claims 91-114, wherein is independently H, unsubstituted alkyl, or cycloalkyl. 【Request Item 154】 【Chemistry 344】 154. The compound or method for use according to any of claims 91 to 153, wherein is a 6-membered monocyclic heteroaryl group. 【Request Item 155】 【Chemistry 345】 155. The compound or method for use of claim 154, wherein is a pyridine group. 【Request Item 156】 【Chemistry 346】 but, 【Transformation 347】 and 【Transformation 348】 but, 【Chemistry 349】 156. The compound or method for use of claim 155, wherein the compound or method indicates a point of attachment to 【Request Item 157】 【Chemicals 350】 154. The compound or method for use according to any of claims 91 to 153, wherein is a 10-membered fused bicyclic heteroaryl group. 【Request Item 158】 【Chemistry 351】 158. The compound or method for use of claim 157, wherein is a quinoline group or an isoquinoline group. 【Request Item 159】 【Chemistry 352】 but, 【Chemistry 353】 and 【Chemistry 354】 but, 【Chemical 355】 159. The compound or method for use of claim 158, wherein the compound or method indicates a point of attachment to [Request Item 160] [Chemistry 356] 160. The compound or method for use according to any of claims 91 to 159, wherein is unsubstituted. 【Request Item 161】 【Chemistry 357】 One or more R ３ and each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, hydroxy, OR １ , aryl, benzyl, —C(O)R １ , or -NR ２ C(O)R １ and each R １ is independently unsubstituted alkyl, cycloalkyl, or aryl, and each R ２ 160. The compound or method for use of any of claims 91-159, wherein is independently H, unsubstituted alkyl, or cycloalkyl.

162. Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, hydroxy, OR １ , aryl, benzyl, or —NHC(O)R １ 162. The compound or method for use of claim 161, wherein:

163. Each R ３ are independently halogen, unsubstituted alkyl, haloalkyl, aryl, benzyl, or —NHC(O)R １ 163. The compound or method for use of claim 162, wherein:

164. Each R １ is independently unsubstituted alkyl or aryl, and each R ２ 164. The compound or method for use of any of claims 91-163, wherein is independently H or unsubstituted alkyl. [Request Item 165] [Chemistry 358] but, 【Chemistry 359】 and 【Chemical 360】 but, 【Chemical 361】 165. The compound or method for use of any of claims 161-164, wherein q represents a point of attachment to and q is an integer from 1 to 4, optionally 1 to 3. 【Request Item 166】 【Chemistry 362】 but, 【Chemical 363】 and R ３ is aryl, haloalkyl, hydroxy, OR １ , or -NR ２ C(O)R １ 166. The compound or method for use of claim 165, wherein: 【Request Item 167】 【Chemistry 364】 but, 【Chemical 365】 167. The compound or method for use of claim 166, wherein:

168. R ３ is aryl, haloalkyl, or —NR ２ C(O)R １ 168. The compound or method for use according to any one of claims 165 to 167, wherein

169. R ３ is aryl or —NR ２ C(O)R １ 169. The compound or method for use of claim 168, wherein:

170. R ３ 169. The compound or method for use of claim 168, wherein is aryl or haloalkyl. 【Request Item 171】 【Chemistry 366】 but, 【Chemical 367】 171. The compound or method for use according to any one of claims 91 to 170, wherein 【Request Item 172】 【Chemistry 368】 but, 【Chemical 369】 172. The compound or method for use of claim 171, wherein: 【Request Item 173】 【Chemistry 370】 but, 【Chemistry 371】 and 【Chemistry 372】 but, 【Chemistry 373】 indicates the point of attachment to R ３ is aryl, haloalkyl, or —NR ２ C(O)R １ 172. The compound or method for use of claim 171, wherein: 【Request Item 174】 【Chemistry 374】 but, 【Chemistry 375】 and R ３ is aryl or —NR ２ C(O)R １ 174. The compound or method for use of claim 173, wherein: [Request Item 175] [Chemistry 376] but, 【Chemical 377】 172. The compound or method for use of claim 171, wherein: 【Request Item 176】 【Chemistry 378】 but, 【Chemistry 379】 176. The compound or method for use of claim 175, wherein:

177. 177. A compound according to any one of claims 1 to 90, or a compound or method for use according to any one of claims 91 to 176, wherein L is hydrogen.

178. X １ and X ２ is O.

179. X １ is O and X ２ is S.

180. X １ is S and X ２ is O.

181. X １ and X ２ is S.

182. 182. The compound, compound for use, or method of any one of claims 1 to 181, wherein Y is S.

183. Z is C=O, CH ２ or CHMe.

184. Z is CH ２ or CHMe.

185. Z is CH ２ 185. The compound, compound for use, or method of claim 184, wherein:

186. 186. The compound, compound for use, or method of any of claims 1-185, wherein each R is independently unsubstituted alkyl or halogen.

187. 187. The compound, compound for use, or method of claim 186, wherein each R is independently Me or F.

188. 188. A compound, compound for use, or method according to any preceding claim, wherein n is 0 or 1.

189. 189. The compound, compound for use, or method of claim 188, wherein n is 0.

190. 190. The compound, compound for use, or method of any one of claims 1 to 189, wherein m is 0.

191. 191. A compound, compound for use, or method according to any preceding claim, wherein y=1.

192. The compound Table 8 95. The compound for use according to claim 91 or the method according to claim 94, selected from: 【Request Item 193】 【Table 9】 193. The compound or method for use according to claim 192, selected from: [Request Item 194] [Table 10] 193. The compound or method for use according to claim 192, selected from: 【Request Item 195】 【Table 11】 193. The compound or method for use according to claim 192, selected from: 【Request Item 196】 【Table 12】 193. The compound or method for use according to claim 192, selected from: 【Request Item 197】 【Table 13】 193. The compound or method for use according to claim 192, selected from: 【Request Item 198】 【Table 14】 198. The compound or method for use of claim 197, selected from:

199. 200. The compound or method for use according to any of claims 91 to 198, wherein the compound is formulated as a pharmaceutical composition.

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