Pyridinyl-substituted oxoisoindoline compounds for cancer treatment

Abstract

Formula (I): TIFF2024515545000156.tif39153, wherein R1, R2, R3, R4, Z, m, n, p, and q are defined in this disclosure, or a salt thereof. Also disclosed are methods of using the compounds and pharmaceutical compositions comprising the compounds to inhibit Helios protein. These compounds are useful for treating viral infections and proliferative diseases (e.g., cancer).

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 170,865, filed April 5, 2021, and U.S. Provisional Application No. 63 / 189,318, filed May 17, 2021, both of which are incorporated by reference in their entireties.

[0002] (explanation) The present invention generally relates to pyridinyl-substituted oxoisoindoline compounds that inhibit the Helios protein. The present invention provides pyridinyl-substituted oxoisoindoline compounds, compositions containing the compounds, and methods of using them. The present invention further relates to pharmaceutical compositions containing at least one compound according to the present invention that are useful for treating proliferative diseases (e.g., cancer) and viral infections. [Background technology]

[0003] Regulatory T cells (Tregs) play an essential role in maintaining self-tolerance and immune homeostasis by suppressing and maintaining immune unresponsiveness against intense immune and inflammatory responses. By maintaining a phenotype that exhibits a stable suppressive effect of immune unresponsiveness, Tregs suppress excessive immune responses and prevent or alleviate autoimmune diseases. Numerous reports have demonstrated the presence of Tregs in human tumor tissues. Studies have shown a clear negative correlation between the number of Tregs and the infiltration and survival rate of T cells in tumors (Curiel et al., 2004, Nat. Med. 10:942-949;Viguier et al., 2004, J Immuno. 1173:1444-1453;Beyer et al., 2006, Blood 108:804-811;Zou et al., 2006, Nat. Rev. Immunol. 6:295-307), implying that Tregs potentially play an important role in inhibiting effective antitumor immunity. Previous evidence has shown that Foxp3+CD25+CD4+Tregs predominantly infiltrate tumors and apparently inhibit immune responses against tumor cells in rodents and humans. Once activated by a specific antigen, Tregs behave in an antigen-nonspecific manner in vitro, suppressing killer T cells by overlooking them (Takahashi et al., 1998, Int Immunol. 10:1969-80;Thornton et al., 1998, J Exp. Med. 188:287-96). Foxp3+CD25+CD4+Tregs can apparently suppress a broad range of antitumor immune responses, including CD4+helper T cells, CD8+T cells, natural killer cells, and natural killer T cells (Tanaka et al., 2017, Cell Research 27:109-118). Depletion of CD25+CD4+Tregs in tumors alters the cytokine environment in the tumor area, resulting in regression of established tumors (Yu et al., 2005, J Exp Med. 201:779-91).Moreover, transplantation of CD4+ T cells deficient in Tregs significantly increases antitumor immune responses compared with transplantation of Tregs containing T cells (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrated Tregs activated by either tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific antitumor immune responses. This means that modulating the activity of key factors to control Treg differentiation is a promising strategy for treating certain diseases, such as cancer and viral infections.

[0004] FoxP3+CD4 Tregs are highly stable. Research is still ongoing to understand this genetic mechanism to see if the phenotype is stable even after the spread of inflammation, infection, or autoimmune disease. Transcription factors (TFs) involved in maintaining the stable immunosuppressive phenotype of Tregs can be used in this study. The Helios (IKZF2) gene, a member of the Ikaros family of TFs, differs from other Ikaros family members on the basis of its selective expression by negatively selected thymocytes, as well as CD4 and CD8 T cells of the suppressive lineage. Helios is expressed by two regulatory T cell lineages, FoxP3+CD4+ and Ly49+CD8+ Tregs, which are essential lineages for maintaining self-tolerance (Kim et al., 2015, Science 350:334-339;Sebastian et al., 2016, J Immunol 196:144-155). Interestingly, recent studies have suggested that Helios is dispensable for Treg activity in the steady state, but is essential for regulating the genetic program of FoxP3+CD4 Tregs during inflammation to maintain a stable phenotype and enhance suppressive function (Thornton et al., 2010, J Immunol. 184:3433-3441; Kim et al., 2015). Expression of Helios was shown to be crucial for Tregs to maintain an immunosuppressive and immunounresponsive phenotype against strong inflammatory responses. Activating the IL-2Rα-STAT5 pathway was shown to be a key associated factor for Treg survival and stability (Kim et al., 2015). Helios exerts a major lymphocyte-intrinsic inhibitory activity, and thus plays an essential role in maintaining the phenotype of FoxP3+CD4 Tregs to prevent autoimmune diseases in the presence of highly activated autoreactive T cells from Scurfy mice lacking the forkhead domain of FoxP3. Bone marrow chimeras reconstituted with Helios- / - / Scurfy bone marrow (BM) (non-Helios+) / + / Scurfy BM cells rapidly established autoimmunity ( Kim et al., 2015 ).These results indicate that Helios is important for the selection, differentiation, and functional expression of autoreactive T cells. Immunosuppression by Tregs can impede antitumor immune responses. Selective deficiency of Helios in FoxP3+CD4 Tregs leads to Treg instability and the transformation of intratumoral CD4 Tregs into effector T cells (Teff). Intratumoral Treg instability can lead to Treg conversion and reduced suppressive activity of Tregs, resulting in increased numbers of Teff cells in the tumor. Furthermore, poor IL-2 response was observed in intratumoral Tregs lacking Helios. This may result in a reduced number of activated Tregs and also contribute to increased intratumoral Teff activity. Interactions between tumor cells and infiltrating immune cells promote the secretion of inflammatory mediators (such as TNF-α, IL-6, IL-17, IL-1, and TGF-β) to form a local inflammatory environment (Kim et al., 2015).

[0005] Lineage instability of Helios-deficient Tregs is also caused by reduced FoxP3 expression, resulting in the production of inflammatory cytokines and effector T cells. The transformation of Helios-deficient Tregs into effector cells within the tumor tissue microenvironment is associated with increased expression of genes governing the Teff phenotype (Yates et al., 2018, PNAS, 2018, 115:2162-2167). Helios deficiency results in an unstable phenotype only within the tumor microenvironment (TME), but not in peripheral lymphoid organs (Nakagawa et al., 2016, PNAS 113:6248-6253). In chronically inflamed TME, Helios deficiency in Tregs increases helper T cells for TFs and effector cytokines, and can significantly alleviate the suppressive gene program for helper T cell differentiation. A subpopulation of Tregs with high affinity for self-antigens showed increased GITR / PD-1 expression and increased responsiveness to self-antigens, which are evident in the genetic alterations of these Helios-deficient Tregs, which combined promote the conversion of Tregs to Teffs in the TME and increase T cell receptor (TCR) engagement and co-stimulatory receptor expression by Tregs, suggesting that the gene expression alterations that are a key feature of Treg conversion vary depending on the immune environment (Yates et al., 2018).

[0006] Decreased Helios expression in FoxP3+CD4 Tregs may convert memory Tregs into Teff cells expressing tumor antigen-specific autoreactive T cell receptors. In chronic inflammatory conditions due to tumor growth, the converted Treg characteristics may be selectively induced. Helios-deficient Tregs express TCRs with high affinity for self-peptides / MHC, which may promote stable activation of Tregs in the TME (Yates et al., 2018). Given the increased autoreactivity of TCRs in CD4 Tregs compared with conventional T cells, the conversion of Tregs may produce highly potent effector CD4 T cells, along with suppressing the suppressive effect mediated by Tregs in the TME. Moreover, a method to selectively convert intratumoral Tregs into Teff cells without affecting the systemic Treg population would be an even more effective strategy. As a key factor for maintaining Treg abundance and functional stability in response to various immune responses, Helios may be pharmacologically relevant to strategies to enhance current tumor immunotherapy. Because the change from Tregs to Teffs can be restricted to the inflammatory tumor microenvironment, antibody or small molecule-based drugs targeting Helios may lead to improved immunotherapy of Treg-dependent cancers. Importantly, the change in Helios-deficient Tregs occurs only within the local inflammatory environment of the tumor. This approach may avoid autoimmune side effects associated with the reduction of systemic Tregs. Therefore, a strategy to specifically suppress Helios-dependent regulation of intratumoral Tregs would be a critical support for improving cancer immunotherapy. Furthermore, it has been reported that depletion of Foxp3+Tregs enhances vaccine-induced antitumor T cell responses (Nishikawa et al., 2010, Int. J. Cancer 127:759-767). This suggests that reducing Helios levels could be effective in enhancing the efficacy of cancer vaccines.

[0007] Antitumor immunotherapy during viral infections may limit the immune response of Treg cells driven by excessive inflammation and inhibit effective antiviral T cell responses, promoting viral persistence (Schmitz et al., 2013, PLOS Pathogens 9:e1003362). Chronic infection of mice with lymphocytic choriomeningitis virus resulted in a significant expansion of Foxp3+ Tregs, implying a potential mechanism by which certain infectious agents may evade the host immune response by activating and expanding Tregs (Punkosdy et al., 2011, PNAS 108:3677-3682). During chronic virus-related diseases, reducing the levels of Helios in activated Tregs may have therapeutic benefits.

[0008] There is a need for compounds that are useful as inhibitors of Helios proteins.

[0009] SUMMARY OF THE PRESENTINVENTION The present invention provides pyridinyl-substituted oxoisoindoline compounds of formula (I) or salts thereof useful for reducing Helios protein levels and Helios activity levels and / or inhibiting Helios expression levels in a cell.

[0010] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and / or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

[0011] The present invention also provides a method for treating a disease or disorder caused by a decrease in the activity of the Helios protein, the method comprising administering to a patient a compound of formula (I) and / or a pharma- ceutical acceptable salt thereof.

[0012] The present invention also provides processes and intermediates for use in the preparation of compounds of formula (I) and / or salts thereof.

[0013] The present invention also provides a compound of formula (I) and / or a pharma- ceutically acceptable salt thereof for use in therapy.

[0014] The present invention also provides the use of a compound of formula (I) and / or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of certain diseases (such as cancer and viral infections) to reduce Helios protein levels and Helios activity levels in cells and / or suppress Helios expression levels to control Treg differentiation.

[0015] The compounds of formula (I) and compositions containing the compounds of formula (I) may be used to treat, prevent or cure viral infections and various proliferative diseases, such as cancer. Pharmaceutical compositions containing these compounds are useful for treating, preventing or inhibiting the progression of diseases or disorders, such as viral infections and cancer, in various treatment sites.

[0016] These and other features of the present invention are set forth in the broader disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Applicant has discovered substituted oxoisoindoline compounds that inhibit Helios protein by promoting the interaction of Helios protein and its corresponding E3 ubiquitin ligase complex (Cullin4-Cereblon, CUL4-CRBN). These compounds reduce Helios protein levels and Helios activity levels in cells and / or suppress Helios expression levels to control Treg differentiation. These compounds are useful for treating certain diseases, such as cancer and viral infections. These compounds provide useful pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values ​​important to their druggability.

[0018] The first aspect of the present invention relates to a compound having at least one formula (I): [ka] [In the formula, Z is CR 6 R 6 or C=O; Ring A is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydropyridazinyl, 1,4-azaphosphinane 4-oxide, pyrazolyl, isoindolinyl, dihydropyrrolo[3,4-c]pyridinyl, decahydroquinolinyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, hexahydrocyclopenta[c]pyrrolyl, hexahydrofuro[3,4-c]pyrrolyl, tetrahydropyrazolo[4,3-c]pyridinyl, tetrahydro [4,5-c]pyridinyl, tetrahydro[1,2,4]triazolo[4,3-a]pyrazinyl, octahydroisoindolyl, octahydropyrrolo[3,4-b]pyridinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, oxazabicyclo[3.1.1]heptanyl, diazaspiro[3.4]octanyl, oxazaspiro[3.4]octanyl, azaspiro[3.5]nonanyl, oxazaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, azaspiro[4.5]deca nyl, diazaspiro[4.5]decanyl, oxazaspiro[4.5]decanyl, diazaspiro[4.5]decanonyl, oxadiazaspiro[4.5]decanyl, spiro[indoline-3,4'-piperidinyl], 2H-spiro[benzofuran-3,4'-piperidinyl], 3H-spiro[isobenzofuran-1,4'-piperidinyl], 2,3-dihydrospiro[indene-1,4'-piperidinyl], azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, oxazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl or oxazabicyclo[3.2.1]octanyl; R 1 are F, -CN, -OH, C1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, -CH 2 OCH 3 , -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NR y R y , -CH 2 NR x C(O)OC(CH 3 ) 3 , -NR x C(O)OCH 3 , -NR x C(O)OC(CH 3 ) 3 , -C(O)NR x (cyclohexyl), -S(O) 2 CH 3 , -P(O)(OH)O(phenyl), -CH 2 (phenyl), -C(O)(cyclopropyl), -C(O)(phenyl), -NR x (phenyl), -CH 2 NR x C(O)(phenyl), -NR x C(O)(phenyl), -CH 2 O(fluorophenyl), -CH 2 O(chloropyridinyl), -NR x S(O) 2 CH 3 , -NR x S(O) 2 (phenyl), cyclopropyl, methyl oxadiazolyl, methylisoxazolyl, thiophenyl, -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl) or 0, 1 or 2 R 1a is a phenyl substituted with; Each R 1a are independently F, Cl, -OH, -CH 3 , -CHF 2 , -CF 3 or -S(O) 2 CH 3 and; Each R 2 are independently F, -CN, -OH, -CH 3 , -CF 3 , -C(CH 3 ) 2 OH or -C(O)C(CH 3 ) 3 and; Each R 3 are independently F, Cl, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 or -NH 2 and; Each R 4 are independently F, Cl or -CH 3 and; Each R 6 are independently hydrogen or C 1 - 3 is alkyl; R x is hydrogen or -CH 3 and; Each R y are independently hydrogen or C 1-4 is alkyl; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; and Wherein q is 0, 1, 2 or 3; however, (1) When ring A is azetidinyl, pyrrolidinyl, or piperidinyl, m is 1; (2) Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; m is 1; and R 1 But, C 1-4 Alkyl, C 1-2 Fluoroalkyl, -C(O)(C 1-3 alkyl), -C(O)NR y R y , -CH 2 (phenyl), phenyl or methylphenyl, R 2 are F, -CN, -OH, -CF 3 , -C(CH 3) 2 OH or -C(O)C(CH 3 ) 3 is] or a salt thereof.

[0019] A second aspect of the present invention relates to a compound having at least one formula (II): [ka] [In the formula, Ring A is azetidinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, 1,4-azaphosphinane 4-oxide, 2,3-dihydrospiro[indene-1,4'-piperidinyl], 2H-spiro[benzofuran-3,4'-piperidinyl], 2-oxa-6-azaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-2,9-diazaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decanyl, 6-oxa-2-azaspiro[3.4]octanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, azaspiro[3.3]heptyl, azaspiro[3.5]nonanyl or spiro[indoline-3,4'-piperidinyl]; R 1 is -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 , -S(O)2 CH 3 , -P(O)(OH)O(phenyl), -C(O)(phenyl), -NH(phenyl), -N(CH 3 )(phenyl), methyl oxadiazolyl, thiophenyl, -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl) or 0, 1 or 2 R 1a is a phenyl substituted with; Each R 1a are independently F, Cl, -OH, -CHF 2 , -CF 3 or -S(O) 2 CH 3 and; Each R 2 are independently F, -CN, -OH or -CH 3 and; Each R 3 is independently F or Cl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1 or 2. or a salt thereof.

[0020] In one embodiment, Z is CR 6 R 6 The compound of this embodiment has the formula (Ia): [ka] It has the structure:

[0021] Included in this embodiment are each R 6 is hydrogen, or included in this embodiment are compounds in which one R 6 is hydrogen and the other R 6 C 1 - 3 Further included in this embodiment are compounds in which one R 6 is hydrogen and the other R 6Ga-CH 3 It is a compound wherein

[0022] One embodiment provides a compound of formula (I) or a salt thereof, where Z is C=O. The compound of this embodiment has the formula (Ib): [ka] It has the structure:

[0023] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein Ring A is azetidinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, or 1,4-azaphosphinane. Included in this embodiment are compounds where m is 1. Also included in this embodiment are compounds where n is 0 or 1.

[0024] One embodiment provides compounds of formula (I) or compounds of formula (II), or a salt thereof, where Ring A is azetidinyl, pyrrolyl, or piperidinyl. Included in this embodiment are compounds where m is 1. Also included in this embodiment are compounds where n is 0 or 1.

[0025] In one embodiment, ring A is 2,3-dihydrospiro[indene-1,4'-piperidinyl], 2H-spiro[benzofuran-3,4'-piperidinyl], 2-oxa-6-azaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-2,9-diazaspiro[4.5]decane ... The present invention provides a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein m is 1. Also included in this embodiment are compounds where n is 0 or 1.

[0026] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, in which Ring A is 2-oxa-6-azaspiro[3.3]heptanyl, 6-oxa-2,9-diazaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decanyl, 6-oxa-2-azaspiro[3.4]octanyl, azaspiro[3.3]heptyl, or azaspiro[3.5]nonanyl. Included in this embodiment are compounds in which m is 1. Also included in this embodiment are compounds in which n is 0 or 1.

[0027] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein Ring A is 3-azabicyclo[3.1.0]hexanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl. Included in this embodiment are compounds where m is 1. Also included in this embodiment are compounds where n is 0 or 1.

[0028] In one embodiment, ring A is azetidinyl and has the structure: [ka] The present invention provides a compound of formula (I) having the formula:

[0029] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0030] In one embodiment, ring A is azetidinyl and has the structure: [ka] The present invention provides a compound of formula (II) or a salt thereof,

[0031] In one embodiment, ring A is pyrrolyl and has the structure: [ka] The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof, having the formula:

[0032] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0033] In one embodiment, ring A is pyrrolyl and has the structure: [ka] The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof, having the formula:

[0034] In one embodiment, ring A is piperidinyl and has the structure: [ka] The present invention provides a compound of formula (I) having the formula:

[0035] Included in this embodiment is Z being CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0036] In one embodiment, ring A is piperidinyl and has the structure: [ka] The present invention provides a compound of formula (II) or a salt thereof,

[0037] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 6-oxa-2,9-diazaspiro[4.5]decanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0038] Included in this embodiment is Z being CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0039] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 6-oxa-2,9-diazaspiro[4.5]decanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0040] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is azaspiro[3.5]nonanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0041] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0042] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is azaspiro[3.5]nonanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0043] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 3-azabicyclo[3.1.0]hexanyl. Included in this embodiment is a compound having the following structure: [ka] It is a compound having the formula:

[0044] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0045] One embodiment provides a compound of formula (II) or a salt thereof, wherein ring A is 3-azabicyclo[3.1.0]hexanyl. Included in this embodiment is a compound having the following structure: [ka] It is a compound having the formula:

[0046] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is spiro[indoline-3,4'-piperidinyl]. Included in this embodiment is a compound having the following structure: [ka] It is a compound having the formula:

[0047] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0048] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is spiro[indoline-3,4'-piperidinyl]. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0049] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 2H-spiro[benzofuran-3,4'-piperidinyl]. Included in this embodiment is a compound having the following structure: [ka] It is a compound having the formula:

[0050] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0051] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 2H-spiro[benzofuran-3,4'-piperidinyl]. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0052] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 2,3-dihydrospiro[indene-1,4'-piperidinyl]. Included in this embodiment is a compound having the following structure: [ka] Included in this embodiment are compounds in which Z is CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0053] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 2,3-dihydrospiro[indene-1,4'-piperidinyl]. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0054] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 3-oxa-6-azabicyclo[3.1.1]heptanyl. Included in this embodiment is a compound of formula (I) or a salt thereof, having the following structure: [ka] It is a compound having the formula:

[0055] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0056] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 3-oxa-6-azabicyclo[3.1.1]heptanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0057] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 6-oxa-3-azabicyclo[3.1.1]heptanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0058] Included in this embodiment is Z being CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0059] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 6-oxa-3-azabicyclo[3.1.1]heptanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0060] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 8-oxa-3-azabicyclo[3.2.1]octanyl. Included in this embodiment is a compound of formula (I) or a salt thereof, having the following structure: [ka] It is a compound having the formula:

[0061] Included in this embodiment is Z being CR 6 R 6Also included in this embodiment are compounds where Z is C=O.

[0062] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 8-oxa-3-azabicyclo[3.2.1]octanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0063] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 1,2,3,6-tetrahydropyridinyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0064] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0065] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 1,2,3,6-tetrahydropyridinyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0066] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 1,4-azaphosphinane 4-oxide. Included in this embodiment is a compound of formula (I) or a salt thereof, having the following structure: [ka] It is a compound having the formula:

[0067] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0068] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 1,4-azaphosphinane 4-oxide. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0069] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is azaspiro[3.3]heptyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0070] Included in this embodiment is Z, CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0071] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is azaspiro[3.3]heptyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0072] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 6-oxa-2-azaspiro[3.4]octanyl. Included in this embodiment is a compound having the following structure: [ka] It is a compound having the formula:

[0073] Included in this embodiment is Z being CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0074] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 6-oxa-2-azaspiro[3.4]octanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0075] One embodiment provides a compound of formula (I) or a salt thereof, wherein Ring A is 6-oxa-2-azaspiro[3.4]octanyl. Included in this embodiment is a compound having the following structure: [ka] It is a compound having the formula:

[0076] Included in this embodiment is Z being CR 6 R 6 Also included in this embodiment are compounds where Z is C=O.

[0077] One embodiment provides a compound of formula (II) or a salt thereof, wherein Ring A is 6-oxa-2-azaspiro[3.4]octanyl. Included in this embodiment is a compound of the following structure: [ka] It is a compound having the formula:

[0078] In one embodiment, m is 1; and R 1 F, -CN, -OH, -CH 3, -C(CH 3 ) 3 , -CF 2 CH 2 CH 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OCH 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OCH 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 , -C(O)NHC(CH 3 ) 3 , -C(O)NH(cyclohexyl), -S(O) 2 CH 3 , -P(O)(OH)O(phenyl), -CH 2 (phenyl), -C(O)(cyclopropyl), -C(O)(phenyl), -NH(phenyl), -N(CH 3 )(phenyl), -CH 2 NHC(O)(phenyl), -CH 2 N(CH 3 )C(O)(phenyl), -N(CH 3 )C(O)(phenyl), -CH 2 O(fluorophenyl), -CH 2 O(chloropyridinyl), -N(CH 3 )S(O) 2 CH 3, -N(CH 3 )S(O) 2 (phenyl), cyclopropyl, methyl oxadiazolyl, methylisoxazolyl, thiophenyl, -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl) or 0, 1 or 2 R 1a The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein R is substituted phenyl with R 1 .

[0079] In one embodiment, m is 1; and R 1 F, -CN, -OH, -CH 3 , -C(CH 3 ) 3 , -CF 2 CH 2 CH 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OCH 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OCH 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 or -C(O)NHC(CH 3 ) 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0080] In one embodiment, m is 1; and R 1 is F, -CN, -OH or C 1-4 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein R is alkyl. 1 F, -CN, -OH, -CH 3 , -C(CH 3 ) 3 Or -CF 2 CH 2 CH 3 It is a compound wherein

[0081] In one embodiment, m is 1; and R 1 But, C 1-3 Hydroxyalkyl, -CH 2 OCH 3 , -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NR y R y , -CH 2 NR x C(O)OC(CH 3 ) 3 , -NR x C(O)OCH 3 or -NR x C(O)OC(CH 3 ) 3 Included in this embodiment is a compound of formula (I) or a compound of formula (II), wherein R 1 But -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -C(O)OC(CH 3 ) 3, -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OCH 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OCH 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 or -C(O)NHC(CH 3 ) 3 Further included in this embodiment are compounds in which R 1 But -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH or -CH 2 OCH 3 It is a compound wherein

[0082] In one embodiment, R 1 But -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 or -S(O) 2 CH 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0083] In one embodiment, R 1is -P(O)(OH)O(phenyl), or a salt thereof.

[0084] In one embodiment, R 1 is -C(O)(phenyl), -NH(phenyl) or -N(CH 3 ) (phenyl), or a salt thereof.

[0085] In one embodiment, R 1 is methyloxadiazolyl or thiophenyl, or a salt thereof.

[0086] In one embodiment, R 1 is -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl) or 0, 1 or 2 R 1a is phenyl substituted with

[0087] In one embodiment, R 1 But -CH 2 (phenyl), -C(O)(cyclopropyl), -C(O)(phenyl), -NR x (phenyl), -CH 2 NR x C(O)(phenyl), -NR x C(O)(phenyl), -CH 2 O(fluorophenyl), -CH 2 O(chloropyridinyl) or -NR x S(O) 2 (phenyl), or a salt thereof.

[0088] In one embodiment, R 1 is cyclopropyl, methyl oxadiazolyl, methylisoxazolyl or thiophenyl, or a salt thereof.

[0089] In one embodiment, R 1 but 0, 1 or 2 R 1a Included in this embodiment is a compound of formula (I) or a compound of formula (II), wherein R is phenyl substituted with 1 but 0 or 1 R 1a Also included in this embodiment are compounds in which R 1 But two R 1a The compound is phenyl substituted with

[0090] In one embodiment, each R 1a are independently F, Cl, -OH, -CHF 2 Or -CF 3 Included in the embodiment is a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein each R 1a are independently F or Cl.

[0091] In one embodiment, R 1 But 1 or 2 R 1a Included in this embodiment is a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein each R is phenyl substituted with 1a are independently F, Cl, -OH, -CH 3 , -CHF 2 Or -CF 3 Also included in this embodiment are compounds in which each R 1a are independently F, Cl, -OH, -CHF 2 , -CF 3 or -S(O) 2 CH 3 It is a compound wherein

[0092] In one embodiment, each R 2 are independently F, -CN, -OH, -CH 3 , -CF 3 or -C(CH 3 ) 2The present invention provides a compound of formula (I) or a salt thereof, wherein n is OH. Included in this embodiment are compounds where n is 1. Also included in this embodiment are compounds where n is 2.

[0093] In one embodiment, each R 2 are independently F, -CN, -OH, -CH 3 Or -CF 3 or a salt thereof. Included in this embodiment are compounds where n is 1. Also included in this embodiment are compounds where n is 2.

[0094] In one embodiment, each R 2 are independently -OH or -CH 3 or a salt thereof. Included in this embodiment are compounds where n is 1. Also included in this embodiment are compounds where n is 2.

[0095] In one embodiment, each R 2 are independently F, -OH or -CH 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0096] In one embodiment, each R 2 is independently F, or a salt thereof.

[0097] In one embodiment, n is 1 and R 2 is -OH, or a salt thereof.

[0098] In one embodiment, n is 1 and R 2 is -CN, or a salt thereof.

[0099] In one embodiment, n is 1 and R 2 Ga-CH 3The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0100] In one embodiment, n is 1 and R 2 Ga-CF 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0101] In one embodiment, each R 3 is independently F. Included in this embodiment are compounds where p is 1. Also included in this embodiment are compounds where p is 2.

[0102] In one embodiment, each R 3 is independently Cl, or a salt thereof.

[0103] In one embodiment, each R 3 But independently, -CH 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0104] In one embodiment, each R 3 But independently, -CF 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0105] In one embodiment, each R 3 But independently, -OCH 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0106] In one embodiment, each R 3 But independently, -OCF 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0107] In one embodiment, each R 3 However, independently, -NH 2The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0108] In one embodiment, p is 1; and R 3 is F, or a salt thereof.

[0109] In one embodiment, p is 1; and R 3 is Cl, or a salt thereof.

[0110] In one embodiment, p is 1; and R 3 Ga-CH 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0111] In one embodiment, p is 1; and R 3 Ga-CF 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0112] In one embodiment, p is 1; and R 3 -OCH 3 The present invention provides a compound of formula (I) or a compound of formula (II), or a salt thereof,

[0113] In one embodiment, each R 4 is independently F or Cl. Included in this embodiment are compounds where q is 1 or 2. Also included in this embodiment are compounds where q is 1.

[0114] In one embodiment, each R 4 are independently F or -CH 3 or a salt thereof. Included in this embodiment are compounds where q is 1 or 2. Also included in this embodiment are compounds where q is 1.

[0115] In one embodiment, each R4 is independently F. Included in this embodiment are compounds where q is 1 or 2. Also included in this embodiment are compounds where q is 1.

[0116] In one embodiment, each R 4 is independently Cl. Included in this embodiment are compounds where q is 1 or 2. Also included in this embodiment are compounds where q is 1.

[0117] In one embodiment, each R 4 However, independently -CH 3 or a salt thereof. Included in this embodiment are compounds where q is 1 or 2. Also included in this embodiment are compounds where q is 1.

[0118] In one embodiment, Z is CR 6 R 6 and each R 4 is independently F. Included in this embodiment are compounds where q is 1. Also included in this embodiment are compounds where one R 6 is hydrogen and the other R 6 Ga-CH 3 Further included in this embodiment are compounds in which each R 6 is a compound in which

[0119] In one embodiment, Z is CO; Ring A is pyrrolidinyl, piperidinyl, or oxazaspiro[3.5]nonanyl; R 1 -OH, -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 OCH 3 or phenyl; R 2 is -OH or -CH 3with the proviso that (i) when ring A is pyrrolidinyl or piperidinyl, then m is 1; and (ii) ring A is pyrrolidinyl or piperidinyl; m is 1; and R 1 is phenyl, R 2 is -OH. Included in this embodiment are compounds where Ring A is pyrrolidinyl or piperidinyl.

[0120] In one embodiment, Z is CR 6 R 6 Ring A is pyrrolidinyl; R 1 But -OH, C 1-3 Hydroxyalkyl or -CH 2 OCH 3 and each R 2 is independently F, -CN or -OH; R 3 But, F, -CH 3 Or -CF 3 ;R 4 The present invention provides a compound of formula (I) or a salt thereof, wherein: is F; m is 1; n is 0 or 1; p is 0 or 1; and q is 0 or 1. Included in this embodiment are compounds where n is 0; p is 0. Also included in this embodiment are compounds where n is 0; p is 0; and q is 0.

[0121] In one embodiment, Z is CR 6 R 6 Ring A is piperidinyl; R 1 But -OH, C 1-3 Hydroxyalkyl or -CH 2 OCH 3 and each R 2 is independently F, -CN or -OH; R 3 But, F, -CH 3 Or -CF 3 ;R 4The present invention provides a compound of formula (I) or a salt thereof, wherein: is F; m is 1; n is 0 or 1; p is 1 or 2; and q is 0 or 1. Included in this embodiment are compounds where n is 0 and p is 1. Also included in this embodiment are compounds where n is 0; p is 1; and q is 0.

[0122] In one embodiment, m is 0; and Ring A is selected from the group consisting of azepanyl, tetrahydropyridazinyl, 1,4-azaphosphinane 4-oxide, pyrazolyl, isoindolinyl, dihydropyrrolo[3,4-c]pyridinyl, decahydroquinolinyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, hexahydrocyclopenta[c]pyrrolyl, hexahydrofuro[3,4-c]pyrrolyl, tetrahydropyrazolo[4,3-c]pyridinyl, tetrahydroisoxazolo[4,5-c]pyridinyl, tetrahydro[1,2,4]triazolo[4,3 -a]pyrazinyl, octahydroisoindolyl, octahydropyrrolo[3,4-b]pyridinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, oxazabicyclo[3.1.1]heptanyl, diazaspiro[3.4]octanyl, oxazaspiro[3.4]octanyl, azaspiro[3.5 ]nonanyl, oxaazaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, oxaazaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, oxadiazaspiro[4.5]decanyl, spiro[indoline-3,4'-piperidinyl], 2H-spiro[benzofuran-3,4'-piperidinyl], 3H-spiro[isobenzofuran The compound of formula (I) or the compound of formula (II), or a salt thereof, is provided, wherein the compound of formula (I) or the compound of formula (II) is 2,3-dihydrospiro[indene-1,4'-piperidinyl], 2,3-dihydrospiro[indene-1,4'-piperidinyl], azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, oxazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl or oxazabicyclo[3.2.1]octanyl.

[0123] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1.

[0124] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein n is 0 or 1.

[0125] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein n is 1 or 2.

[0126] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein n is 0.

[0127] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein n is 1.

[0128] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein n is 2.

[0129] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein p is 0 or 1.

[0130] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein p is 1 or 2.

[0131] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein p is 0.

[0132] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein p is 1.

[0133] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein p is 2.

[0134] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 0; n is 0 or 1; and p is 0.

[0135] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 0 or 1; and p is 0.

[0136] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 0; and p is 0.

[0137] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 1; and p is 0.

[0138] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 0 or 1; and p is 1.

[0139] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 0; and p is 1.

[0140] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 1; and p is 1.

[0141] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 2; and p is 0.

[0142] One embodiment provides a compound of formula (I) or a compound of formula (II), or a salt thereof, wherein m is 1; n is 2; and p is 1.

[0143] One embodiment provides a compound of formula (I) or a salt thereof, the compound being 3-(5-(5-chloro-4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1); 3-(5-(5-fluoro-4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2); 3-(5-(4-(( 3-(3,4-difluorophenyl)azetidin-1-yl)methyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(3);3-(5-(5-fluoro-4-((3-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(4);3-(5-(5-fluoro-4-((3-hydroxy-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin 3-(5-(4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(6);3-(5-(3-fluoro-4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(7);3-(5-(3-fluoro-4-((2-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-fluoro-4-((3-hydroxy-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9); 3-(5-(4-((2-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10);3-(5-(4-((3-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(11);3-(5-(4-((3-(2-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(12);3-(5-(4-((3-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine 3-(5-(4-((3-(2-chlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(14);3-(5-(4-((3-(3-chlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(15);3-(5-(4-((3-(4-chlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin 3-(1-oxo-5-(4-((3-(3-(trifluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione(17);3-(1-oxo-5-(4-((3-(3-(trifluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione(18);3-(1-oxo-5-(4-((3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione(19); 3-(5-(4-((3-(3-(difluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20);3-(5-(4-((3-(4-(difluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21);3-(5-(4-((3-(2,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(22);3-(5-(4-((3-(2,3-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(23);3-(5-(4-((3-(3,5-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl )piperidine-2,6-dione(24);3-(5-(4-((3-(3,4-dichlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(25);3-(5-(4-((3-(3,5-dichlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(26);3-(1-oxo-5-(4-((3-(thiophen-3-yl)azetidin-1-yl)methyl)pyridin-2-yl )isoindolin-2-yl)piperidine-2,6-dione (27);tert-butyl (1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)carbamate (28);3-(1-oxo-5-(4-((3-(phenylamino)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (29);3-(5-(4-((3-(methyl(phenyl)amino)azetidin-1-yl)methyl) 3-(5-(4-((3-fluoro-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (31); tert-butyl (4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate (32);3-(5-(4-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33);3-(5-(4-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (34);3-(5-(4-(((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35); 3-(5-(4-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(36);3-(5-(4-((3-hydroxy-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(37);3-(1-oxo-5-(4-((3-phenoxyazetidin-1-yl)methyl)pyridin-2-yl)- 3-(5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(39);3-(5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(40);3-(5-(4-(((S)-3-fluoro 3-(5-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (42); 3-(5-(4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (43);3-(1-oxo-5-(4-((1-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (44);tert-butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (45);3-(1-oxo-5-(4-((3-phenoxypyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (46);3-(5-(4-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine 3-(5-(4-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (48);1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-4-phenylpiperidine-4- Carbonitrile (49); 3-(1-oxo-5-(4-((4-phenoxypiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (50); 3-(1-oxo-5-(4-(spiro[indoline-3,4'-piperidine]-1'-ylmethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (51); 3-(5-(4-((2H-spiro[benzofuran-3,4'-piperidine]-1'-yl)methyl )pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (52); 3-(5-(4-((2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (53); 3-(5-(4-((4-hydroxypiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (54);3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55);3-(5-(4-((2-hydroxy-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (56);3-(5-(4-((4-(4-(methylsulfonyl)phenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin Indolin-2-yl)piperidine-2,6-dione (57);3-(5-(4-((4-(3-hydroxyphenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (58);3-(1-oxo-5-(4-((4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (59);3-(5-(4-((4-(3-chlorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (59); 3-(5-(4-((4-(4-chlorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60);3-(5-(4-((4-(4-chlorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (61);3-(5-(4-((4-(2-fluorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (62);3-(5-(4-((4-(3-fluorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (63); 3-(5-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (64); 3-(5-(4-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (65);3-(5-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (66);Methyl 4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)benzoate (67);3-(5-(4-((6-oxa-2,9-diazaspiro[4.5]decane-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68);3-(5-( 4-((9-benzoyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69);3-(5-(4-((2-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70);3-(5-(4-((3-(meth 3-(5-(4-((3,6-dihydropyridin-1(2H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72); phenyl hydrogen (1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline -5-yl)pyridin-4-yl)methyl)pyrrolidin-2-yl)phosphonate (73);3-(5-(4-((4-methyl-4-oxido-1,4-azaphosphinan-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (74);1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidi; 3-(5-(4-((3,3-difluoro-2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (76); 3-(5-(4-((2-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (78);1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxamide (79);Methyl 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxylate (80);3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (81);3-(5-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82);3-(5-(4-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (83);3-(5-(4-((3-(methylsulfonyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (84);tert-butyl((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin tert-butyl (1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)(methyl)carbamate (86); or 3-(5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87).

[0144] One embodiment provides a compound of formula (I) or a salt thereof, the compound being 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (88); 3-(5-(3-fluoro-4-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (89); 3-(5-( 3-Fluoro-4-(((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90);3-(5-(3-fluoro-4-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (91);3-(5-(5-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridine- 2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (92);3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (93);3-(5-(3-chloro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94);3-(5-(3-chloropyridin 3-(5-(3-chloro-4-(((R)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96); 3-(5-(3-chloro-4-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (97);tert-Butyl (4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]non-2-yl)oxy)phenyl)carbamate (98); 3-(5-(4-((3-(methoxymethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (99); 3-(5-(4-((2-oxa-7-azaspiro[3.5]non-7-yl)methyl) 3-(5-(4-(((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(101);3-(5-(4-(((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6 -dione (102); 3-(5-(4-((6-chloro-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (103); 3-(5-(4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (104); 3-(5-(4-(((S)-3-(hydroxymethyl)pyrrolidine-1 -yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (105); 3-(5-(4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (106); 3-(5-(4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (107);3-(5-(4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (108);3-(5-(3-fluoro-4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (109);3-(5-(3-fluoro-4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl) 3-(5-(3-fluoro-4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(110);3-(5-(3-fluoro-4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(111);3-(5-(3-fluoro-4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6 -dione (112); 3-(5-(3-fluoro-4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (113); 3-(5-(3-fluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (114); 3-(5-(3-fluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (114); )pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (115); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)isoindoline-1,3-dione (116); 3-(5-(4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (117);3-(5-(4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (118); 3-(5-(4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (119); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl )methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(120);3-(5-(4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(121);3-(5-(4-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(1 22;3-(5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (123);3-(5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (124);3-(5-(4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (126);(R)-3-((R)-4-fluoro-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127);(S)-3-((R)-4-fluoro-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (128); (S)-3-((R)-4-fluoro-5-(4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129); (S)-3-((R)-4-fluoro-5-(4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130); (S)-3-((R)-4-fluoro-5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 31);(S)-3-((R)-4-fluoro-5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (132);(S)-3-((R)-4-fluoro-5-(4-(((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 33);(3S)-3-((3R)-4-fluoro-5-(4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (134);(3S)-3-((3R)-4-fluoro-5-(4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (135);(S)-3-((R)-5-(4-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (136); (S)-3-((R)-4-fluoro-5-(4-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (137); (S)-3-((R)-4-fluoro-5-(4-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (137); -3-methylazetidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (138);(3S)-3-((3R)-4-fluoro-5-(4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (139);(3S)-3-((3R)-4-fluoro-5-(4-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridine -2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140);(S)-3-((R)-4-fluoro-3-methyl-1-oxo-5-(4-(((R)-3-phenoxypyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (141);S)-3-((R)-4-fluoro-5-(4-(((S)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine 3-((R)-4-fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (143); (S)-3-((R)-4-fluoro-5-(3-fluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (144);(S)-3-(5-(4-((6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (145); (3S)-3-(5-(4-((5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (146); (3S)-3-(5-(4-((5-hydroxy-5-methylhexahydrocyclopenta[c ]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147);(3S)-3-(5-(4-((5-methyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (148);(3S)-3-(5-(3-fluoro-4-(((3aR,7aS)-5-hydroxyoctahydro-2H-isoindol-2-yl) (S)-3-(5-(3-fluoro-4-((1-oxo-2,8-diazaspiro[4.5]decane-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (149);(S)-3-(5-(3-fluoro-4-((1-oxo-2,8-diazaspiro[4.5]decane-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150);(S)-3-(5-(3-fluoro-4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin (S)-3-(1-oxo-5-(4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (152); (S)-3-(5-(3-fluoro-4-((6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (153);tert-Butyl (3aS,6aS)-5-((2-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (154);(3S)-3-(5-(3-fluoro-4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (155);tert-Butyl; (3aR,6aS)-5-((2-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (156); 3-(5-(4-((2-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (157); (S)-3-(5-(4-((7-oxa-2-azaspiro[3.5]nonane-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (158);N-((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)benzamide (159);(S)-N-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl )-N-methylbenzamide (160);(S)-N-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)-N-methylmethanesulfonamide (161);(S)-N-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)-N-methylbenzenesulfonamide (162);Methyl(S)-(1-( (2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)(methyl)carbamate (163);(S)-N-((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)-N-methylbenzamide (164);3-(5-(4-((1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin (S)-3-(5-(4-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (166);3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (167);3-(5-(4-((2-azaspiro[3.3-(5-(4-((3-cyclopropylpyrrolidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (168);3-(5-(4-((3-cyclopropylpyrrolidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (169);3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (170);3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (171);3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (172);3-(5-(4-((3-cyclopropylpyrrolidin 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (173);3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (174);3-(5-(4-((3-cyclopropylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (175);3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (176);3-(5-(4-((3-(methoxymethyl)azetidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (177);3-(5-(4-((2-azaspiro[3.3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (179); 3-(5-(4-((2-azaspiro[3.3-(5-(4-((3-(methoxymethyl)azetidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180); 3-(5-(4-((3-(methoxymethyl)azetidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (181); 3-(5-(3-fluoro-4-((4-(trifluoromethoxy)piperidine-1 -yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (182);3-(5-(3-fluoro-4-((3-(trifluoromethoxy)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (183);3-(5-(3-fluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindoline -2-yl)piperidine-2,6-dione (184);3-(5-(3-fluoro-4-((3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185);3-(5-(3-fluoro-4-((4-fluoroisoindolin-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (186); 3-(5-(4-((5-chloroisoindolin-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (187); N-(tert-butyl)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide (188); 3-(5-(4-((1-(methoxymethyl)-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (189);(2S)-N-cyclohexyl-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide (190);3-(5-(4-(((R)-2-((( 6-chloropyridin-3-yl)oxy)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (191);3-(5-(4-((2-((4-fluorophenoxy)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (192);Ethyl 3-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (193);3-(5-(4-((2-azabicyclo[3.1.0]Hexane-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (194); tert-butyl (((2S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-yl)methyl)carbamate (195); 3-(5-(4-((2-(isopropoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (196); 3-(5-(4-((3-fluoro-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione(197);3-(5-(3-fluoro-4-((4-fluoro-4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(198);3-(5-(4-((2-acetyltetrahydropyridazin-1(2H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(199);3-(5-(4-((4-(1,1-difluoropropyl)piperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200);tert-butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,5-diazaspiro[3.5]nonane-5-carboxylate (201); 3-(5-(4-((1-acetyl-1,8-diazaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (202); methyl 8-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,8-diazaspiro[4.5]Decane-1-carboxylate (203);tert-butyl 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (204);3-(5-(3-fluoro-4-((3-fluoropiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (205);3-(5-(4-((6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (206);tert-butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (207); tert-butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (208); 3-(5-(3-fluoro-4-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (209);3-(5-(4-((8-azaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (210);3-(5-(3-fluoro-4-((4-hydroxy-2-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (211-212);tert-butyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,7-diazaspiro[4.4] Nonane-1-carboxylate (213); tert-Butyl (2S,4R)-4-(tert-butoxy)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)pyrrolidine-2-carboxylate (214-215); tert-Butyl 6-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,6-diazaspiro[3.5]nonane-1-carboxylate (216);3-(5-(3-fluoro-4-(((R)-2-((R)-1-hydroxy-1-phenylethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (217);3-(5-(3-fluoro-4-(((R)-2-((S)-1-hydroxy-1-phenylethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (218);3-(5 -(3-fluoro-4-((6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (219);3-(5-(3-fluoro-4-((4-hydroxy-4-methylazepan-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (220);3-(5-(3-fluoro-4-((4-hydroxy-3,3-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (221);3-(5-(3-fluoro-4-((3-hydroxy-1-oxa-8-azaspiro[4.5]Decan-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (222);3-(5-(3-fluoro-4-((3-hydroxy-2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (223);3-(5-(3-fluoro-4-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin 3-(5-(3-fluoro-4-((2-hydroxy-7-azaspiro[3.5]non-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (225);3-(5-(3-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (226). ;3-(5-(4-((3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (227);Methyl 8-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (228);3-(5-(4-((3-benzoyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-fluoro-4-((3-hydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (230);3-(5-(4-((1-(cyclopropanecarbonyl)-1,8-diazaspiro[4.5]decane-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine 3-(5-(3-fluoro-4-(((3S,4R)-3-hydroxy-4-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (232); 3-(5-(4-((5-acetyl-2,5-diazaspiro[3.5]nonan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (233);3-(5-(3-fluoro-4-((3-(4-fluorophenyl)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (234);3-(5-(4-((4-benzyl-4-hydroxypiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (235);tert-Butyl ((3S,5S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-5-fluoropiperidin-3-yl)carbamate (236); 3-(5-(3-fluoro-4-((4-(4-fluorophenyl)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (237); 3-(5-(4-(( 3-(2-chlorophenyl)-3-hydroxypyrrolidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (238);3-(5-(3-fluoro-4-(((4aR,8R,8aR)-8-hydroxyoctahydroquinolin-1(2H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (239);Methyl(2S,3R)-1-((2-(2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-3-hydroxypyrrolidine-2-carboxylate (240); 3-(5-(3-fluoro-4-((3-hydroxy-3-(p-tolyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (241); 3-(5-(4-((3-(3-chlorophenyl)-3-hydroxypyrrolidin-1-yl)methyl)-3-fluoropyrrolidine-2-yl 3-(5-(3-fluoro-4-((4-fluoro-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (243);3-(5-(3-fluoro-4-((2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (244);3-(5-(3-fluoro-4-(((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (245); tert-butyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (246); 3-(5-(3-fluoro-4-((4-hydroxy-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (247); Methyl ((3S,4S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-4-hydroxypyrrolidin-3-yl)carbamate ( 248;3-(5-(4-((3H-spiro[isobenzofuran-1,4'-piperidine]-1'-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(249);3-(5-(3-fluoro-4-((3-hydroxy-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(250);3-(5-(4-((2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(251);Methyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (252); 3-(5-(3-fluoro-4-((3-fluoro-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (253);3-(5-(3-fluoro-4-((1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (254); 3-(5-(3-fluoro-4-((5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (255); 3-(5-(4 -((3-(2,5-dimethylphenyl)-3-hydroxypyrrolidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (256); 3-(5-(3-fluoro-4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (257); 3-(5-(3-fluoro-4-(((R)-3-fluoropyrrolidine-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (258); 3-(5-(4-((6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(259);3-(5-(3-fluoro-4-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl ) piperidine-2,6-dione (260); 3-(5-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (261); 3-(5-(3-fluoro-4-((3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (262);3-(5-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (263);3-(5-(4-((1,3-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- 3-(5-(4-((2,3-dimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (265); 3-(5-(3-fluoro-4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)-1-oxo isoindolin-2-yl)piperidine-2,6-dione (266);3-(5-(4-((5-chloro-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (267);3-(5-(4-((8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine 3-(5-(4-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(269);3-(5-(4-((1-acetyl-1,7-diazaspiro[4.4]nonan-7-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(270);Methyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (271);3-(5-(4-((6-acetyl-2,6-diazaspiro[3.4]octan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (272);Methyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (273);3-(5-(4-((6-acetyloctahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (274);Methyl 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (275);3-(4-fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (276);3-(4-fluoro-5-(3-fluoro-4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (277);3 -(4-fluoro-5-(3-fluoro-4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (278); 3-(4-fluoro-5-(3-fluoro-4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (279); 3-(4-fluoro-5-(3-fluoro-4-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (280);3-(4-fluoro-5-(3-fluoro-4-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (281); 3-(4-fluoro-5-(3-fluoro-4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (282); 3 -(5-(4-((5-chloro-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)methyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (283); 3-(5-(4-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (284); 3-(5-(6-amino-5-((8-benzoyl)methyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (285); 3-(5-(5-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (286);3-(5-(3,5-difluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (287);3-(5-(3,5-difluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (288); oxoisoindolin-2-yl)piperidine-2,6-dione (287); 3-(5-(3,5-difluoro-4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (288); or 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3,5-difluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (289).

[0145] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses any and all combinations of the aspects and / or embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention may be combined with any and all other embodiments to describe further embodiments. It is also understood that individual elements of the embodiments are meant to be combined with any and all other elements from any and all embodiments to describe further embodiments.

[0146] The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described in the context of another embodiment may be combined to form a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may be combined to form subcombinations thereof. The embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0147] Unless otherwise specified herein, words referred to in the singular may also include the plural. For example, "a" and "an" can refer to either "one" or "one or more."

[0148] As used herein, the phrase "compound and / or salt thereof" refers to at least one compound, a salt of at least one compound, or a combination thereof. For example, a compound of formula (I) and / or a salt thereof includes one compound of formula (I); two compounds of formula (I); a salt of one compound of formula (I); one compound of formula (I) and one or more salts of compounds of formula (I); and a salt of two or more compounds of formula (I).

[0149] Unless otherwise specified, any atom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

[0150] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0151] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification, either individually (unless otherwise limited in specific instances) or as part of a larger group.

[0152] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0153] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0154] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, and I.

[0155] The term "cyano" refers to the group --CN.

[0156] The term "amino" refers to the group -NH 2 This refers to.

[0157] The term "oxo" refers to the group =O.

[0158] The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups, for example, having 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular group may contain. For example, "C 1-4 "Alkyl" means straight and branched chain alkyl groups having 1 to 4 carbon atoms.

[0159] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, 1-4 "Fluoroalkyl" means a C alkyl group substituted with one or more fluorine atoms. 1 , C 2 , C 3 , and C 4 Representative examples of fluoroalkyl groups include, but are not limited to, -CF 3 and -CH 2 CF 3 Examples include:

[0160] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, such as a methoxy group (-OCH 3 For example, "C 1-3 "Alkoxy" means an alkoxy group having 1 to 3 carbon atoms.

[0161] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" refer to a fluoroalkyl group as defined above attached via an oxygen linkage (-O-). For example, 1-4 Fluoroalkoxy" is C 1 , C 2 , C 3 , and C 4 Fluoroalkoxy groups are intended to be included.

[0162] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When the symbol "C" is followed by a number in subscript, the subscript more specifically qualifies the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3 -C 6 "Cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms.

[0163] The present invention is intended to include all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent otherwise used.

[0164] As used herein, the phrase "pharmacologically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of ordinary medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication and that afford a reasonable benefit / risk ratio.

[0165] Compounds of formula (I) may form salts, which are also within the scope of the present invention. Unless otherwise specified, a reference to a compound of the invention is understood to include a reference to one or more salts thereof. The term "salt" refers to acid and / or base salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (internal salts), for example, when a compound of formula (I) has both a basic moiety (e.g., an amine or a pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, for example, acceptable metal salts and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may also be useful, for example, in isolation or purification steps that may be used in the preparation process, and therefore other salts are considered to be within the scope of the present invention. Salts of compounds of formula (I) may be formed, for example, by reacting a compound of formula (I) with a certain amount of acid or base (e.g., one equivalent) and precipitating the salt in a solvent, for example, or from an aqueous solution followed by lyophilization.

[0166] Examples of acid addition salts include acetates (e.g., acetates prepared from acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, hydrogensulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid), hydrobromides (prepared from hydrobromide), and the like. salts such as those described herein), hydroiodides, maleates (prepared from maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (prepared from methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., prepared from sulfuric acid), sulfonates (e.g., those described herein), tartrates, thiocyanates, toluenesulfonates (e.g., tosylates), undecanoates, and the like.

[0167] Examples of base salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), barium, zinc, and aluminum salts, organic base salts such as organic amines (e.g., trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine), or similar pharma- ceutically acceptable amines, and amino acid salts (e.g., arginine, lysine), and the like. Basic nitrogen-containing groups may be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), longer chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and other groups.

[0168] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as a solid by lyophilization.

[0169] In addition, solvates (e.g., hydrates) of the compounds of formula (I) should be considered within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0170] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0171] In addition, the compounds of formula (I) may be prepared, isolated, purified, and obtained as compositions containing 99% or greater of the compound of formula (I) ("substantially pure"), which are then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the invention.

[0172] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, or upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0173] The term "Helios inhibitor" refers to an agent that reduces Helios protein levels and Helios activity levels in cells and / or suppresses Helios expression levels to regulate Treg differentiation. Helios inhibitors can be reversible or irreversible inhibitors.

[0174] As used herein, "Helios" protein refers to a protein that is a member of the Ikaros family of zinc finger proteins. In humans, Helios is encoded by the IKZF2 gene. Helios is also known as Ikaros family zinc finger 2, ANF1A2, ZNF1A2, ZNFN1A2, zinc finger proteins, subfamilies 1A, 2, and Ikaros family zinc finger protein 2. Members of this protein family include Ikaros, Helios, Aiolos, Eos, and Pegasus. As used herein, Helios protein includes various isoforms, including isoforms 1-5 listed below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0175] The "Helios" isoforms 1, 2, 4, 6, and 7 contain a degron, FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (bold underlined). A degron is a part of a protein that plays a role in regulating the rate of protein degradation.

[0176] As used herein, the "Eos" protein is encoded by the IKZF4 gene and is also known as Ikaros family zinc finger 4, ZNFN1A4, zinc finger protein, subfamily 1A, 4, Ikaros family zinc finger protein 4, and KIAA1782. The "Eos" protein includes isoforms encoded by the following two human isoforms 1 (Q9H2S9-1) and 2 (Q9H2S9-2). [Table 6] [Table 7]

[0177] The "Eos" protein isoforms 1 and 2 contain a degron, FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (bold underlined portion), which is identical to the degron of the "Helios" protein.

[0178] As used herein, the "Ikaros" protein is encoded by the IKZF1 gene. Ikaros is also known as Ikaros family zinc finger 1, ZNFN1A1, zinc finger protein, subfamily 1A, 1, Ikaros family zinc finger protein 1, IK1, lymphoid transcription factor LyF-1, Hs.54452, PPP1R92, protein phosphatase 1, regulatory subunit 92, PRO0758, CVID13, and CLL-associated antigen KW-6. Ikaros proteins include isoforms encoded by amino acid sequences Q13422-1, Q13422-2, Q13422-3, Q13422-4, Q13422-7, and Q13422-8. Ikaros proteins also include isoforms encoded by amino acid sequences Q13422-5 and Q13422-6.

[0179] As used herein, the "Aiolos" protein is encoded by the IKZF3 gene. Aiolos protein is also known as Ikaros family zinc finger 3, ZNFN1A3, zinc finger protein, subfamily 1A, 3, Ikaros family zinc finger protein 3, and AIO. Aiolos protein includes isoforms encoded by the amino acid sequences Q9UKT9-1, Q9UKT9-3, Q9UKT9-4, Q9UKT9-6, Q9UKT9-7, Q9UKT9-8, Q9UKT9-9, and Q9UKT9-14. Aiolos proteins also include isoforms encoded by the amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12, and Q9UKT9-13, Q9UKT9-15, and Q9UKT9-16.

[0180] As used herein, the "Pegasus" protein is also known as Ikaros family zinc finger 5, ZNFN1A5, zinc finger protein, subfamily 1A, 5, and Ikaros family zinc finger protein 5. Pegasus is encoded by the IKZF5 gene.

[0181] As used herein, the term "contacting" refers to bringing together a specified moiety in vitro or in vivo. For example, "contacting" a Helios protein with a compound of formula (I) includes administering a compound of the present invention to an individual or patient (e.g., a human) having a Helios protein, as well as introducing a compound of formula (I) into, for example, a sample containing cells or a purification product containing a Helios protein.

[0182] As used herein, the terms "treat" and "treatment" refer to any intervention, method, or administration of an active agent to a subject for the purpose of ameliorating, alleviating, ameliorating, inhibiting, delaying, or suppressing the progression, onset, severity, or recurrence of a symptom, complication, condition, or biochemical manifestation of a disease. In contrast, "prophylaxis" or "prevention" refers to administration to a non-affected subject to prevent the onset of a disease. "Treat" and "treatment" do not include prophylaxis or prevention.

[0183] "Therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with a claimed compound, or in combination with other active ingredients, effective to reduce Helios protein levels and Helios activity levels in a cell and / or inhibit Helios expression levels, or to treat or prevent viral infections and proliferative diseases (e.g., cancer).

[0184] As used herein, the term "cell" is intended to refer to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be part of a tissue sample removed from an organism (e.g., a mammal). In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a living cell in an organism (e.g., a mammal).

[0185] The term "patient" includes human and other mammalian subjects receiving either therapeutic or prophylactic treatment.

[0186] The term "subject" includes any animal, human or non-human. For example, the methods and compositions disclosed herein are used to treat subjects suffering from cancer. Non-human animals include any vertebrate, for example, mammals and non-mammals (non-human primates, sheep, dogs, cows, birds, amphibians, reptiles, etc.). In some embodiments, the subject is a human.

[0187] As used herein, the phrase "pharmaceutical acceptable carrier" refers to a pharma- ceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, processing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulant, which is involved in the transport or delivery of a particular compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation (i.e., including adjuvants, excipients, or vehicles (e.g., diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispensing agents) depending on the nature of the method of administration and the dosage form) and not deleterious to the patient.

[0188] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional pharma- ceutically acceptable carrier.

[0189] (Usefulness) The compounds of formula (I) are useful in the treatment of cancer.

[0190] In one embodiment, the present invention provides a pharmaceutical combination of a compound of formula (I) and / or a pharma- ceutical acceptable salt thereof, a stereoisomer thereof or a tautomer thereof with another therapeutic agent for simultaneous, separate or sequential use in the treatment and / or prevention of diseases or disorders associated with the activity of Helios protein, which is used to reduce Helios protein levels, Helios activity levels and / or Helios expression levels in cells to modulate the differentiation of Tregs.

[0191] The compounds of formula (I) and pharmaceutical compositions comprising at least one compound of formula (I) are useful for treating or preventing any disease or condition associated with the activity of Helios protein. Such diseases or conditions include viral and other infectious diseases (e.g., skin infections, GI infections, urinary tract infections, urogenital infections, systemic infections), and proliferative diseases (e.g., cancer). The compounds of formula (I) and pharmaceutical compositions comprising at least one compound of formula (I) can be administered to animals, preferably mammals (e.g., laboratory animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration can be used to deliver the compound or pharmaceutical composition to the patient. In some embodiments, the compounds of formula (I) or pharmaceutical compositions comprising at least one compound of formula (I) are administered orally. In other embodiments, the pharmaceutical compositions comprising formula (I) or at least one compound of formula (I) are administered parenterally.

[0192] The compound of formula (I) can selectively reduce Helios protein levels and Helios activity levels and / or suppress Helios expression levels in cells to control Treg differentiation. For example, the compound of formula (I) can be used to reduce Helios activity levels and / or inhibit Helios expression levels in subjects or cells in need of selectively reducing Helios protein levels and Helios activity levels and / or suppressing Helios expression levels to control Treg differentiation, and the compound of formula (I) or a salt thereof can be administered in an inhibitory amount.

[0193] In some embodiments, the compound of formula (I) is administered sequentially prior to administration of the immuno-oncology agent. In other embodiments, the compound of formula (I) is administered simultaneously with the immuno-oncology agent. In yet other embodiments, the compound of formula (I) is administered sequentially following administration of the immuno-oncology agent.

[0194] In another embodiment, the compound of formula (I) may be formulated with an immuno-oncology agent.

[0195] The immuno-oncology agent includes, for example, small molecule drugs, antibodies, or other biological molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized antibody or a human antibody.

[0196] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory receptor (including costimulatory), or (ii) an antagonist of an inhibitory signal (including co-inhibitory) on a T cell, both of which result in amplification of an antigen-specific T cell response (often referred to as an immune checkpoint regulator).

[0197] Certain stimulatory and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors are the TNF family molecules that bind to the cognate TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, April, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, E Includes DAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0198] In certain embodiments, T cell responses may be stimulated by a combination of a compound of formula (I) of the present invention and one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin 1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0199] For cancer treatment, other drugs that can be combined with the compound of formula (I) can include antagonists of inhibitory receptors on NK cells, or agonists of activating receptors on NK cells. For example, the compound of formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0200] Further agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including, but are not limited to, CSF-1R antagonists, such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or CSF-1R antagonist antibodies, including FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0201] In another embodiment, the compounds of formula (I) may be used with one or more of agonistic agents that bind positive co-stimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase the frequency of anti-tumor T cells systemically, agents that overcome different immune suppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Treg cells (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by depletion with anti-CD25 beads in vitro), inhibiting metabolic enzymes such as IDO, or restoring / preventing T cell anergy or T cell depletion), and agents that cause innate immune activation and / or inflammation in the tumor area.

[0202] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy (ipilimumab), or tremelimumab.

[0203] In another embodiment, the immuno-oncology agent is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach targeting the PD-1 receptor involves the use of IgG 1 There is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of AMP-224.

[0204] In another embodiment, the immuno-oncology agent includes a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), and MSB0010718C (WO2013 / 79174).

[0205] In another embodiment, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0206] In another embodiment, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0207] In another embodiment, the immuno-oncology agent is a GITR agonist, for example, an agonistic GITR antibody. Suitable CD137 antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0208] In another embodiment, the immuno-oncology agent is an IDO antagonist.Suitable IDO antagonists include, for example, INCB-024360 (WO206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0209] In another embodiment, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0210] In another embodiment, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0211] In another embodiment, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody.In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody.Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0212] In another embodiment, the immuno-oncology agent is a CD27 agonist, such as an antagonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0213] In another embodiment, the immuno-oncology agent (against B7H3) is MGA271 (WO11 / 109400).

[0214] Combination therapy is intended to include administration of the therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of the therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form of each therapeutic agent with a fixed ratio, or a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be performed by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The administration of the therapeutic agents described above can also be combined with other biologically active ingredients and non-pharmaceutical therapies (e.g., surgery or radiation therapy) to perform combination therapy. When the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the synergistic action of the combination of the therapeutic agent and the non-drug treatment is achieved, e.g., in suitable cases, the beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from administration of the therapeutic agent.

[0215] The types of cancer that may be treated with the compounds of formula (I) include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer and bone cancer. Examples of such cancer types include neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors), Hodgkin's lymphoma, and tumors, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia-lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma.

[0216] One or more additional pharmaceutical agents or therapeutic methods (e.g., antiviral agents, chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors) may be used in combination with the compounds of formula (I) as appropriate to treat a disease, disorder, or condition associated with a Helios protein. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially in different dosage forms.

[0217] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethylenimine derivatives, alkylsulfonic acids, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0218] In the treatment of melanoma, suitable agents for use in combination with the compounds of formula (I) include dacarbazine (DTIC), optionally with other chemotherapeutic agents (e.g., carmustine (BCNU) and cisplatin); the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin and tamoxifen; cisplatin, vinblastine, and DTIC, temozolomide or Yervoy. TM The compounds of formula (I) may also be combined with immunotherapeutic agents, such as cytokines, such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF), in the treatment of melanoma.

[0219] The compounds of formula (I) can also be used in combination with vaccine therapy in the treatment of melanoma.Anti-melanoma vaccines are similar in some respects to anti-viral vaccines used to prevent diseases caused by viruses (e.g., polio, measles, and mumps).Attenuated melanoma cells or parts of melanoma cells called antigens can be injected into patients to stimulate the body's immune system to destroy melanoma cells.

[0220] Melanomas confined to the arms or legs may also be treated using hyperthermic perfusion therapy with a combination of drugs including one or more compounds of formula (I). This treatment protocol involves temporarily isolating the circulatory system of the affected limb from the rest of the body and injecting high concentrations of chemotherapy drugs into the arteries of the affected limb, delivering high doses to the tumor site that would cause serious side effects if exposed to internal organs. Typically, this treatment involves warming bodily fluids to 38.9°C to 40°C. Melphalan is the drug most frequently used in this chemotherapy. Another drug called tumor necrosis factor (TNF) may also be used.

[0221] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0222] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons (especially IFNα), etoposide, and teniposide.

[0223] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene.

[0224] Suitable cytotoxic agents also include, for example, epipodophyllotoxins; anti-neoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes (e.g., cisplatin and carboplatin); biological response modifiers; growth inhibitory agents; anti-hormonal therapeutics; leucovorin; tegafur; and hematopoietic growth factors.

[0225] Other anti-cancer agents include antibody drugs such as trastuzumab (Herceptin®), antibodies against costimulatory molecules (such as CTLA-4, 4-1BB and PD-1), or antibodies against cytokines (IL-1O or TGF-β).

[0226] Other anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors (eg, CCR2 and CCR4).

[0227] Other anti-cancer drugs also include anti-cancer drugs that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[0228] Anti-cancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines and recombinant viral vaccines.

[0229] The pharmaceutical compositions of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more critical steps in a signal transduction pathway in the normal function of cancer cells, thereby inducing apoptosis. Suitable STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (IRESSA®, SSI-774)) and antibodies (Imclone: ​​C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors (e.g., farnesyltransferase inhibitors (FTIs) (e.g., L-744,832 [Kohl et al., Nat. Med., 1(8):792-797 (1995)]); (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513 (200)); (v) cell cycle kinase inhibitors (e.g., flavopiridol and UCN-O1 (see, e.g., Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203)); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248 (204)); (1994)). Alternatively, at least one STI and at least one compound of formula (I) can be formulated in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one compound of formula (I) and at least one STI can be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) can be administered first, at least one STI can be administered first, or at least one compound of formula (I) and at least one STI can be administered simultaneously.Furthermore, when more than one compound of formula (I) and / or an STI is used, the compounds may be administered in any order.

[0230] The present invention further provides pharmaceutical compositions comprising at least one compound of formula (I), optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent, in a pharma- ceutically acceptable carrier for treating a chronic viral infection in a patient.

[0231] Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of the pharmaceutical composition.

[0232] In certain embodiments of the present invention, at least one compound of formula (I) and at least one chemotherapeutic agent are administered to patient simultaneously or sequentially.In other words, at least one compound of formula (I) can be administered first, at least one chemotherapeutic agent can be administered first, or at least one compound of formula (I) and at least one chemotherapeutic agent can be administered simultaneously.In addition, when more than one compound of formula (I) and / or chemotherapeutic agent are used, the compounds can be administered in any order.Similarly, any antiviral drug or STI can be administered at any time compared to the administration of the compound of formula (I).

[0233] Chronic viral infections that may be treated using the combination therapy include, but are not limited to, diseases caused by Hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).

[0234] Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

[0235] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also called β-L-D4C, which has the name β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Representative suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral drugs include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0236] Combination therapy is intended to include administration of the therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of the therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form of each therapeutic agent with a fixed ratio, or a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be performed by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The administration of the therapeutic agents described above can also be combined with other biologically active ingredients and non-pharmaceutical therapies (e.g., surgery or radiation therapy) to perform combination therapy. When the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the synergistic action of the combination of the therapeutic agent and the non-drug treatment is achieved, e.g., in suitable cases, the beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from administration of the therapeutic agent.

[0237] Pharmaceutical Composition The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I), formulated together with one or more pharma- ceutically acceptable carriers (excipients) and / or diluents, and optionally one or more further therapeutic agents as described above.

[0238] The compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such route, and in a dosage effective for the intended treatment. The compounds of formula (I) and compositions of compounds of formula (I) may be administered for any of the uses described herein by any suitable method, for example, oral administration (e.g., tablets, capsules (including sustained or timed release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions); sublingual administration; buccal administration; parenteral administration (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasal administration, including administration to the nasal membranes (e.g., inhalation sprays); topical administration (e.g., in the form of cream formulations or ointments); or rectal administration (e.g., in the form of suppositories). They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the selected route of administration and standard pharmaceutical practice.

[0239] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably formulated in a dosage unit form with a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose to be administered to a human or other mammal may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0240] Any pharmaceutical composition discussed herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration. In order to provide a medicament that is easy to swallow, the pharmaceutical compositions described in the present invention can include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0241] Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof with at least one non-toxic, pharma-ceutically acceptable additive suitable for tablet preparation. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binding agents (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). In addition, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the digestive tract, thus prolonging the effect of the active ingredient for a longer period of time. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0242] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one salt thereof with at least one inert solid diluent (e.g., calcium carbonate, calcium phosphate, and kaolin).

[0243] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0244] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof with at least one excipient suitable for the preparation of aqueous suspensions. Examples of excipients suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic), dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and Examples of suitable condensation products include condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (e.g., but not limited to, sucrose, saccharin, and aspartame).

[0245] Oil suspensions can be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof in either vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or mineral oil (e.g., liquid paraffin). Oil suspensions can also include at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide a palatable oil suspension, at least one sweetener already described above and / or at least one flavoring agent can be added to the oil suspension. Oil suspensions can further include at least one preservative, including but not limited to, for example, an antioxidant (e.g., butylated hydroxyanisole, and alpha-tocopherol).

[0246] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preserving agent. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). In addition, dispersible powders and granules can also include at least one excipient (e.g., but are not limited to, sweeteners, flavoring agents, and coloring agents).

[0247] The emulsion of at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof may be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of formula (I) may be composed of known ingredients in a known manner. The oil phase may be provided, for example, but not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase may include only an emulsifier, but may also include a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier, with or without stabilizer, makes up the so-called emulsifying wax, and the wax, together with the oil and fat, makes up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. The emulsion may also include sweeteners, flavorings, preservatives, and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or with wax; or other materials known in the art.

[0248] The compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0249] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more carriers or diluents described for use in preparations for oral administration, or by using other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffer solutions. Other adjuvants and methods of administration are known and widely known in the pharmaceutical field. The active ingredient may also be administered by injection in a composition with a suitable carrier (e.g., saline, dextrose, or water), or cyclodextrin (i.e., Captisol), solubilizing cosolvent (i.e., propylene glycol), or solubilizing micelle (i.e., Tween 80).

[0250] A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used as injectable preparations.

[0251] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin), 2) combining the oil phase containing formula (I) with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0252] Sterile aqueous suspension or sterile oily suspension can be prepared according to a method known to those skilled in the art. For example, sterile aqueous solution or sterile aqueous suspension can be prepared using a non-toxic, parenterally acceptable diluent or solvent (e.g., 1,3-butanediol), and sterile oily suspension can be prepared using a non-toxic, acceptable solvent or suspension medium (e.g., sterile fixed oil (e.g., synthetic monoglyceride or diglyceride), and fatty acid (e.g., oleic acid).

[0253] Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent to be formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the therapeutic indications to be targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can include many different components and additives in addition to the active agent, and such additional components are included in the formulation for various reasons, such as stabilization of the active agent, binders, etc., as known to those skilled in the art. Descriptions of suitable pharmacopoeia acceptable carriers and factors in selecting them can be found in a variety of readily available literature, such as Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0254] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, salts, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins (e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives)) may also be effectively used to enhance the delivery of compounds of the formulae described herein.

[0255] The pharma- ceutical active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or can contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills can additionally be prepared with enteric coatings. Such compositions can also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and aromatic agents).

[0256] For treatment, the active compound of the present invention is usually combined with one or more adjuvants suitable for intended administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can include controlled release formulations, and can be provided with active compound dispersed in hydroxypropylmethylcellulose.

[0257] The amount of compound administered to treat a condition using the compounds and / or compositions of the present invention, and the dosing schedule will depend on a variety of factors, such as age, weight, sex, the condition of the patient, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound utilized. Thus, the dosing schedule may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 to about 50 mg / kg body weight, and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered 1 to 4 times a day. Other dosing schedules include weekly and biday cycles.

[0258] The pharmaceutical compositions of the present invention include at least one compound of formula (I) and / or at least one pharma- ceutically acceptable salt thereof, and optionally an excipient selected from any pharma- ceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention includes a compound of formula (I) as described herein, or a prodrug thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0259] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of Helios protein-associated diseases or disorders, and other diseases described herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I). Such kits may further include one or more of a variety of conventional pharmaceutical kit components, as desired (e.g., a container containing one or more pharma- ceutically acceptable carriers, another container), which will be readily apparent to those of skill in the art. Instructions, either in the form of a package insert or label, indicating the amounts of components to be administered, administration guidelines, and / or mixing guidelines for the components, may also be included in the kit.

[0260] Dosing regimens for the compounds of the invention will, of course, vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its method and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the condition; type of concomitant treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect.

[0261] As a general guidance, the daily oral dose of each active ingredient, when used to obtain the intended effect, will range from about 0.001 to about 5000 mg / day, preferably about 0.01 to about 1000 mg / day, and most preferably between about 0.1 and about 250 mg / day. The most preferred dose for intravenous constant rate infusion is in the range of about 0.01 to about 10 mg / kg / min. Compounds of formula (I) may be administered in a single daily dose or in divided doses of two, three, or four total daily doses.

[0262] The compounds will generally be administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with conventional pharmaceutical standards.

[0263] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 mg to about 200 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1 to 95% by weight of the total weight of the composition.

[0264] A typical capsule for oral administration contains at least one compound of formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg), which mixture is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule.

[0265] A typical injectable formulation is prepared by aseptically adding at least one compound of formula (I) (250 mg) to a vial, aseptically lyophilizing and sealing the vial, and at the time of use, mixing the contents of the vial with saline (2 mL) to prepare the injectable formulation.

[0266] The present invention includes within its scope pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) as an active ingredient, alone or in combination with a pharmaceutical carrier. Compounds of formula (I) may be used alone, in combination with other compounds of formula (I), or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharma- ceutical active substances), as appropriate.

[0267] Regardless of the route of administration selected, the compounds of formula (I) and / or pharmaceutical compositions of the present invention, which may be used in a suitable hydrated form, are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those of skill in the art.

[0268] Actual dosage levels of the active ingredient in the pharmaceutical compositions of formula (I) may be varied to contain an amount of the active ingredient effective to obtain a therapeutic effect for a particular patient, composition and mode of administration, without being toxic to the patient.

[0269] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of formula (I) or its esters, salts or amides employed, the route of administration of the particular compound employed, the time of administration, the rate of excretion or metabolism, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular compound employed, the age, sex, weight, symptoms, health and medical history of the patient being treated, and factors well known in the medical arts.

[0270] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the compound of formula (I) used in the pharmaceutical composition at a lower level than required to achieve a therapeutic effect, and gradually increase the dosage until an effect is achieved.

[0271] In general, the suitable daily dose of the compound of formula (I) is the lowest effective dose of the compound to obtain a therapeutic effect. Such an effective dose is generally determined by the above factors. In general, the dose of the compound of formula (I) to a patient is about 0.01 to about 50 mg / kg body weight / day for oral, intravenous, intracerebroventricular and subcutaneous administration.

[0272] If desired, the effective daily dose of the active compound may be administered in two, three, four, five, six or more divided doses at appropriate intervals throughout the day, conveniently in unit dosage forms. In some embodiments of the invention, dosing is once a day.

[0273] While it is possible for a compound of formula (I) to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0274] The other therapeutic agents described above, when used in combination with the compounds of formula (I), may be used, for example, in amounts as set forth in the Pharmaceutical Description (PDR) or as determined by one of ordinary skill in the art. In the methods of the invention, the other therapeutic agents may be administered prior to, simultaneously with, or after administration of the compounds of the invention.

[0275] (Manufacturing method) The compounds of the present invention can be prepared by many methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized by the following methods using synthetic methods known in the art of organic synthetic chemistry, or by analogous synthetic methods that will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, the following methods. All documents cited herein are incorporated by reference in their entirety.

[0276] The compounds of the present invention may be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents suitable for the reagents and materials used and are appropriate for the transformations effected. It is also understood that in the description of the synthetic methods described below, all of the reaction conditions presented (including the choice of solvent, reaction atmosphere, reaction temperature, experimental time, and work-up method) are selected to be conditions that are standard for the reactions, which should be readily recognized by those skilled in the art. It is understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule must be compatible with the reagents and reactions presented. Such restrictions on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must be used. The reactions may require the decision to change the order of synthetic steps or to select certain reaction courses differently in order to obtain the desired compounds of the present invention. It is also recognized that another important consideration in planning any synthetic route in this field is the selection of appropriate protecting groups to be used to protect reactive functional groups present in the compounds described in the present invention. For the experienced experimenter, an authoritative reference describing many protecting group alternatives is Protective Groups In Organic Synthesis by Greene and Wuts (Fourth Edition, Wiley & Sons, 2007).

[0277] Compounds of formula (I) may be prepared by reference to the methods depicted in the following schemes. As depicted in the schemes, the final product is a compound having the same structural formula as formula (I). It is understood that by selecting appropriate reagents for the appropriate substituents, any compound of formula (I) may be prepared by the schemes. Solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. The components of the compounds are defined as described herein.

[0278] The general synthetic routes for the compounds described in this invention are illustrated in Schemes 1-2. 1 , R 2 , R 4 and R 6 is as defined above or is a functional group that can be converted to a final substituent. Substituent X is a leaving group, such as a halide (preferably I, Br, or Cl) or a triflate. Substituent M is a suitable coupling partner, such as a boronic acid, a boronic ester, or a stannane. Substituent R is a carboxylic acid protecting group, such as tert-butyl, methyl, ethyl, or benzyl. As shown in Scheme 1, a general method for preparing the compounds of the invention can begin with a suitable substituted aryl fluoride 1. Treatment with a suitable nucleophile, for example intermediate 2, where M can be MgBr or Li, can produce a substituted aryl halide, such as 3. Halogenation, preferably bromination, can be achieved by treating 3 with a reagent such as N-bromosuccinimide to give bromide 4. Treatment of 4 with an amine 5 under basic conditions, such as potassium carbonate, results in initial displacement of the secondary bromide, followed by subsequent cyclization to give lactam 6.

[0279] [ka]

[0280] When M is a stannane, 6 can be prepared by a Stille coupling reaction using a suitable catalyst (e.g., Pd(PPh 3 ) 4or bis(triphenylphosphine)dichloropalladium(II) / CuI) to provide 8. Alternatively, 6 can be converted to boronic acid or boronic ester 9 using conditions well known to those skilled in the art. The boronic acid or boronic ester 9 can be reacted with a suitable palladium catalyst (e.g., Pd(PPh 3 ) 4 Alternatively 1,1'-bis(diphosphinylferino)ferrocene]dichloropalladium(II) can be used to provide 8 in the presence of a suitable base such as cesium carbonate, potassium phosphate or sodium bicarbonate.

[0281] Depending on which acid protecting group R is selected in intermediate 8, different conditions are required for conversion to compound 11 (Scheme 2). For example, when R is methyl, ethyl or benzyl, base-induced cyclization of 8 may be preferred to convert 8 directly to 11 using a suitable base (e.g. LiHMDS) in a suitable solvent (e.g. tetrahydrofuran). When R is tert-butyl, acid-induced cyclization of 12 may be preferred to convert 8 directly to 11 using a suitable acid (e.g. benzenesulfonic acid) in a suitable solvent (e.g. acetonitrile). In other cases, a two-step method may be preferred, first generating the corresponding free carboxylic acid 8 using conditions appropriate for the particular acid protecting group R. These are methods well known to those skilled in the art of organic synthesis. For example, when R is tert-butyl, acid hydrolysis using a suitable acid (e.g. trifluoroacetic acid or hydrochloric acid) is preferred. When R is methyl, ethyl or benzyl, base hydrolysis using a suitable base (e.g. LiOH) is preferred. In other cases, when R is benzyl, deprotection by palladium catalyzed hydrogenolysis is preferred. Once the carboxylic acid is generated, it can be activated by the action of thionyl chloride / dimethylformamide or carbonyldiimidazole / dimethylaminopyridine to undergo intramolecular attack by the pendant primary amide to give 11.

[0282] [ka] EXAMPLES

[0283] (Example) The following examples are illustrative of certain embodiments of the invention and are not intended to limit the scope of the invention. Chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their usual and customary meanings unless otherwise specified. Additional abbreviations used in the examples and elsewhere in this specification are defined above. Common intermediates are generally useful in the preparation of one or more of the examples. Example compounds are identified by the example and step by which they are prepared (e.g., "1-A" represents step A of Example 1), or by the example only if the compound is the title compound of the example (e.g., "1" represents the title compound of Example 1). In some cases, alternative methods of preparation of intermediates or examples are described. Chemists skilled in the synthetic arts will frequently devise alternative preparation methods that are desirable based on one or more considerations (e.g., shorter reaction times, cheaper starting materials, ease of handling and purification, higher yields, ease of catalysis, avoidance of toxic reagents, availability on specialized equipment, and fewer steps). The intent of describing alternative preparation methods is to make the examples of the invention more amenable to preparation. In some cases, some of the functional groups in the outlined examples and claims may be substituted with bioisosteric replacements known to those of skill in the art (e.g., replacing a carboxylic acid group with a tetrazole or phosphate moiety).

[0284] [Table 8]

[0285] Preparative HPLC Method 1: XBridge C18, 200mm x 19mm, particle size: 5μm; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 10mM ammonium acetate); Gradient: start B; 0% B, end B; 100% B over 3 minutes, then hold at 100% B for 0.5 minutes; Flow rate: 1 mL / min; Fraction collection was triggered by the MS signal.

[0286] UHPLC-MS method: Column: Waters Acquity BEH Phenyl 1.7 μm 2.1 x 50 mm; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Gradient: start B; 0% B, end B; 100% B over 3 min, then hold at 100% B for 0.5 min; Flow rate: 1 mL / min; Fraction collection was triggered by the MS signal.

[0287] Example 1 3-(5-(5-chloro-4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 1A: tert-butyl (S)-5-amino-4-(5-(5-chloro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 20 mL vial, add (2,5-dichloropyridin-4-yl)methanol (0.2 g, 1.124 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (0.749 g, 1.685 mmol), Pd(dtbpf)Cl 2(0.022 g, 0.034 mmol), 1,4-dioxane (5.62 mL) and 3M K 3 PO 4 Aqueous solution (1.873 mL, 5.62 mmol) was added. The vial was sealed and the air was replaced with nitrogen. The reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (25 mL), washed with brine, and the layers were separated. The organic material was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by ISCO column chromatography using a silica gel column (40 g Gold column, eluted with DCM-20% methanolic ammonia in DCM 0-100%) to give tert-butyl-5-amino-4-(5-(5-chloro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (320 mg, 0.668 mmol, 59.4% yield) as a light brown solid. The enantiomeric excess of this material and subsequent intermediates was not determined. MS (ES): m / z = 460.05 [M+H] + .

[0288] Intermediate 1B: 3-(5-(5-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Thionyl chloride (0.132 mL, 1.826 mmol) was added dropwise to a cooled (0 °C) solution of tert-butyl-5-amino-4-(5-(5-chloro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.280 g, 0.609 mmol) in DCM (3.00 mL). After 10 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated to dryness. The residue was dissolved in acetic acid (3 mL), benzenesulfonic acid (0.212 g, 1.339 mmol) was added, and the reaction mixture was heated at 120 °C in a microwave oven for 25 min. The reaction mixture was concentrated to dryness and 2 mL of 3M HCl / MeOH was added and stirred at 0 °C (ice-water bath) until complete dissolution. Then, 8 mL of EtOAc was added and the reaction mixture was stirred. After 5 min, the reaction mixture was placed in an ice-water bath for 30 min. The precipitate was filtered, washed with EtOAc, and then air-dried to give 3-(5-(5-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 0.401 mmol, 65.8% yield) as the hydrochloride salt. MS(ES): m / z = 404.3, 406.3 [M+H] + .

[0289] Example 1: To a solution of 3-(5-(5-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (40 mg, 0.091 mmol) in DMF (0.5 mL) was added 3-(3,4-difluorophenyl)azetidine, HCl (21.5 mg, 0.104 mmol) followed by Hunig's base (95 μL, 0.545 mmol). The resulting mixture was heated to 80° C. with stirring for 3 h. It was then cooled and further diluted with DMF (0.5 mL). The crude material was purified by preparative LC / MS with the following conditions: Column; XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 35% B at 0 min hold, 35-75% B at 22 min hold, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. The product-containing fractions were combined and dried by centrifugal evaporation to give 3-(5-(5-chloro-4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25.2 mg, 0.046 mmol, 51% yield). LCMS (Method A): Retention time 1.97 min; MS (ES): m / z = 537.17 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d 6) δ 8.89 (s, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 8.24 (m, m 1H), 7.99 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.41-7.31 (m, 5H), 7.26-7.20 (m, 1H), 5.16 (m, 1H), 4.56 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 3.80-3.66 (m, 5H), 3.26-3.18 (m, 2H), 3.00-2.88 (m, 1H), 2.49-2.37 (m, 1H), 2.10-2.01 (m, 1H).

[0290] Examples 2 to 5 The compounds in Table 1 were prepared according to the procedure described in Example 1, substituting the appropriate amine for 3-phenylazetidine. [ka]

[0291] Examples 6 to 9 The compounds in Table 2 were prepared following the general method described for Example 1, substituting the appropriate amine for 3-phenylazetidine. [ka]

[0292] Example 10 3-(5-(4-((2-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0293] Intermediate 10A: 1-Cyclopropyl-3-fluorobenzene In a 20 mL scintillation vial, add 1-bromo-3-fluorobenzene (500 mg, 2.86 mmol), cyclopropylboronic acid (258 mg, 3.00 mmol), Pd(dtbpf)Cl 2 (55.9 mg, 0.086 mmol), THF (10 mL) and K 3 PO 4 Aqueous solution (2.86 mL, 8.57 mmol) was added. The air was replaced with nitrogen and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature. The reaction was quenched with brine. The reaction mixture was diluted with ether. The organic layer was concentrated and purified by ISCO using a 40 gram silica gel column eluted with 0-5% EtOAc / Hexanes. The appropriate fractions were combined and the solvent was evaporated to give the title compound (261 mg, 67% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.26-7.19 (m, 1H), 6.91-6.81 (m, 2H), 6.76 (dt, J=10.4, 2.1 Hz, 1H), 1.95-1.87 (m, 1H), 1.04-0.98 (m, 2H), 0.74-0.69 (m, 2H).

[0294] Intermediate 10B: 1-(1,3-dibromopropyl)-3-fluorobenzene To a solution of 1-cyclopropyl-3-fluorobenzene (180 mg, 1.322 mmol) in DCM (10 mL) at room temperature was added a solution of potassium bromide (346 mg, 2.91 mmol) and cerium ammonium nitrate (1667 mg, 3.04 mmol) in water (10 mL). The reaction mixture was stirred. After 0.75 h, the organic layer was separated, washed with brine and concentrated. The residue was purified by column chromatography on silica gel (40 g) using hexane as eluent to give the title product in 64% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35 (td, J=8.0, 5.9 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.16 (dt, J=9.6, 2.1 Hz, 1H), 7.04 (t, J=8.2 Hz, 1H), 5.18 (dd, J=8.9, 5.8 Hz, 1H), 3.58 (ddd, J=10.4, 7.9, 5.4 Hz, 1H), 3.44 (dt, J=10.4, 5.8 Hz, 1H), 2.76 (ddt, J=14.8, 9.0, 5.8 Hz, 1H), 2.55 (ddt, J=15.0, 7.9, 5.7 Hz, 1H).

[0295] Example 10: To 1-(1,3-dibromopropyl)-3-fluorobenzene (25 mg, 0.084 mmol) dissolved in DMF (1 mL) was added 3-(5-(4-(aminomethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,2HCl (35.8 mg, 0.084 mmol) followed by Hunig's base (0.118 mL, 0.676 mmol). The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature and purified by preparative HPLC method 1 to give the title compound (3.2 mg). Analytical HPLC; Method B; Retention time 1.68 min; [M+H] + 485.2.

[0296] Example 11 3-(5-(4-((3-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 11A: tert-Butyl 3-(2-tosylhydrazinylidene)azetidine-1-carboxylate To tert-butyl 3-oxoazetidine-1-carboxylate (4 g, 23.4 mmol) was added 4-methylbenzenesulfonohydrazide (4.35 g, 23.4 mmol), followed by toluene (8 mL). The reaction mixture was heated at reflux for 40 min. The reaction mixture was cooled. The solid was collected by filtration to give tert-butyl 3-(2-tosylhydrazinylidene)azetidine-1-carboxylate (7.133 g, 21 mmol, 90% yield). MS(ES):m / z = 337.9 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δ 10.85 (br s, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 4.53-4.44 (m, 4H), 3.32 (s, 3H), 2.40 (s, 3H), 1.39 (s, 9H). References:1) Allwood, DMJ Org. Chem. 2014, 79, 328-338;2) Barluenga, J. Nat. Chem., 2009, 1, 494-499.

[0297] Intermediate 11B: tert-Butyl 3-(3-fluorophenyl)azetidine-1-carboxylate tert-Butyl 3-(2-tosylhydrazinylidene)azetidine-1-carboxylate (200 mg, 0.589 mmol), (3-fluorophenyl)boronic acid (124 mg, 0.884 mmol) and cesium carbonate (288 mg, 0.884 mmol) were placed in a pressure relief vial under vacuum for 30 min. The vial was backfilled with nitrogen. Dry 1,4-dioxane (3 mL) was added under nitrogen. The vial was sealed and heated at 110 °C for 18 h before being cooled to room temperature. The reaction mixture was washed with saturated NaHCO 3 The mixture was quenched with aqueous CH 2 Cl 2 The organic phase was extracted with Na 2 SO 4Drying over and removal of the solvent gave a residue which was purified by flash column chromatography (0-40% EtOAc / hexanes) to give tert-butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (65 mg, 0.26 mmol, 43.9% yield). 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.47-7.30 (m, 1H), 7.21-7.15 (m, 1H), 7.13-7.07 (m, 1H), 7.04-6.97 (m, 1H), 4.41-4.33 (m, 2H), 3.98-3.90 (m, 2H), 3.89-3.80 (m, 1H), 1.49 (s, 9H).

[0298] Example 11: To tert-butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (61 mg, 0.243 mmol) was added TFA / DCM (1:1, 1 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give the TFA salt of 3-(3-fluorophenyl)azetidine. To 3-(5-(4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione HCl salt (25 mg, 0.062 mmol) was added 3-(3-fluorophenyl)azetidine TFA salt (20 mg, 0.075 mmol) in DMF (2 mL), followed by N-ethyl-N-isopropylpropan-2-amine (0.107 mL, 0.615 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((3-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (13.8 mg, 0.028 mmol, 46.3% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 20-60% B over 25 min; Flow rate: 20 mL / min; Column temperature: 25 °C. The enantiomeric excess of 3-(5-(4-((3-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione) was not determined. LCMS (Method A): Retention time 1.16 min. MS(ES): m / z = 484.9 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.64 (d, J=4.6 Hz, 1H), 8.32 (br s, 1H), 8.23 ​​(br d, J=7.8 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.41-7.34 (m, 2H), 7.26-7.17 (m, 2H), 7.05 (br t, J=8.2 Hz, 1H), 5.21-5.11 (m, 1H), 4.56 (br d, J=17.2 Hz, 1H), 4.43 (br d, J=17.3 Hz, 1H), 3.77 (s, 2H), 3.74-3.69 (m, 3H), 3.22 (br s, 2H), 2.96-2.82 (m, 1H), 2.63 (br d, J=17.3 Hz, 1H), 2.44 (br dd, J=12.4, 4.0 Hz, 1H), 2.19-1.99 (m, 1H).

[0299] Examples 12 to 27 The compounds in Table 3 were prepared according to the methods described in Example 1. [Table 9] [Table 10]

[0300] Examples 28 to 30 The compounds in Table 4 were prepared following the general procedures described in Example 1 using commercially available amines. [Table 11]

[0301] Example 32 tert-Butyl (4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate [ka] To a suspension of tert-butyl (4-((7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate (17.53 mg, 0.053 mmol) and 3-(5-(4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.041 mmol) in DMF (1 mL) was added Hunig's base (0.071 mL, 0.406 mmol) at room temperature. The reaction mixture became a clear solution. The vial was sealed and heated at 80° C. for 1.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 38% B at 0 min hold, 38-78% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. The product yield was 5.2 mg, (19%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.11-9.01 (m, 1H), 8.68-8.58 (m, 1H), 8.33-8.29 (m, 1H), 8.24-8.12 (m, 1H), 7.99-7.92 (m, 1H), 7.89-7.79 (m, 1H), 7.40-7.18 (m, 3H), 6.75-6.64 (m, 2H), 5.19-5.06 (m, 1H), 4.66-4.61 (m, 1H), 4.58-4.32 (m, 2H), 3.62-3.51 (m, 5H), 2.97-2.84 (m, 1H), 2.71-2.60 (m, 1H), 2.47-2.18 (m, 7H), 2.13-1.99 (m, 1H), 1.77-1.65 (m, 2H), 1.67-1.55 (m, 5H), 1.4.

[0302] Examples 33 to 67 The compounds in Table 5 were prepared following the procedure described in Example 1, substituting the appropriate primary or secondary amine for tert-butyl (4-((7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate. [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0303] Example 68 3-(5-(4-((6-oxa-2,9-diazaspiro[4.5]decan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2024515545000065.tif39153 tert-Butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (9.3 mg, 0.012 mmol) in a 2-dram vial was diluted with 20% TFA / CH 2 Cl 2(1 mL, 0.012 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and dissolved in DMF. The crude material was purified by preparative LC / MS with the following conditions: Column; XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 0% B hold for 0 min, 0-40% B over 20 min, then 100% B hold for 0 min; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by MS signal. Fractions containing product were combined and dried by centrifugal evaporation. The product yield was 4.0 mg. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.70-8.61 (m, 1H), 8.34-8.27 (m, 1H), 8.25-8.14 (m, 1H), 8.00-7.94 (m, 1H), 7.89-7.81 (m, 1H), 7.37 (br d, J=4.3 Hz, 1H), 5.13 (br dd, J=13.3, 5.3 Hz, 1H), 4.65-4.35 (m, 2H), 3.58-3.42 (m, 2H), 2.98-2.86 (m, 1H), 2.81-2.73 (m, 1H), 2.69-2.32 (m, 14H), 2.11-1.98 (m, 1H), 1.88-1.82 (m, 2H), 1.81-1.70 (m, 2H). LC MS:M+H=476.1 tr=0.88 min. (Method A).

[0304] Example 69 3-(5-(4-((9-benzoyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of 3-(5-(4-((6-oxa-2,9-diazaspiro[4.5]decan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10 mg, 0.021 mmol) in DMF (1 mL) was added benzoic acid (3.85 mg, 0.032 mmol), followed by HATU (11.99 mg, 0.032 mmol) and Hunig's base (0.037 mL, 0.210 mmol). The reaction mixture was stirred at room temperature for 5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with 0.05% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.05% trifluoroacetic acid); Gradient: 1% B at 0 min hold, 1-41% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the product were combined and dried by centrifugal evaporation. The product yield was 22.5 mg. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.12-10.89 (m, 1H), 8.89-8.74 (m, 1H), 8.39-8.17 (m, 3H), 7.96-7.84 (m, 1H), 7.61-7.39 (m, 5H), 5.24-5.02 (m, 1H), 4.67-4.40 (m, 3H), 3.84-3.62 (m, 1H), 3.03-2.84 (m, 1H), 2.72-2.59 (m, 1H), 2.58-2.49 (m, 13H), 2.48-2.31 (m, 2H), 2.15-1.93 (m, 2H).LC MS:M+H=580.2 tr=1.01 min. (Method A).

[0305] Examples 70 to 88 The compounds in Table 6 were prepared according to the general procedures described in Example 1. [Table 17] [Table 18] [Table 19]

[0306] Example 87 3-(5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 87A: tert-butyl-5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 100 mL round bottom flask was added (2-chloro-3-fluoropyridin-4-yl)methanol (1.00 g, 6.19 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (3.16 g, 7.12 mmol), Pd(OAc) 2 (0.069 g, 0.309 mmol), di-tert-butyl(methyl)phosphonium tetrafluoroborate (0.154 g, 0.619 mmol), dioxane (50 mL) and K 2 CO 3 Aqueous solution (10.32 mL, 30.9 mmol) was added. The reaction vessel was sealed and the air was replaced with nitrogen. The reaction mixture was heated at 80 °C with stirring for 24 h. It was cooled to room temperature, diluted with EtOAc, washed with brine, the organic layer was separated and diluted with MgSO 4After drying and concentration, the crude mixture was purified by ISCO using a 120 g silica gel column eluting with 0-10% DCM / MeOH to give the title compound [2.37 g (86%)]. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.56 (d, J=4.68 Hz, 1 H) 8.08 (d, J=7.86 Hz, 2 H) 8.07 (s, 1 H) 7.94 (d, J=7.70 Hz, 1 H) 7.54 (t, J=4.98 Hz, 1 H) 6.41 (br s, 1 H) 5.38 (br s, 1 H) 4.92-4.99 (m, 3 H) 4.51-4.64 (m, 2 H) 2.16-2.45 (m, 5 H) 1.45 (s, 9 H).

[0307] Intermediate 87B: 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl To tert-butyl 5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.38 g, 5.37 mmol) dissolved in DCM (50 mL) and cooled in an ice-water bath was added thionyl chloride (1.168 mL, 16.10 mmol) dropwise. After 10 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 20 min, the reaction mixture was concentrated to dryness and the resulting residue was dissolved in acetic acid (60 mL) followed by addition of PhSO 3 H (1.867 g, 11.81 mmol) was added. The reaction mixture was refluxed (118° C.). After 3 h, the reaction mixture was concentrated to dryness and 3M HCl / MeOH (30 mL) was added and stirred at 0° C. for about 0.25 h. Then, EtOAc (70 mL) was added and the reaction mixture was stirred. After 5 min, the mixture was placed in an ice-water bath for about 0.5 h. The title compound precipitated out and was filtered, washed with EtOAc, and air-dried (74% yield). 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.02 (s, 1 H) 8.61 (d, J=4.68 Hz, 1 H) 8.14 (s, 1 H) 8.05 (d, J=8.00 Hz, 1 H) 7.89 (d, J=8.00 Hz, 1 H) 7.68 (t, J=5.07 Hz, 1 H) 5.17 (dd, J=13.32, 5.12 Hz, 1 H) 4.94 (s, 2 H) 4.53-4.62 (m, 1 H) 4.41-4.50 (m, 1 H) 2.88-3.00 (m, 1 H) 2.58-2.69 (m, 1 H) 2.36-2.48 (m, 1 H) 2.02-2.11 (m, 1 H).

[0308] Example 87: A 40 mL vial was charged with 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (700 mg, 1.650 mmol), N-ethyl-N-isopropylpropan-2-amine (2.87 mL, 16.50 mmol), DMF (20 mL) and N-ethyl-N-isopropylpropan-2-amine (2.87 mL, 16.50 mmol) and heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed twice with 10% aqueous LiCl and brine, and diluted with MgSO 4 The mixture was purified by ISCO using a 24 gram silica gel column eluted with 0-90% B / DCM (B=15% EtOH / EtOAc+0.1% triethylamine) to give the title compound as the free base in 58.4% yield (486 mg). MS (ES): m / z = 495.2 [M+H] + , (C 27 H 31 FN 4 O 4 494.2); UHPLC-MS retention time was 1.16 min; 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.01 (s, 1 H) 8.53 (d, J=4.68 Hz, 1 H) 8.12 (s, 1 H) 8.04 (d, J=8.00 Hz, 1 H) 7.87 (d, J=8.39 Hz, 1 H) 7.53 (t, J=4.93 Hz, 1 H) 5.16 (dd, J=13.32, 5.12 Hz, 1 H) 4.56 (d, J=17.56 Hz, 1 H) 4.44 (d, J=17.46 Hz, 1 H) 4.05 (s, 1 H) 3.64 (s, 2 H) 2.88-2.99 (m, 3 H) 2.59-2.67 (m, 1H) 2.36-2.48 (m, 1 H) 2.02-2.09 (m, 1 H) 1.98 (br t, J=10.78 Hz, 2 H) 1.67 (br d, J=12.10 Hz, 2 H) 1.29 (qd, J=12.21, 3.37 Hz, 2 H) 1.12-1.22 (m, 1 H) 1.04 (s, 6 H).

[0309] Analytical HPLC Method A: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0310] Analytical HPLC Method B: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water, 0.1% trifluoroacetic acid; Temperature: Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0311] Examples 88 to 91 The compounds in Table 7 were prepared following the general procedures described in Example 87. [Table 20]

[0312] Example 92 3-(5-(5-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0313] Intermediate 92A: tert-butyl 5-amino-4-(5-(5-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 20 mL vial, add (2-chloro-5-fluoropyridin-4-yl)methanol (0.4 g, 2.476 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared according to the method set out in WO2018102725) (1.650 g, 3.71 mmol), Pd(dtbpf)Cl 2 (0.048 g, 0.074 mmol), 1,4-dioxane (12.38 mL) and 3M K 3 PO 4Aqueous solution (4.13 mL, 12.38 mmol) was added. The vial was sealed and the air was replaced with nitrogen. The reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate:water (25:5 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified using ISCO silica gel column chromatography (40 g Gold column, eluted with DCM-20% methanolic ammonia in DCM 0-100%) to give tert-butyl-5-amino-4-(5-(5-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (650 mg, 1.466 mmol, 59.2% yield) as a light brown solid. The enantiomeric excess of the material and subsequent intermediates were not determined. MS (ES): m / z = 444.04 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 8.62 (d, J=4.68 Hz, 1 H) 8.08 (d, J=7.86 Hz, 2 H) 8.07 (s, 1 H) 7.94 (d, J=7.70 Hz, 1 H) 7.54 (t, J=4.98 Hz, 1 H) 6.41 (br s, 1 H) 5.38 (br s, 1 H) 4.92-4.99 (m, 3 H) 4.51-4.64 (m, 2 H) 2.16-2.45 (m, 5 H) 1.45 (s, 9 H).

[0314] Intermediate 92B: 3-(5-(5-fluoro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl salt Thionyl chloride (0.319 mL, 4.40 mmol) was added dropwise to a cooled solution (0 °C) of tert-butyl 5-amino-4-(5-(5-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.65 g, 1.466 mmol) in DCM (7.5 mL). After 10 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated to dryness. The residue was dissolved in acetic acid (3 mL) and benzenesulfonic acid (0.510 g, 3.22 mmol) was added. The reaction mixture was heated in a microwave at 120 °C for 25 min. The reaction mixture was concentrated to dryness and 3M hydrochloric acid in MeOH (4 mL) was added and stirred at 0 °C (ice-water bath) until completely dissolved. To this solution was added ethyl acetate (12 mL). The reaction mixture was stirred for 5 min. The reaction mixture was placed in an ice-water bath for 30 min. The precipitate was filtered, washed with EtOAc, and air-dried to give 3-(5-(4-(chloromethyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (480 mg, 1.238 mmol, 84% yield) as the hydrochloride salt. MS(ES): m / z = 388.2 [M+H] + .

[0315] Example 92: To 3-(5-(3-(chloromethyl)-4-fluorophenyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (55 mg, 0.130 mmol) dissolved in DMF (650 μL) was added 2-(piperidin-4-yl)propan-2-ol hydrochloride (50 mg, 0.280 mmol) followed by Hunig's base (136 μL, 0.780 mmol). The resulting mixture was heated to 80° C. with stirring for 1 h. The reaction mixture was cooled and further diluted with DMF (0.5 mL). The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 35% B at 0 min hold, 35-75% B at 22 min hold, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined, centrifuged and evaporated to dryness to give 3-(5-(5-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (13.6 mg, 0.027 mmol, 21.21% yield). LCMS (Method A): Retention time 1.02 min; MS (ES): m / z = 495.10 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.01 (s, 1 H) 8.53 (d, J=4.68 Hz, 1 H) 8.12 (s, 1 H) 8.04 (d, J=8.00 Hz, 1 H) 7.87 (d, J=8.39 Hz, 1 H) 7.53 (t, J=4.93 Hz, 1 H) 5.16 (dd, J=13.32, 5.12 Hz, 1 H) 4.56 (d, J=17.56 Hz, 1 H) 4.44 (d, J=17.46 Hz, 1 H) 4.05 (s, 1 H) 3.64 (s, 2 H) 2.88-2.99 (m, 3 H) 2.59-2.67 (m, 1H) 2.36-2.48 (m, 1 H) 2.02-2.09 (m, 1 H) 1.98 (br t, J=10.78 Hz, 2 H) 1.67 (br d, J=12.10 Hz, 2 H) 1.29 (qd, J=12.21, 3.37 Hz, 2 H) 1.12-1.22 (m, 1 H) 1.04 (s, 6 H).

[0316] Example 93 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Example 93 was prepared following the general method described in Example 92. m / z = 449.00 [M+H] + ;Retention time (Method B): 1.06 minutes.

[0317] Example 94 3-(5-(3-chloro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 94A: tert-butyl 5-amino-4-(5-(3-chloro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 20 mL vial, add (2,3-dichloropyridin-4-yl)methanol (400 mg, 2.247 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared by the method disclosed in WO2018102725) (1498 mg, 3.37 mmol), Pd(dtbpf)Cl 2 (43.9 mg, 0.067 mmol), 1,4-dioxane (12 mL) and 3MK 3 PO 4 Aqueous solution (3.75 mL, 11.24 mmol) was added. The vial was sealed and the air was replaced with nitrogen. The reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled and diluted with ethyl acetate-water (25:5 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by ISCO column chromatography on a silica gel column (40 g Gold column, eluted with 0-100% DCM-20% methanolic ammonia in DCM) to give tert-butyl 5-amino-4-(5-(3-chloro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (700 mg, 1.400 mmol, 62.3% yield) as a light brown solid. The enantiomeric excess of this material and subsequent intermediates was not determined. MS (ES): m / z = 460.03 [M+H] + . 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.62 (d, J=4.68 Hz, 1 H) 7.85 - 7.62 (m, 6H), 5.71 (br s, 1 H) 5.38 (br s, 1 H) 4.92-4.99 (m, 3 H) 4.51-4.64 (m, 2 H) 2.16-2.45 (m, 5 H) 1.45 (s, 9 H).

[0318] Intermediate 94B: 3-(5-(3-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione HCl salt Thionyl chloride (0.33 mL, 4.52 mmol) was added to a cooled solution (0° C.) of tert-butyl 5-amino-4-(5-(3-chloro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.7 g, 1.52 mmol) in DCM (7.5 mL). After 10 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated to dryness. The residue was dissolved in acetic acid (3 mL) and benzenesulfonic acid (0.53 g, 3.35 mmol) was added. The reaction mixture was heated at 120° C. in a microwave oven for 25 min. The reaction mixture was concentrated to dryness. 3M HCl / MeOH (4 mL) was then added to the residue and the reaction mixture was stirred at 0° C. (ice-water bath) until completely dissolved. Ethyl acetate (12 mL) was then added and the reaction mixture was stirred. After 5 min, the reaction mixture was placed in an ice-water bath for 30 min. The precipitate was filtered, washed with ethyl acetate, and air-dried to give 3-(5-(3-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (400 mg, 0.940 mmol, 61.8% yield) as the HCl salt. MS (ES): m / z = 404.1, 406.1 [M+H], respectively. + and [M+2H] + .

[0319] Example 94: To 3-(5-(3-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (25 mg, 0.06 mmol) dissolved in DMF (650 μL) was added 2-(piperidin-4-yl)propan-2-ol, HCl (15.3 mg, 0.09 mmol) followed by Hunig's base (60 μL, 0.30 mmol). The resulting mixture was heated to 80° C. with stirring for 1 h. The reaction mixture was cooled and further diluted with DMF (0.5 mL). The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 35% B at 0 min hold, 35-75% B over 22 min, 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined, centrifuged and evaporated to dryness to give 3-(5-(3-chloro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15.8 mg, 0.030 mmol, 52.3% yield). LCMS (Method A): retention time 1.03 min; MS(ES): m / z = 511.20 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.01 (s, 1 H) 8.21 (d, J=4.68 Hz, 1 H) 8.04 (s, 1 H) 7.81 (m, 2 H) 7.41 (t, J=4.93 Hz, 1 H) 5.16 (dd, J=13.32, 5.12 Hz, 1 H) 4.56 (d, J=17.56 Hz, 1 H) 4.44 (d, J=17.46 Hz, 1 H) 4.05 (s, 1 H) 3.64 (s, 2 H) 2.88-2.99 (m, 3 H) 2.59-2.67 (m, 1 H) 2.36-2.48 (m, 1 H) 2.02-2.09 (m, 1 H) 1.98 (br t, J=10.78 Hz, 2 H) 1.67 (br d, J=12.10 Hz, 2 H) 1.29 (qd, J=12.21, 3.37 Hz, 2 H) 1.12-1.22 (m, 1 H) 1.04 (s, 6 H).

[0320] Examples 95-97 The compounds in Table 8 were prepared following the general procedures described in Example 93. [Table 21]

[0321] Example 98 tert-Butyl (4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate [ka] Intermediate 98A: tert-butyl (S)-5-amino-4-(5-(4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 100 mL flask, add (2-chloropyridin-4-yl)methanol (1.50 g, 10.45 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (6.96 g, 15.67 mmol), Pd(dtbpf)Cl 2 (0.204 g, 0.313 mmol), dioxane (50 mL) and K 3 PO 4 Aqueous solution (17.41 mL, 52.2 mmol) was added. The flask was sealed, purged with nitrogen, and then heated at 60 °C with stirring overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and the organic layer was diluted with MgSO 4 After drying at 4°C and concentration, the solid was purified using a silica gel column by ISCO eluting with 0-85% DCM / B [B=15% EtOH / EtOAc+0.1% triethylamine] to give the title compound [3.01 g (68% yield)]. MS (ES): m / z = 426.2 [M+H] + .

[0322] Intermediate 98B: (S)-3-(5-(4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To tert-butyl (S)-5-amino-4-(5-(4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (7.1 g, 16.69 mmol) dissolved in DCM (110 mL) and cooled in an ice-water bath was added thionyl chloride (3.63 mL, 50.1 mmol) dropwise. After 10 min, the ice-water bath was removed and the reaction mixture was allowed to warm to room temperature. After 0.5 h, the reaction mixture was concentrated to dryness. The resulting residue was dissolved in acetic acid (110 mL) and diluted with PhSO 3H (5.81 g, 36.7 mmol) was added. The reaction mixture was refluxed at 118° C. for 3 h. Then, 3M HCl / MeOH (70 mL) was added and the mixture was stirred at 0° C. (ice-water bath) until completely dissolved. Then, EtOAc (150 mL) was added and the mixture was stirred. After about 5 min, the mixture was left in an ice-water bath for about 0.5 h. The precipitate was filtered, washed with cold EtOAc, and then air-dried to give the title compound in 89% yield. 1 H NMR (400 MHz, DMSO-d 6 )δ 11.05-10.98 (m, 1H), 8.76 (d, J=5.0 Hz, 1H), 8.34 (s, 1H), 8.24 (dd, J=8.0, 1.4 Hz, 1H), 8.19 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.56 (dd, J=5.1, 1.2 Hz, 1H), 5.16 (dd, J=13.3, 5.2 Hz, 1H), 4.90 (s, 2H), 4.56 (d, J=1.0 Hz, 1H), 4.45 (d, J=1.0 Hz, 1H), 3.00-2.88 (m, 1H), 2.67-2.59 (m, 1H), 2.48-2.38 (m, 1H), 2.11-1.99 (m, 1H).

[0323] Example 98: To a suspension of tert-butyl (4-((7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate (17.53 mg, 0.053 mmol) and 3-(5-(4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.041 mmol) in DMF (1 mL) was added Hunig's base (0.071 mL, 0.406 mmol) at room temperature. The reaction mixture became a clear solution. The vial was sealed and heated at 80° C. for 1.5 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 38% B at 0 min hold, 38-78% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and centrifuged to dryness. Product yield was 5.2 mg, (19%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.11-9.01 (m, 1H), 8.68-8.58 (m, 1H), 8.33-8.29 (m, 1H), 8.24-8.12 (m, 1H), 7.99-7.92 (m, 1H), 7.89-7.79 (m, 1H), 7.40-7.18 (m, 3H), 6.75-6.64 (m, 2H), 5.19-5.06 (m, 1H), 4.66-4.61 (m, 1H), 4.58-4.32 (m, 2H), 3.62-3.51 (m, 5H), 2.97-2.84 (m, 1H), 2.71-2.60 (m, 1H), 2.47-2.18 (m, 7H), 2.13-1.99 (m, 1H), 1.77-1.65 (m, 2H), 1.67-1.55 (m, 5H), 1.48-1.40 (m, 9H) LCMS (Method B): Retention time 1.56 min, [M+H]+ 660.2.

[0324] Examples 99 to 108 The compounds in Table 9 were prepared following the general method described for Example 98, substituting tert-butyl (4-((7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate with the appropriate primary or secondary amine. [Table 22] [Table 23]

[0325] Examples 109 to 115 The compounds in Table 10 were prepared following the general method described for Example 149 using the appropriate primary or secondary amines. [Table 24]

[0326] Example 116 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)isoindoline-1,3-dione [ka] Intermediate 116A: 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione To 5-bromoisobenzofuran-1,3-dione (5g, 22.03 mmol), tert-butyl 4,5-diamino-5-oxopentanoate (4.45 g, 22.03 mmol) and sodium acetate (1.807 g, 22.03 mmol) in a 250 mL vial was added acetic acid (50 mL). The bottle was sealed and heated at 150° C. for 16 h. The reaction mixture was cooled to room temperature and a precipitate formed. The solid was collected by filtration and dried under vacuum for 6 h to give 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2 g, 25% yield) as an off-white solid. MS: MH=335.

[0327] Intermediate 116B: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)pyridin-2-yl)isoindoline-1,3-dione To a stirred solution of (2-chloropyridin-4-yl)methanol (500 mg, 3.48 mmol) in dioxane (20 mL) was added hexamethylditin 97% (1.083 mL, 5.22 mmol). The mixture was purged with nitrogen for 5 minutes and then [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (227 mg, 0.348 mmol) was added. The reaction vessel was sealed and heated at 100°C for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through a pad of Celite and washed with dioxane. The combined filtrate was transferred to a 250 mL sealed bottle. Then 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1 g, 2.97 mmol) was added. The mixture was purged with N 2 The reaction vessel was sealed and heated at 110 °C for 3 h. The reaction mixture was filtered through Celite. The filtrate was concentrated and purified using an ISCO 80 g column, 65 mL / min, 0-15% MeOH / CH 2 Cl 2 The target product was purified with 10% MeOH / CH 2Cl 2 After concentration, 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)pyridin-2-yl)isoindoline-1,3-dione (370 mg, 0.962 mmol, 32.4% yield) was obtained as an off-white solid. MS: M+H=366; 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.12 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 8.57 (d, J=7.9 Hz, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.42 (d, J=4.6 Hz, 1H), 5.17 (dd, J=12.8, 5.2 Hz, 1H), 4.64 (s, 2H), 2.97-2.75 (m, 1H), 2.62-2.50 (m, 9H), 2.18-2.01 (m, 1H).

[0328] Intermediate 116C: 5-(4-(chloromethyl)pyridin-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)pyridin-2-yl)isoindoline-1,3-dione (370 mg, 1.013 mmol) / CH 2 Cl 2 (3 mL) was added dropwise with thionyl chloride (0.220 mL, 3.04 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give 5-(4-(chloromethyl)pyridin-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (389 mg, 0.912 mmol, 90% yield) as an off-white solid. MS: M+H=384.2.

[0329] Example 116: To a solution of 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.039 mmol) in DMF (1 mL) was added 1-(pyrrolidin-3-yl)ethan-1-ol (8.91 mg, 0.077 mmol) at room temperature. The reaction vessel was sealed and heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 3% B hold at 0 min, 3-43% B over 20 min, then 100% B hold at 0 min; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)isoindoline-1,3-dione (1.1 mg, 2.453 μmol, 6.28% yield). M+H=449.1, tr= 0.95 min (Method B). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 8.83 (br s, 2H), 8.62 (br d, J=7.6 Hz, 2H), 8.56 (s, 1H), 8.35 (br s, 2H), 8.09 (br d, J=7.9 Hz, 2H), 7.59 (br s, 1H), 5.20 (br dd, J=13.0, 5.6 Hz, 2H), 3.89 (s, 1H), 3.40 (br d, J=12.8 Hz, 2H), 3.16 (s, 2H), 3.00-2.78 (m, 4H), 2.75-2.56 (m, 3H), 2.56-2.52 (m, 4H), 2.21-2.00 (m, 3H), 1.90 (s, 1H), 1.16 (t, J=7.3 Hz, 3H)

[0330] Examples 117 to 126 The compounds in Table 11 were prepared following the general method described in Example 116, substituting 5-(4-(chloromethyl)pyridin-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione with the appropriate primary or secondary amine. [Table 25] [Table 26]

[0331] Example 127 (R)-3-((R)-4-Fluoro-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 127A: 4-Bromo-2-ethyl-3-fluorobenzoic acid A solution of 4-bromo 2,3-difluorobenzoic acid (2.0 g, 8.44 mmol) in tetrahydrofuran (40 mL) was cooled to -78°C and a 1M solution of ethylmagnesium bromide (8.44 mL, 25.3 mmol) in THF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 12 h. The reaction was quenched at 0°C by the dropwise addition of MeOH (15 mL). The volatiles were removed in vacuo and the residue was partitioned between EtOAc and 2M aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The crude product was purified by flash chromatography (SiO 2Purification by HPLC (40 g column, 0-80% EtOAc / petroleum-ether) gave 4-bromo-2-ethyl-3-fluorobenzoic acid (1 g, 48% yield). LCMS (Method A): retention time 0.69 min, [MH]+ 245.1, 247.1; 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.36 (s, 1 H), 7.68-7.53 (m, 2H), 2.95 (qd, J = 7.4, 2.6 Hz, 2H), 1.24-1.06 (m, 3H)

[0332] Intermediate 127B: Methyl 4-bromo-2-ethyl-3-fluorobenzoate 4-Bromo-2-ethyl-3-fluorobenzoic acid (0.7 g, 2.83 mmol) and K in acetone (15 mL) 2 CO 3 To a stirred mixture of (0.783 g, 5.67 mmol) was added dimethyl sulfate (0.541 mL, 5.67 mmol) dropwise at room temperature. The reaction mixture was stirred at 50° C. for 14 h and filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by flash chromatography (SiO 2 Purification by elution with hexanes (24 g column, 0-50% EtOAc / petroleum-ether) gave methyl 4-bromo-2-ethyl-3-fluorobenzoate (0.51 g, 69% yield) as a colorless oil. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.58-7.51 (m, 1H), 7.49-7.37 (m, 1H), 3.90 (s, 3H), 3.01 (qd, J = 7.4, 2.6 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H).

[0333] Intermediate 127C: Methyl 4-bromo-2-(1-bromoethyl)-3-fluorobenzoate To a stirred solution of methyl 4-bromo-2-ethyl-3-fluorobenzoate (0.515 g, 1.972 mmol) in DCE (10 mL) was added NBS (0.386 g, 2.170 mmol) followed by AIBN (0.065 g, 0.394 mmol). The reaction mixture was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous 10% sodium sulfate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO 2 Purification by elution with 24 g column, 0-30% EtOAc / petroleum-ether) gave methyl 4-bromo-2-(1-bromoethyl)-3-fluorobenzoate (0.6 g, 89% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.70-7.53(m, 1H), 7.52-7.44(m, 1H), 6.16-5.87(m, 1H), 3.93(s, 3H), 1.95(dd, J = 7.0, 1.3 Hz, 3H).

[0334] Intermediate 127D: tert-Butyl (4S)-5-amino-4-(5-bromo-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate Methyl 4-bromo-2-(1-bromoethyl)-3-fluorobenzoate (0.86 g, 2.53 mmol) and H-GLU(OTBU)-NH 2 To a stirred solution of HCl (0.845 g, 3.54 mmol) in acetonitrile (15 mL) was added DIPEA (1.325 mL, 7.59 mmol). The reaction mixture was heated at 85° C. for 15 h. The volatiles were removed in vacuo and purified by flash chromatography (SiO 2, 40 g column, 0~10% MeOH / DCM) to give tert-butyl (4S)-5-amino-4-(5-bromo-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.23 g, 21% yield) as a pale yellow solid. LCMS (Method A): Retention time 1.19 min, [M+23H] + 451.3, 453.4.

[0335] Intermediate 127E: tert-butyl (S)-5-amino-4-((R)-5-bromo-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate Intermediate 127D was separated by preparative SFC using the following conditions: Chiralpak IG column (250 x 30 mm (5 μm); 65% CO 2 ;40% 5 nM NH 4 Elution with OAc / ACN:MeOH (1:1); 100 bar; flow rate: 160 g / min; 40° C.; monitoring at 220 nM. Intermediate 127E eluted at 5.5 min. Analytical SFC conditions: Chiralpak IG column (250 x 4.6 mm (5 μm); 65% CO 2 ;35% 5 nM NH 4 Elution with OAc / ACN:MeOH (1:1); 100 bar; flow rate: 3.0 g / min; 35° C.; monitoring at 220 nM (RT = 7.5 min).

[0336] Intermediate 127F: ((R)-2-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-5-yl)boronic acid A stirred solution of intermediate 127E (3.5 g, 8.15 mmol), potassium acetate (1.200 g, 12.23 mmol), and BisPin (3.11 g, 12.23 mmol) in DME (150 mL) was purged with argon for 5 min and then treated with PdCl 2 (dppf) 2 -CH 2Cl 2 The adduct (0.666 g, 0.815 mmol) was added at 25° C. The reaction mixture was sealed, heated to 90° C. and stirred for 16 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAC (20 mL). The filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was redissolved in diethyl ether (150 mL), filtered through a pad of Celite and washed with EtOAC (20 mL) and the filtrate was evaporated under reduced pressure to give crude tert-butyl (S)-5-amino-4-((R)-4-fluoro-3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-5-oxopentanoate as a black liquid. MS: M+H=477.

[0337] Intermediate 127G: tert-butyl (S)-5-amino-4-((R)-4-fluoro-5-(4-(hydroxymethyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 250 mL round bottom flask was added (2-chloropyridin-4-yl)methanol (1.754 g, 12.22 mmol), tert-butyl (S)-5-amino-4-((R)-4-fluoro-3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-5-oxopentanoate (3.88 g, 8.15 mmol), dioxane (80 mL) and 2 MK 3 PO 4 The flask was filled with N 2 Purge with Pd(dtbpf)Cl for 5 min. 2 (0.265 g, 0.407 mmol) was added. The reaction flask was sealed and heated at 60 °C overnight. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated and concentrated. The crude material was purified using an ISCO 80 g column (60 mL / min, 0-20% MeOH / CH 2 Cl 2 The desired product was purified by elution with 10% MeOH / CH2 Cl 2 The column was eluted with 500 rpm. Fractions containing the desired product were pooled and concentrated to give tert-butyl (S)-5-amino-4-((R)-4-fluoro-5-(4-(hydroxymethyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (700 mg, 1.530 mmol, 18.78% yield) as a pale yellow solid. LC MS: tr=0.76 min. M+H=458.1.

[0338] Intermediate 127H: tert-butyl (S)-5-amino-4-((R)-5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate Intermediate 127G (700 mg, 1.530 mmol) / CH 2 Cl 2 (10 mL) was added thionyl chloride (0.222 mL, 3.06 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The mixture was rotary evaporated to remove the solvent to give tert-butyl (S)-5-amino-4-((R)-5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (700 mg, 1.471 mmol, 96% yield). MS: M+H=476.4.

[0339] Intermediate 127I: (R)-3-((R)-5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione To intermediate 127H (525 mg, 1.103 mmol) in a vial was added AcOH (5 mL) followed by benzenesulfonic acid (174 mg, 1.103 mmol). The reaction vessel was sealed and heated at 120° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed. (R)-3-((R)-5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (443 mg, 0.937 mmol, 85% yield) was obtained as a black solid. MS: M+H=402.3.

[0340] Example 127: To a solution of 5-(4-(chloromethyl)pyridin-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (15 mg, 0.039 mmol) in DMF (1 mL) was added (S)-pyrrolidin-3-ol (6.50 mg, 0.075 mmol) and Hunig's base (0.033 mL, 0.187 mmol) at room temperature. The reaction vessel was sealed and heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 1% B at 0 min hold, 1-41% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. (R)-3-((R)-4-fluoro-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12.6 mg, 0.027 mmol, 73.3% yield) was obtained. LC MS: M+H=453.2 tr=0.90 min (Method B). 1H NMR (500 MHz, DMSO-d 6) δ 8.67 (d, J=4.9 Hz, 2H), 8.04 (br t, J=7.2 Hz, 2H), 7.79 (s, 2H), 7.71-7.57 (m, 2H), 7.39 (d, J=4.6 Hz, 2H), 5.05 (br d, J=6.7 Hz, 1H), 4.94 (q, J=6.5 Hz, 1H), 4.82 (br dd, J=12.8, 5.2 Hz, 1H), 4.73 (br s, 1H), 4.22 (br s, 2H), 3.76-3.64 (m, 3H), 2.94-2.78 (m, 2H), 2.77-2.56 (m, 8H), 2.54 (s, 13H), 2.48-2.43 (m, 2H), 2.41-2.20 (m, 3H), 2.10-1.94 (m, 4H), 1.90 (s, 4H), 1.63-1.47 (m, 8H).

[0341] Examples 128 to 142 The compounds in Table 12 were prepared following the method described in Example 127, substituting the appropriate primary or secondary amine for the chloride of intermediate 127H. [Table 27] [Table 28]

[0342] Example 143 3-((R)-4-Fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 143A: tert-butyl (S)-5-amino-4-((R)-4-fluoro-5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate To a solution of (2-chloro-3-fluoropyridin-4-yl)methanol (100 mg, 0.619 mmol) in dioxane (3 mL) was added hexamethylditin (243 mg, 0.743 mmol) at room temperature. The mixture was diluted with N 2 The reaction mixture was purged with 500 mL of ethyl acetate for 2 min. Then, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (40.3 mg, 0.062 mmol) was added. The reaction vessel was sealed and heated at 100° C. for 80 min. The reaction mixture was filtered through Celite. M+H=292.1.

[0343] To the filtrate was added Intermediate 130E (50 mg, 0.116 mmol). The mixture was diluted with N 2 The reaction vessel was then purged with 500 mL of ethyl acetate for 2 min. Bis(triphenylphosphine)palladium(II) dichloride (8.18 mg, 0.012 mmol) was then added, the reaction vessel was sealed, and heated at 110 °C for 2 h. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was concentrated and purified using an ISCO 40 g column (40 mL / min, 0–10% MeOH / CH 2 Cl 2 The desired product was purified using 10% MeOH / CH 2 Cl 2 Fractions containing the desired product were combined and concentrated to give tert-butyl (S)-5-amino-4-((R)-4-fluoro-5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (26 mg, 0.049 mmol, 42.3% yield) as a light brown solid. LC MS: M+H=476 tr=0.86 min (Method A). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (d, J=4.8 Hz, 1H), 7.84-7.70 (m, 2H), 7.60 (t, J=5.0 Hz, 1H), 7.38-7.17 (m, 2H), 6.73 (br s, 1H), 5.41-5.28 (m, 1H), 5.00-4.85 (m, 3H), 4.75 (t, J=7.7 Hz, 1H), 2.63-2.50 (m, 1H), 2.44-2.18 (m, 4H), 1.69-1.58 (m, 5H), 1.49-1.40 (m, 10H), 1.37-1.22 (m, 2H), 1.05-0.79 (m, 1H).

[0344] Intermediate 143B: tert-butyl (S)-5-amino-4-((R)-5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate tert-Butyl (S)-5-amino-4-((R)-4-fluoro-5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (26 mg, 0.055 mmol) / CH 2 Cl 2 (1 mL) was added dropwise with thionyl chloride (7.93 μL, 0.109 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The solvent was evaporated to give tert-butyl (S)-5-amino-4-((R)-5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (27 mg, 0.049 mmol, 90% yield) as a light brown solid.

[0345] Intermediate 143C: (R)-3-((R)-5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl (S)-5-amino-4-((R)-5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (27 mg, 0.055 mmol) in AcOH (2 mL) was added benzenesulfonic acid (8.65 mg, 0.055 mmol) at room temperature. The reaction vessel was sealed and heated at 130° C. for 3 h. The solvent was removed to give (R)-3-((R)-5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (22 mg, 0.047 mmol, 86% yield) as a brown solid. LC MS: M+H=420.3.

[0346] Example 143: To a solution of 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.039 mmol) in DMF (1 mL) at room temperature was added 2-(piperidin-4-yl)propan-2-ol (6.82 mg, 0.048 mmol), followed by Hunig's base (0.021 mL, 0.119 mmol). The reaction vessel was sealed and heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size: Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 8% B hold at 0 min, 8-48% B over 20 min, then 100% B hold at 0 min: Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 3-((R)-4-fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7.8 mg, 0.014 mmol, 59.1% yield).LC MS:tr=0.968 min(Method B), M+H=527.2. 1H NMR((500 MHz, DMSO-d6) δ 10.98 (br d, J=19.7 Hz, 1H), 8.54 (d, J=4.7 Hz, 2H), 7.78-7.64 (m, 4H), 7.59 (t, J=5.0 Hz, 2H), 5.06 (q, J=6.5 Hz, 1H), 4.95 (q, J=6.6 Hz, 1H), 4.82 (br dd, J=12.4, 5.2 Hz, 1H), 4.72 (br s, 1H), 4.09 (s, 1H), 3.62 (s, 3H), 3.52-3.31 (m, 2H), 2.99 (s, 1H), 2.94-2.79 (m, 5H), 2.78-2.70 (m, 1H), 2.69-2.57 (m, 4H), 2.54 (s, 16H), 2.48-2.28 (m, 1H), 2.20-2.01 (m, 2H), 1.96 (br t, J=11.0 Hz, 4H), 1.66 (br d, J=11.8 Hz, 4H), 1.53 (br d, J=6.7 Hz, 3H), 1.51 (br d, J=6.8 Hz, 3H), 1.38-1.21 (m, 4H), 1.21-1.09 (m, 2H), 1.03 (s, 11H).

[0347] Example 144 The compounds in Table 13 were prepared following the general method described in Example 14 by substituting the appropriate primary or secondary amine for the benzyl chloride in Intermediate 143C. [Table 29]

[0348] Example 145 (S)-3-(5-(4-((6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (43 mg, 0.202 mmol) / CH 2 Cl 2 To a solution of (0.5 mL) was added 3M hydrogen chloride (0.504 mL, 2.016 mmol) in methyl t-butyl ether. The resulting solution was stirred for 2 h. The volatiles were removed and the residue was redissolved in DMF (1 mL). To this solution was added Intermediate 101B (74.6 mg, 0.202 mmol) followed by Hunig's base (0.070 mL, 0.403 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70 °C for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: Mobile phase A: 5:95 acetonitrile:water (with 0.05% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.05% trifluoroacetic acid); Gradient: 0% B 2 min hold, 0-40% B over 20 min, then 100% B 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 3.7 mg, (3.9%). MS(ES): m / z = 447.10 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 11.02 (s, 1H), 8.79 (br d, J=4.6 Hz, 1H), 8.32 (s, 1H), 8.23 ​​(br d, J=7.6 Hz, 1H), 8.13 (s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.47 (br d, J=4.6 Hz, 1H), 5.16 (dd, J=13.0, 5.0 Hz, 1H), 4.63-4.51 (m, 1H), 4.47 (s, 2H), 4.50-4.41 (m, 1H), 4.23-4.07 (m, 4H), 3.98 (br t, J=7.0 Hz, 1H), 2.93 (br s, 1H), 2.63 (br d, J=16.5 Hz, 1H), 2.48-2.28 (m, 2H), 2.10-1.98 (m, 4H).

[0349] Example 146 (3S)-3-(5-(4-((5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (30 mg, 0.132 mmol) / CH 2 Cl 2To a solution of (1 mL) was added TFA (10.17 μL, 0.132 mmol). The resulting solution was stirred for 2 h. The volatiles were removed and the residue was redissolved in DMF (1 mL). To this solution was added Intermediate 101B (48.8 mg, 0.132 mmol) followed by Hunig's base (0.046 mL, 0.264 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 6% B at 0 min hold, 6-47% B at 23 min hold, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 40.5 mg, (64.4%). MS(ES): m / z = 461.20 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.67 (d, J=4.9 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.34 (d, J=4.6 Hz, 1H), 5.15 (dd, J=13.4, 5.2 Hz, 1H), 4.56 (br d, J=17.1 Hz, 1H), 4.43 (d, J=17.4 Hz, 1H), 4.03-3.81 (m, 1H), 3.73 (s, 2H), 3.01-2.78 (m, 1H), 2.66 (br d, J=9.5 Hz, 2H), 2.61 (br d, J=4.6 Hz, 1H), 2.59-2.55 (m, 2H), 2.50-2.38 (m, 1H), 2.37-2.21 (m, 2H), 2.17-1.99 (m, 1H), 1.97-1.84 (m, 2H), 1.42 (br d, J=12.8 Hz, 2H).

[0350] Example 147 (3S)-3-(5-(4-((5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 147A: tert-Butyl 5-hydroxy-5 methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (56 mg, 0.249 mmol) in THF was added methylmagnesium bromide (746 μL, 0.746 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with ammonium acetate. The reaction mixture was extracted with ethyl acetate (3× 10 mL). The organics were combined, dried over sodium sulfate and concentrated. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.55-3.42 (m, 2H), 3.35 (dd, J=11.2, 3.5 Hz, 2H), 2.68 (br d, J=4.2 Hz, 2H), 1.93 (br dd, J=13.4, 8.4 Hz, 2H), 1.67 (br dd, J=13.4, 5.0 Hz, 2H), 1.48-1.43 (m, 9H), 1.32 (s, 3H).

[0351] Example 147: tert-Butyl 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (30 mg, 0.124 mmol) / CH 2 Cl 2To a solution of (1 mL) was added TFA (9.58 μL, 0.124 mmol). The resulting solution was stirred for 2 h. The volatiles were removed and the residue was redissolved in DMF (1 mL). To this solution was added Intermediate 101B (46.0 mg, 0.124 mmol), followed by Hunig's base (0.043 mL, 0.249 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 9% B at 0 min hold, 9-49% B over 23 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. This material was further purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 12% B at 0 min hold, 12-52% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was monitored by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 20.2 mg, (32%). MS (ES): m / z = 475.30 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.68 (d, J=4.9 Hz, 1H), 8.32 (s, 1H), 8.23 ​​(br d, J=7.9 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.34 (br d, J=5.2 Hz, 1H), 5.16 (br dd, J=13.3, 5.0 Hz, 1H), 4.56 (br d, J=17.4 Hz, 1H), 4.44 (br d, J=17.4 Hz, 1H), 3.73 (s, 2H), 3.04-2.82 (m, 1H), 2.72 (br d, J=9.2Hz, 2H), 2.68-2.58 (m, 3H), 2.49-2.37 (m, 1H), 2.30 (br t, J=7.6 Hz, 2H), 2.17-1.99 (m, 1H), 1.81 (br dd, J=12.8, 8.5 Hz, 2H), 1.50 (br d, J=12.8 Hz, 2H), 1.16 (s, 3H).

[0352] Example 148 (3S)-3-(5-(4-((5-methyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] tert-Butyl 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (30 mg, 0.124 mmol) / CH 2 Cl 2To a solution of (1 mL) was added TFA (9.58 μL, 0.124 mmol). The resulting solution was stirred for 2 h. The volatiles were removed and the residue was redissolved in DMF (1 mL). To this solution was added Intermediate 101B (46.0 mg, 0.124 mmol), followed by Hunig's base (0.043 mL, 0.249 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 9% B at 0 min hold, 9-49% B over 23 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. This material was further purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with 0.05% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.05% trifluoroacetic acid); Gradient: 0% B hold for 0 min, 0-40% B over 20 min, then 100% B hold for 0 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 8.1 mg (14.3%). MS(ES): m / z = 457.20 [M+H] + .

[0353] Example 149 (3S)-3-(5-(3-fluoro-4-(((3aR,7aS)-5-hydroxyoctahydro-2H-isoindol-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0354] Intermediate 149A: tert-butyl (S)-5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 200 mL flask, add (2-chloro-3-fluoropyridin-4-yl)methanol (2.55 g, 15.78 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (8.00 g, 18.00 mmol), Pd(OAc) 2 (0.202 g, 0.900 mmol), di-tert-butyl(methyl)phosphonium tetrafluoroborate (0.447 g, 1.800 mmol), dioxane (90 mL) and 3 MK 2 CO 3 Aqueous solution (30.0 mL, 90 mmol) was added. The flask was sealed and the air was replaced with nitrogen. The reaction mixture was heated at 80 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, the organic layer was separated and diluted with MgSO 4 The mixture was purified by ISCO using a 220 g silica gel column eluted with 0-10% DCM / MeOH to give the title compound [5.45 g (68% yield)].

[0355] Intermediate 149B: (S)-3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To tert-butyl 5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (5.30 g, 11.95 mmol) dissolved in DCM (120 mL) and cooled in an ice-water bath was added thionyl chloride (2.60 mL, 35.9 mmol) (dropwise). After 10 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated to dryness. The resulting residue was dissolved in acetic acid (60 mL) and diluted with PhSO 3 H (4.16 g, 26.3 mmol) was added. The mixture was refluxed (118° C.) for 3 h. The mixture was concentrated to dryness and 3M HCl / MeOH (30 mL) was added. The mixture was stirred at 0° C. until complete dissolution. Then, 70 mL of EtOAc was added and the mixture was stirred. After about 5 min, the mixture was placed in an ice-water bath for about 0.5 h. The precipitate was filtered, washed with cold EtOAc, and air-dried to give the title compound in 87% yield. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.02 (s, 1 H) 8.61 (d, J=4.68 Hz, 1 H) 8.14 (s, 1 H) 8.05 (d, J=8.00 Hz, 1 H) 7.89 (d, J=8.00 Hz, 1 H) 7.68 (t, J=5.07 Hz, 1 H) 5.17 (dd, J=13.27, 5.07 Hz, 1 H) 4.94 (s, 2 H) 4.58 (d, J=17.46 Hz, 1 H) 4.45 (d, J=17.56 Hz, 1 H) 2.89-2.99 (m, 1 H) 2.57-2.67 (m, 1 H) 2.38-2.48 (m, 1 H) 2.01-2.10 (m, 1 H).

[0356] Example 149: To a solution of (S)-3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55 mg, 0.142 mmol) was added (3aR,7aS)-octahydro-1H-isoindol-5-ol hydrochloride (25.2 mg, 0.142 mmol), followed by Hunig's base (0.050 mL, 0.284 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70 °C for 4.5 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 4% B at 0 min hold, 4-44% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 35.1 mg, (50.2%). MS(ES): m / z = 493.20 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ 8.58-8.50 (m, 1H), 8.12 (s, 1H), 8.04 (br d, J=7.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.63-7.52 (m, 1H), 5.16 (dd, J=13.3, 5.0 Hz, 1H), 4.57 (br d, J=17.4 Hz, 1H), 4.44 (br d, J=17.4 Hz, 1H), 3.95-3.79 (m, 2H), 3.75-3.57 (m, 1H), 2.99-2.90 (m, 1H), 2.90-2.79 (m, 1H), 2.73-2.66 (m, 1H), 2.66-2.58 (m, 2H), 2.49-2.31 (m, 2H), 2.30-1.10 (m, 9H).

[0357] Example 150 (S)-3-(5-(3-fluoro-4-((1-oxo-2,8-diazaspiro[4.5]decan-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of intermediate 149B (55 mg, 0.142 mmol) was added 2,8-diazaspiro[4.5]decan-1-one hydrochloride (27.0 mg, 0.142 mmol) followed by Hunig's base (0.074 mL, 0.425 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 5% B at 0 min hold, 5-45% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. The product yield was 28.7 mg, (40.2%). MS(ES): m / z = 506.20 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6)δ 8.54 (d, J=4.6 Hz, 1H), 8.12 (s, 1H), 8.04 (br d, J=8.2 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.62-7.47 (m, 2H), 5.16 (dd, J=13.1, 5.2 Hz, 1H), 4.57 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 3.68 (s, 2H), 3.16 (t, J=6.7 Hz, 2H), 3.06-2.86 (m, 1H), 2.80 (br d, J=11.6 Hz, 2H), 2.63 (br d, J=17.4 Hz, 1H), 2.50-2.31 (m, 1H), 2.16 (br t, J=11.0 Hz, 2H), 2.10-2.00 (m, 1H), 1.92 (t, J=6.7 Hz, 2H), 1.74 (td, J=12.5, 3.7 Hz, 2H), 1.35 (br d, J=11.9 Hz, 2H).

[0358] Example 151 (S)-3-(5-(3-fluoro-4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of Intermediate 149B (30 mg, 0.077 mmol) was added (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (8.75 mg, 0.077 mmol), followed by Hunig's base (0.027 mL, 0.155 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 4% B at 0 min hold, 4-44% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 20.0 mg, (54.8%). MS(ES): m / z = 465.20 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 8.54 (d, J=4.6 Hz, 1H), 8.11 (s, 1H), 8.03 (br d, J=7.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.54 (t, J=4.9 Hz, 1H), 5.15 (dd, J=13.4, 5.2 Hz, 1H), 4.57 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 3.73-3.68 (m, 4H), 3.44 (m 1H), 3.07-2.86 (m, 1H), 2.79-2.69 (m, 2H), 2.68-2.59 (m, 3H), 2.49-2.34 (m, 3H), 2.15-1.96 (m, 1H).

[0359] Example 152 (S)-3-(1-oxo-5-(4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of intermediate 98B (30 mg, 0.081 mmol) was added (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (9.18 mg, 0.081 mmol), followed by Hunig's base (0.028 mL, 0.162 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70 °C for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 2% B at 0 min hold, 2-42% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 36.6 mg, (99.0%). MS(ES): m / z = 447.20 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.65 (d, J=4.9 Hz, 1H), 8.31 (s, 1H), 8.23 ​​(d, J=7.9 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.38 (d, J=4.9 Hz, 1H), 5.15 (dd, J=13.1, 5.2 Hz, 1H), 4.56 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 3.81-3.70 (m, 2H), 3.68 (s, 2H), 3.44 (br s, 1H), 3.02-2.83 (m, 1H), 2.74 (br s, 2H), 2.65-2.57 (m, 3H), 2.49-2.39 (m, 1H), 2.37 (dd, J=9.0, 2.0 Hz, 2H), 2.18-1.96 (m, 1H).

[0360] Example 153 (S)-3-(5-(3-fluoro-4-((6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (50 mg, 0.234 mmol) / CH 2 Cl 2To a solution of (0.5 mL) was added 3M hydrogen chloride (0.584 mL, 2.344 mmol) in methyl t-butyl ether. The resulting solution was stirred for 2 h. The volatiles were removed and the residue was redissolved in DMF (1 mL). To this solution was added Intermediate 153B (91 mg, 0.234 mmol) followed by Hunig's base (0.082 mL, 0.469 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: 0% B at 0 min hold, 0-40% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. The product yield was 16.4 mg, (14.4%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.55 (br d, J=4.3 Hz, 1H), 8.11 (s, 1H), 8.03 (br d, J=7.9 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.49 (br t, J=4.6 Hz, 1H), 5.16 (dd, J=13.4, 4.9 Hz, 1H), 4.57 (d, J=17.7 Hz, 1H), 4.44 (d, J=17.1 Hz, 1H), 4.00-3.81 (m, 1H), 3.06-2.87 (m, 1H), 2.69-2.60 (m, 1H), 2.49-2.37 (m, 3H), 2.23-2.00 (m, 1H), 2.00-1.87 (m, 2H).

[0361] Example 154 tert-Butyl (3aS,6aS)-5-((2-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] To a solution of Intermediate 153B (10 mg, 0.026 mmol) was added tert-butyl (3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5.47 mg, 0.026 mmol), followed by Hunig's base (0.009 mL, 0.052 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Gradient: 17% B at 0 min hold, 17-57% B over 20 min, then 100% B at 4 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 5.2 mg, (34.7%). MS(ES): m / z = 564.40 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.53 (d, J=4.9 Hz, 1H), 8.11 (s, 1H), 8.03 (br d, J=7.6 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.56 (t, J=4.7 Hz, 1H), 5.15 (dd, J=13.3, 5.0 Hz, 1H), 4.56 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 4.03 (s, 2H), 2.98-2.80 (m, 5H), 2.69-2.58 (m, 3H), 2.43 (br dd, J=13.1, 4.9 Hz, 1H), 2.32-2.15 (m, 2H), 2.14-1.93 (m, 1H), 1.40 (s, 9H).

[0362] Example 155 (3S)-3-(5-(3-fluoro-4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] tert-Butyl hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (30 mg, 0.142 mmol) / CH 2 Cl 2To a solution of (0.5 mL) was added 3M hydrogen chloride (0.292 mL, 1.17 mmol) in methyl t-butyl ether. The resulting solution was stirred for 2 h. The volatiles were removed and the residue was redissolved in DMF (1 mL). To this solution was added Intermediate 153B (30 mg, 0.077 mmol) followed by Hunig's base (0.054 mL, 0.311 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70 °C for 4.5 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Gradient: 21% B at 0 min hold, 21-61% B over 20 min, then 100% B at 4 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 10.2 mg, (27.9%). MS(ES): m / z = 463.20 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.11 (s, 1H), 8.03 (br d, J=8.2 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.53 (t, J=4.8 Hz, 1H), 5.16 (dd, J=13.2, 5.1 Hz, 1H), 4.56 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.5 Hz, 1H), 3.70 (s, 2H), 3.00-2.87 (m, 1H), 2.69-2.58 (m, 3H), 2.49-2.36 (m, 1H), 2.31-2.21 (m, 2H), 2.14-2.01 (m, 1H), 1.71-1.59 (m, 4H), 1.51-1.34 (m, 4H).

[0363] Example 156 tert-Butyl (3aR,6aS)-5-((2-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] To a solution of Intermediate 149B (42 mg, 0.108 mmol) was added tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (22.9 mg, 0.108 mmol), followed by Hunig's base (0.038 mL, 0.226 mmol). The reaction mixture became a clear solution. The vial was sealed and heated at 70° C. for 4.5 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 20% B at 0 min hold, 20-60% B over 20 min, then 17% B at 0 min hold, 17-57% B over 20 min, then 100% B at 4 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. Product yield was 41.1 mg, (64.3%). MS (ES): m / z = 564.40 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.53 (d, J=4.6 Hz, 1H), 8.11 (s, 1H), 8.03 (br d, J=7.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.53 (t, J=4.6 Hz, 1H), 5.15 (dd, J=13.4, 5.2 Hz, 1H), 4.56 (d, J=17.4 Hz, 1H), 4.43 (d, J=17.4 Hz, 1H), 3.76 (s, 2H), 3.15 (br d, J=8.9 Hz, 2H), 3.03-2.83 (m, 1H), 2.77 (br s, 2H), 2.65-2.58 (m, 3H), 2.50-2.29 (m, 3H), 2.13-2.00 (m, 1H), 1.43-1.35 (m, 9H).

[0364] Example 157 3-(5-(4-((2-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To intermediate 98B (20 mg, 0.049 mmol), 2-aza-spiro[3.5]nonane hydrochloride (9.55 mg, 0.059 mmol) was added DMF (2 mL) and N-ethyl-N-isopropylpropan-2-amine (0.069 mL, 0.394 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((2-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10.2 mg, 0.022 mmol, 45.2% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 13-53% B in 20 min; Flow rate: 20 mL / min; Column temperature: 25° C. The enantiomeric excess of 3-(5-(4-((2-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 1.08 min. MS(ES): m / z = 459.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.63 (d, J=4.6 Hz, 1H), 8.31 (s, 1H), 8.23 ​​(br d, J=8.2 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.32 (br d, J=4.6 Hz, 1H), 5.16 (br dd, J=13.4, 4.9 Hz, 1H), 4.56 (br d, J=17.7 Hz, 1H), 4.43 (br d, J=17.4 Hz, 1H), 3.70 (s, 2H), 3.01-2.91 (m, 4H), 2.63 (br d, J=18.0 Hz, 1H), 2.44 (br dd, J=13.3, 4.4 Hz, 1H), 2.16-1.99 (m, 1H), 1.92 (s, 1H), 1.60 (br s, 4H), 1.43-1.24 (m, 6H).

[0365] Example 158 The compounds in Table 14 were prepared following the general procedures described in Example 157. [Table 30]

[0366] Example 159 N-((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)benzamide [ka]

[0367] Intermediate 159A: 3-(5-(4-((3-(aminomethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl salt To tert-butyl (azetidin-3-ylmethyl)carbamate (44.0 mg, 0.236 mmol) in DMF (2 mL) was added Intermediate 98B (80 mg, 0.197 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.275 mL, 1.575 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction was quenched with water. The reaction mixture was extracted with ethyl acetate. The organic layers were combined and the solvent was evaporated. To the residue was added 4 N HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated to give 3-(5-(4-((3-(aminomethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl salt (86 mg, 83% yield). MS(ES): m / z = 420.1 [M+H] + .

[0368] Example 159: To 3-(5-(4-((3-(aminomethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl salt (19 mg, 0.036 mmol), benzoic acid (11.06 mg, 0.091 mmol) in DMF (2 mL) was added HATU (17.22 mg, 0.045 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.063 mL, 0.362 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and purified by preparative HPLC to give N-((1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)benzamide (5.2 mg, 27.8% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 5-45% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25 °C. The enantiomeric excess of N-((1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)benzamide was not determined. LCMS (Method B): Retention time 1.05 min. MS(ES): m / z = 524.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.63 (d, J=5.2 Hz, 1H), 8.56 (br t, J=5.2 Hz, 1H), 8.31 (s, 1H), 8.22 (br d, J=7.9 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J=7.6 Hz, 2H), 7.54-7.43 (m, 3H), 7.32 (br d, J=4.6 Hz, 1H), 5.15 (br dd, J=13.1, 4.6 Hz, 1H), 4.55 (br d, J=17.4 Hz, 1H), 4.43 (br d, J=17.4 Hz, 1H), 3.68 (s, 2H), 3.50 -3.32 (m, 2H), 3.18 (s, 2H), 3.03 (br t, J=6.3 Hz, 2H), 2.97 -2.90 (m, 1H), 2.80-2.58 (m, 2H), 2.49-2.40 (m, 1H), 2.12-1.98 (m, 1H).

[0369] Examples 160 to 164 The compounds in Table 15 were prepared following the general method described in Example 159. [Table 31]

[0370] Example 165 3-(5-(4-((1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To 1H-pyrazole (6.70 mg, 0.098 mmol) in DMF (2 mL) was added NaH (2.95 mg, 0.074 mmol). The mixture was stirred at room temperature for 10 min. Intermediate 101B (20 mg, 0.049 mmol) was added. The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and the reaction was quenched with water. The reaction mixture was filtered and purified by preparative HPLC to give 3-(5-(4-(1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (6.6 mg, 32.6 yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 3-43% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25° C. The enantiomeric excess of 3-(5-(4-((1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 0.97 min. MS(ES): m / z = 402.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.65 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 8.16 (br d, J=8.2 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.91-7.81 (m, 2H), 7.64-7.47 (m, 1H), 7.09 (d, J=4.3 Hz, 1H), 6.36 (t, J=2.0 Hz, 1H), 5.50 (s, 2H), 5.27-5.06 (m, 1H), 4.56 (br d, J=17.4 Hz, 1H), 4.43 (br d, J=17.4 Hz, 1H), 3.01-2.85 (m, 1H), 2.63 (br d, J=15.6 Hz, 1H), 2.43 (br dd, J=13.0, 4.1 Hz, 1H), 2.23-2.01 (m, 1H).

[0371] Example 166 The compounds in Table 16 were prepared following the general procedures described in Example 165. [Table 32]

[0372] Example 167 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0373] Intermediate 167A: (2-chloro-5-methylpyridin-4-yl)methanol To a solution of 2-chloro-5-methyl-isonicotinic acid methyl ester (0.115 g, 0.620 mmol) in THF (1.5 mL) was added sodium borohydride (0.070 g, 1.859 mmol) followed by MeOH (0.6 mL). The reaction mixture was stirred at room temperature for 2 h and water was added to quench the reaction. The solvent was evaporated and the residue was dissolved in EtOAc and washed with brine. The solvent was evaporated to give (2-chloro-5-methylpyridin-4-yl)methanol (0.095 g, 0.603 mmol, 97% yield). MS (ES): m / z = 158.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.42 (s, 1H), 5.51 (t, J=5.5 Hz, 1H), 4.55-4.50 (m, 2H), 2.16 (s, 3H).

[0374] Intermediate 167B: tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a vial equipped with a pressure relief valve, (2-chloro-5-methylpyridin-4-yl)methanol (0.092 g, 0.584 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared by the method shown in WO2018 / 102725) (0.285 g, 0.642 mmol), Pd(dtbpf)Cl 2 (0.011 g, 0.018 mmol), dioxane (2 mL) and 2 MK 3 PO 4 (0.876 mL, 1.751 mmol) was added. The reaction mixture was purged with nitrogen for 5 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was washed with Na 2 SO 4 Drying on a kettle and evaporation of the solvent gave a residue which was purified by flash column chromatography (0-20% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.140 g, 54.6% yield). The enantiomeric excess of tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and subsequent intermediates was not determined. MS(ES): m / z = 440.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 8.44 (s, 1H), 8.28 (s, 1H), 8.17 (dd, J=8.0, 1.2 Hz, 1H), 8.03 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.58 (s, 1H), 7.20 (s, 1H), 5.47 (t, J=5.4 Hz, 1H), 4.79-4.52 (m, 5H), 2.28-2.16 (m, 6H), 2.08-1.97 (m, 1H), 1.34 (s, 9H).

[0375] Intermediate 167C: 3-(5-(4-(chloromethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.14 g, 0.319 mmol) in DCM (2 mL) at 0° C. was added thionyl chloride (0.069 mL, 0.956 mmol) in DCM (1 mL) dropwise. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated to give tert-butyl 5-amino-4-(5-(4-(chloromethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. MS (ES): m / z=458.0 [M+H]+. To the tert-butyl 5-amino-4-(5-(4-(chloromethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was added benzenesulfonic acid (0.111g, 0.701mmol) in acetic acid (1.1mL) and the reaction mixture was heated at reflux for 2 hours. Water was added to the residue. A solid precipitated. The solid was filtered and washed with water to give 3-(5-(4-(chloromethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.107 g, 88% yield). MS(ES):m / z = 384.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 8.23 ​​(d, J=7.7 Hz, 1H), 8.15 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 5.19-5.13 (m, 1H), 4.89 (s, 2H), 4.59-4.42 (m, 2H), 2.99-2.89 (m, 1H), 2.69-2.64 (m, 1H), 2.53-2.40 (m, 4H), 2.10-2.01 (m, 1H).

[0376] Example 167: To 3-(5-(4-(chloromethyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.036 mmol), 2-(4-piperidyl)-2-propanol (7.67 mg, 0.054 mmol) was added DMF (2 mL), followed by N-ethyl-N-isopropylpropan-2-amine (0.05 mL, 0.286 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9.6 mg, 54.4% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 12-52% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25 °C. The enantiomeric excess of 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 0.96 min. MS (ES): m / z = 491.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 11.02 (s, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 8.26-8.15 (m, 2H), 7.89 (d, J=8.2 Hz, 1H), 5.14 (dd, J=13.3, 5.0 Hz, 1H), 4.63-4.50 (m, 1H), 4.50-4.34 (m, 3H), 3.24-3.04 (m, 2H), 3.02-2.86 (m, 2H), 2.64 (br d, J=18.3 Hz, 1H), 2.49-2.39 (m, 4H), 2.20-1.99 (m, 1H), 1.89 (br d, J=13.4 Hz, 2H), 1.63-1.43 (m, 3H), 1.17 (t, J=7.3 Hz, 1H), 1.06 (s, 6H).

[0377] Examples 168 to 169 The compounds in Table 17 were prepared according to the methods described in Example 167. [Table 33]

[0378] Example 170 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 170A: (2-chloro-3-methylpyridin-4-yl)methanol To a solution of methyl 2-chloro-3-methylpyridine-4-carboxylate (0.157 g, 0.846 mmol) in THF (1.5 mL) was added sodium borohydride (0.096 g, 2.54 mmol) followed by MeOH (0.6 mL). The reaction mixture was stirred at room temperature for 2 h and water was added to quench the reaction. The solvent was evaporated and the residue was dissolved in EtOAc and washed with brine. The solvent was evaporated to give (2-chloro-3-methylpyridin-4-yl)methanol (0.12 g, 90% yield). MS (ES): m / z = 158.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 ​​(d, J=4.8 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 5.52 (t, J=5.4 Hz, 1H), 4.59-4.53 (m, 2H), 2.25 (s, 3H).

[0379] Intermediate 170B: tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a vial equipped with a pressure relief valve, (2-chloro-3-methylpyridin-4-yl)methanol (0.117 g, 0.742 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared by the method shown in WO2018 / 102725) (0.363 g, 0.817 mmol), Pd(dtbpf)Cl 2 (0.014g, 0.022mmol), dioxane (2mL) and 2M K 3 PO 4 (1.114 mL, 2.227 mmol) was added. The reaction mixture was purged with nitrogen for 5 min. The vial was sealed and the reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was washed with Na 2 SO 4The mixture was dried over 100 ml and the solvent was evaporated to give a residue. To this residue was added ether. A solid precipitated out. The solid was filtered and washed with ether to give tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.22 g, 67.4% yield). The enantiomeric excess of tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and subsequent intermediates was not determined. MS(ES):m / z = 440.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d, J=4.8 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.69 (s, 1H), 7.63-7.54 (m, 2H), 7.48 (d, J=4.8 Hz, 1H), 7.20 (br s, 1H), 5.47 (br s, 1H), 4.81-4.73 (m, 1H), 4.70-4.50 (m, 4H), 2.24-2.13 (m, 6H), 2.10-1.90 (m, 1H), 1.34 (s, 9H).

[0380] Intermediate 170C: 3-(5-(4-(chloromethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.185g, 0.421mmol) in DCM (2mL) was added thionyl chloride (0. 092mL, 1.263mmol) in DCM (1mL) dropwise at 0°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated to give tert-butyl 5-amino-4-(5-(4-(chloromethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. MS(ES):m / z=458.0[M+H]+. To the tert-butyl 5-amino-4-(5-(4-(chloromethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was added benzenesulfonic acid (0.146 g, 0.92 mmol) in acetic acid (0.8 mL) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled and the solvent was evaporated to give 3-(5-(4-(chloromethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.105 g, 65% yield). MS (ES): m / z = 384.0 [M+H]+.

[0381] Example 170: To 3-(5-(4-(chloromethyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.036 mmol), 2-azaspiro[3.3]heptane (5.20 mg, 0.054 mmol) was added DMF (2 mL), followed by N-ethyl-N-isopropylpropan-2-amine (0.05 mL, 0.286 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((2-azaspiro[3.3]heptane-2-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.9 mg, 23.4% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 9-49% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25° C. The enantiomeric excess of 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 0.89 min. MS (ES): m / z = 445.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.45 (br d, J=3.7 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.32 (br d, J=4.9 Hz, 1H), 5.16 (br dd, J=13.4, 5.2 Hz, 1H), 4.54 (br d, J=17.4 Hz, 1H), 4.41 (br d, J=17.7 Hz, 1H), 3.64 (s, 2H), 3.31 (s, 4H), 3.03-2.88 (m, 1H), 2.63 (br d, J=17.4 Hz, 1H), 2.47-2.39 (m, 1H), 2.21 (s, 3H), 2.16-2.01 (m, 5H), 1.81-1.75 (m, 2H), 1.92 (s, 1H), 1.78 (quin, J=7.5 Hz, 2H), 1.17 (t, J=7.3 Hz, 1H).

[0382] Example 171 The compounds in Table 18 were prepared following the general method described in Example 170. [Table 34]

[0383] Example 172 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 172A: (2-chloro-3-methoxypyridin-4-yl)methanol To a solution of 2-chloro-3-methoxypyridine-4-carbaldehyde (0.035 g, 0.204 mmol) in THF (1.5 mL) was added sodium borohydride (0.015 g, 0.408 mmol) followed by MeOH (0.6 mL). The reaction mixture was stirred at room temperature for 2 h and the reaction was quenched by the addition of water. The solvent was evaporated and the residue was dissolved in EtOAc and washed with brine. The solvent was evaporated to give (2-chloro-3-methoxypyridin-4-yl)methanol (0.033 g, 0.19 mmol, 93% yield). MS (ES): m / z = 174.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (d, J=4.8 Hz, 1H), 7.49 (d, J=4.8 Hz, 1H), 5.52 (t, J=5.6 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 3.80 (s, 3H).

[0384] Intermediate 172B: tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a vial equipped with a pressure relief valve, (2-chloro-3-methoxypyridin-4-yl)methanol (0.139 g, 0.801 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared by the method shown in WO2018102725) (0.391 g, 0.881 mmol), Pd(dtbpf)Cl 2 (0.016 mg, 0.024 mmol), dioxane (2 mL) and 2M K 3 PO 4 (1.2 mL, 2.4 mmol) was added. The reaction mixture was purged with nitrogen for 5 min. The vial was sealed and the reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was washed with Na2 SO 4 Drying on a kettle and evaporation of the solvent gave a residue which was purified by flash column chromatography (0-20% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.264 g, 72.4% yield). The enantiomeric excess of tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and subsequent intermediates was not determined. MS(ES): m / z = 456.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d, J=4.8 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=4.6 Hz, 1H), 7.20 (s, 1H), 5.46 (t, J=5.6 Hz, 1H), 4.81-4.75 (m, 1H), 4.72-4.65 (m, 3H), 4.58-4.51 (m, 1H), 3.46 (s, 3H), 2.24-2.14 (m, 3H), 2.06-1.98 (m, 1H), 1.34 (s, 9H).

[0385] Intermediate 172C: 3-(5-(4-(chloromethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.15 g, 0.329 mmol) in DCM (2 mL) was added thionyl chloride (0.072 mL, 0.99 mmol) in DCM (1 mL) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated to give tert-butyl 5-amino-4-(5-(4-(chloromethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. MS(ES):m / z = 474.1 [M+H] + To the tert-butyl 5-amino-4-(5-(4-(chloromethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was added benzenesulfonic acid (0.115 g, 0.724 mmol) in acetic acid (1.2 mL) and the reaction mixture was heated at reflux for 2 h. The residue was dissolved in EtOAc and washed with water. The organic phases were combined and the solvent was evaporated to give 3-(5-(4-(chloromethyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.075 g, 57% yield). MS(ES):m / z = 400.0 [M+H] + .

[0386] Example 172: To intermediate 98B (12 mg, 0.028 mmol) was added 2-(4-piperidyl)-2-propanol (5.91 mg, 0.042 mmol), DMF (2 mL) followed by N-ethyl-N-isopropylpropan-2-amine (0.038 mL, 0.22 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9.1 mg, 62% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 1-41% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25° C. The enantiomeric excess of 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 0.93 min. MS (ES): m / z = 507.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 11.01 (s, 1H), 8.44 (d, J=4.7 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.47 (d, J=4.7 Hz, 1H), 5.15 (dd, J=13.2, 5.0 Hz, 1H), 4.55 (d, J=17.4 Hz, 1H), 4.42 (d, J=17.2 Hz, 1H), 4.08 (s, 3H), 3.60-3.46 (m, 4H), 3.00-2.85 (m, 3H), 2.63 (br dd, J=16.0, 2.1 Hz, 1H), 2.47-2.37 (m, 1H), 2.06-1.94 (m, 2H), 1.68 (br d, J=12.4 Hz, 2H), 1.35-1.14 (m, 2H), 1.04 (s, 6H).

[0387] Example 173 The compounds in Table 19 were prepared following the general method described in Example 172. [Table 35]

[0388] Example 174 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0389] Intermediate 174A: (2-chloro-6-methoxypyridin-4-yl)methanol To a solution of methyl 2-chloro-6-methoxyisonicotinate (0.057 g, 0.283 mmol) in THF (1.5 mL) was added sodium borohydride (0.032 g, 0.848 mmol) followed by MeOH (0.6 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water. The solvent was evaporated and the residue was dissolved in EtOAc and washed with brine. The solvent was evaporated to give (2-chloro-6-methoxypyridin-4-yl)methanol (0.048 g, 98% yield). MS (ES): m / z = 174.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.01 (s, 1H), 6.75 (s, 1H), 5.50 (t, J=5.8 Hz, 1H), 4.51 (d, 2H), 3.85 (s, 3H).

[0390] Intermediate 174B: tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a vial equipped with a pressure relief valve, (2-chloro-6-methoxypyridin-4-yl)methanol (0.046 g, 0.265 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared according to the method shown in WO2018102725) (0.13 g, 0.291 mmol), Pd(dtbpf)Cl 2 (0.005 g, 0.008 mmol), dioxane (2 mL) and 2M K 3 PO 4 (0.4 mL, 0.8 mmol) was added. The reaction mixture was purged with nitrogen for 5 min. The vial was sealed and the reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was washed with Na 2 SO 4Drying on a kettle and evaporation of the solvent gave a residue which was purified by flash column chromatography (0-20% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.052 g, 43.1% yield). The enantiomeric excess of tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and subsequent intermediates was not determined. MS(ES): m / z = 456.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.64-7.56 (m, 2H), 7.20 (br s, 1H), 6.79 (s, 1H), 5.47 (t, J=5.7 Hz, 1H), 4.80-4.74 (m, 1H), 4.71-4.65 (m, 1H), 4.61-4.54 (m, 3H), 3.99 (s, 3H), 2.23-1.97 (m, 3H), 2.08-1.97 (m, 1H), 1.35 (s, 9H).

[0391] Intermediate 174C: 3-(5-(4-(chloromethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.050 g, 0.110 mmol) in DCM (2 mL) was added thionyl chloride (0. 024 mL, 0.329 mmol) in DCM (1 mL) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated to give tert-butyl 5-amino-4-(5-(4-(chloromethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. MS (ES): m / z = 474.1 [M+H] + To the tert-butyl 5-amino-4-(5-(4-(chloromethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was added p-toluenesulfonic acid (0.046 g, 0.241 mmol) in acetic acid (0.8 mL) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic phases were combined and the solvent was evaporated to give 3-(5-(4-(chloromethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.036 g, 82% yield) without further purification. MS(ES):m / z = 400.0 [M+H] + .

[0392] Example 174: To 3-(5-(4-(chloromethyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12 mg, 0.028 mmol), 2-azaspiro[3.3]heptane (4 mg, 0.042 mmol) was added DMF (2 mL) followed by N-ethyl-N-isopropylpropan-2-amine (0.038 mL, 0.220 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((2-azaspiro[3.3]heptane-2-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.6 mg, 43% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 11-51% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25° C. The excess of 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 1.09 min. MS(ES): m / z = 461.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 8.31 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 6.71 (s, 1H), 5.15 (dd, J=13.1, 5.1 Hz, 1H), 4.55 (d, J=17.3 Hz, 1H), 4.42 (d, J=17.2 Hz, 1H), 3.97 (s, 3H), 3.57 (s, 2H), 3.17 (s, 4H), 2.98-2.78 (m, 1H), 2.76-2.58 (m, 1H), 2.43 (br dd, J=13.1, 4.0 Hz, 1H), 2.10-2.02 (m, 5H), 1.79-1.73 (m, 2H).

[0393] Example 175 The compounds in Table 20 were prepared following the general procedures described in Example 174. [Table 36]

[0394] Example 176 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 176A: (2-chloro-3-(trifluoromethyl)pyridin-4-yl)methanol To a solution of methyl 2-chloro-3-(trifluoromethyl)isonicotinate (0.250 g, 1.044 mmol) in THF (10 mL) was added sodium borohydride (0.118 g, 3.13 mmol), followed by MeOH (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was incomplete as monitored by LCMS. To the reaction mixture was added sodium borohydride (0.1 g, 2.63 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was incomplete as monitored by LCMS. To the reaction mixture was added sodium borohydride (0.08 g, 2.11 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was incomplete as monitored by LCMS. The reaction was quenched by the addition of saturated ammonium chloride solution (1 mL). The solvent was evaporated and the residue was dissolved in EtOAc and washed with brine. The organic phase was dried over sodium sulfate and the solvent was evaporated to give (2-chloro-3-(trifluoromethyl)pyridin-4-yl)methanol (0.094 g, 43% yield). MS(ES): m / z = 212.0 [M+H] + .

[0395] Intermediate 176B: tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a vial equipped with a pressure relief valve, (2-chloro-3-(trifluoromethyl)pyridin-4-yl)methanol (0.094 g, 0.444 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared by the method shown in WO2018102725) (0.217 g, 0.489 mmol), Pd(dtbpf)Cl 2 (0.009 g, 0.013 mmol), dioxane (3 mL) and 2M K 3 PO 4(0.666 mL, 1.333 mmol) was added. The reaction mixture was purged with nitrogen for 5 min. The vial was sealed and the reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was washed with Na 2 SO 4 Drying on a kettle and evaporation of the solvent gave a residue which was purified by flash column chromatography (0-20% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.09 g, 41% yield). The enantiomeric excess of tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and subsequent intermediates was not determined. MS(ES): m / z = 494.1 [M+H] + .

[0396] Intermediate 176C: 3-(5-(4-(chloromethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.09 g, 0.182 mmol) in DCM (2 mL) was added thionyl chloride (0.04 mL, 0.547 mmol) in DCM (1 mL) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated to give tert-butyl 5-amino-4-(5-(4-(chloromethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. MS (ES): m / z = 550.1 [M+K] +To the tert-butyl 5-amino-4-(5-(4-(chloromethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was added benzenesulfonic acid (0.064 g, 0.401 mmol) in acetic acid (2 mL) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled and the solvent was evaporated to give 3-(5-(4-(chloromethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.075 g, 94% yield). MS(ES):m / z = 438.1 [M+H] + .

[0397] Example 176: To 3-(5-(4-(chloromethyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.032 mmol), 2-(4-piperidyl)-2-propanol (6.80 mg, 0.047 mmol) was added DMF (2 mL) followed by N-ethyl-N-isopropylpropan-2-amine (0.044 mL, 0.253 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-(trifluoromethyl)-pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (8.3 mg, 46.1% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 16-56% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25 °C. The enantiomeric excess of 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 0.96 min. MS (ES): m / z = 545.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 11.02 (br s, 1H), 9.10-8.95 (m, 1H), 8.09-7.92 (m, 1H), 7.85 (br d, J=7.3 Hz, 1H), 7.77-7.64 (m, 1H), 7.57 (br d, J=7.3 Hz, 1H), 5.23-5.02 (m, 1H), 4.62 - 4.54(m, 3H), 4.42 (d, J=17.2 Hz, 1H), 3.56-3.34 (m, 2H), 3.14-2.90 (m, 3H), 2.68-2.60 (m, 1H), 2.49-2.32 (m, 1H), 2.14-1.98 (m, 1H), 1.88 (br d, J=12.8 Hz, 2H), 1.67-1.45 (m, 3H), 1.07 (s, 6H).

[0398] Examples 177 to 178 The compounds in Table 21 were prepared following the general procedures described in Example 176. [Table 37]

[0399] Example 179 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 179A: (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methanol To a solution of 2-chloro-5-(trifluoromethyl)-pyridine-4-carboxaldehyde (0.174 g, 0.830 mmol) in THF (1.5 mL) was added sodium borohydride (0.063 g, 1.66 mmol) followed by MeOH (0.6 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water. The solvent was evaporated and the residue was dissolved in EtOAc and washed with brine. The solvent was evaporated to give (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methanol (0.160 g, 91% yield). MS(ES):m / z = 212.0 [M+H] + .

[0400] Intermediate 179B: tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a vial equipped with a pressure relief valve, (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methanol (0.16 g, 0.756 mmol), tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (prepared according to the method shown in WO2018102725) (0.37 g, 0.832 mmol), Pd(dtbpf)Cl 2 (0.015 g, 0.023 mmol), dioxane (2 mL) and 2M K 3 PO 4 (1.134 mL, 2.268 mmol). The reaction mixture was purged with nitrogen for 5 min. The vial was sealed and the reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was washed with Na 2 SO 4After drying, the solvent was evaporated to give a residue which was purified by flash chromatography (0-20% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.188 g, 50.4% yield). The enantiomeric excess of tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate and subsequent intermediates was not determined. MS(ES): m / z = 494.1 [M+H] + .

[0401] Intermediate 179C: 3-(5-(4-(chloromethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To tert-butyl 5-amino-4-(5-(4-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.14 g, 0.284 mmol) in DCM (2 mL) was added thionyl chloride (0.062 mL, 0.851 mmol) in DCM (1 mL) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated to give tert-butyl 5-amino-4-(5-(4-(chloromethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. MS(ES):m / z=550.0. To tert-butyl 5-amino-4-(5-(4-(chloromethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate was added benzenesulfonic acid (0.099 g, 0.624 mmol) in acetic acid (1.2 mL) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled and the solvent was evaporated to give 3-(5-(4-(chloromethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.12 g, 97% yield) without further purification. MS(ES):m / z = 438.1 [M+H] + .

[0402] Example 179: To 3-(5-(4-(chloromethyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15 mg, 0.032 mmol), 2-(4-piperidyl)-2-propanol (6.80 mg, 0.047 mmol) was added DMF (2 mL) followed by N-ethyl-N-isopropylpropan-2-amine (0.044 mL, 0.253 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-(trifluoromethyl)-pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12.8 mg, 73% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 25-65% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25 °C. The enantiomeric excess of 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 1.18 min. MS (ES): m / z = 545.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 11.02 (br s, 1H), 8.99 (br s, 1H), 8.35 (s, 1H), 8.32 (br s, 1H), 8.25 (br d, J=8.2 Hz, 1H), 7.92 (br d, J=7.6 Hz, 1H), 5.16 (br dd. J=15.9Hz, 1H), 2.48-2.41 (m, 1H), 2.11-1.91 (m, 3H), 1.68 (br d, J=11.9 Hz, 2H), 1.47-1.26 (m, 2H), 1.26-1.12 (m, 1H), 1.05 (s, 6H).

[0403] Examples 180 to 182 The compounds in Table 22 were prepared following the general procedures described for Example 184. [Table 38]

[0404] Example 182 3-(5-(3-fluoro-4-((4-(trifluoromethoxy)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To intermediate 149B (19 mg, 0.045 mmol), 4-trifluoromethoxy-piperidine (11.36 mg, 0.067 mmol) was added DMF (2 mL) followed by N-ethyl-N-isopropylpropan-2-amine (0.063 mL, 0.358 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC to give 3-(5-(3-fluoro-4-((4-(trifluoromethoxy)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (14 mg, 59.2% yield). Preparative HPLC conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 24-64% B over 20 min; Flow rate: 20 mL / min; Column temperature: 25° C. The enantiomeric excess of 3-(5-(3-fluoro-4-((4-(trifluoromethoxy)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was not determined. LCMS (Method B): Retention time 1.14 min. MS(ES): m / z = 521.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.54 (br s, 1H), 8.11 (br s, 1H), 8.07-7.97 (m, 1H), 7.95-7.80 (m, 1H), 7.55 (br s, 1H), 5.27-5.07 (m, 1H), 4.70-4.51 (m, 1H), 4.51-4.34 (m, 2H), 3.59-3.46 (m, 1H), 3.46-3.26 (m, 1H), 3.01-2.81 (m, 1H), 2.79-2.68 (m, 2H), 2.63 (br d, J=15.3 Hz, 1H), 2.48-2.35 (m, 3H), 2.21-2.01 (m, 1H), 2.01-1.88 (m, 2H), 1.76 (br s, 2H).

[0405] Examples 188 to 197 The compounds in Table 23 were prepared following the general method described in Example 182. [Table 39]

[0406] Example 188 N-(tert-butyl)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide [ka] A 1-dram vial was charged with Intermediate 98B (25 mg, 0.062 mmol), N-(tert-butyl)pyrrolidine-2-carboxamide (10.48 mg, 0.062 mmol), DMF (1 mL) and N-ethyl-N-isopropylpropan-2-amine (0.107 mL, 0.615 mmol) and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and AcOH (0.5 mL) was added. The crude material was purified using preparative HPLC method 1 described above. The product yield was 23.7 mg with an estimated purity of 95% by LCMS analysis. Analytical HPLC was used to determine final purity. HPLC Method A Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). HPLC Method A Results: Purity: 98.3%; Found: 504.30; Retention time: 1.44 min. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 11.02 (s, 1 H) 8.77 (d, J=4.88 Hz, 1 H) 8.30 (s, 1 H) 8.22 (br d, J=7.93 Hz, 1 H) 8.13 (s, 1 H) 8.09 (br s, 1 H) 7.91 (d, J=7.93 Hz, 1 H) 7.53 (d, J=4.88 Hz, 1 H) 5.15 (br dd, J=13.58, 5.04 Hz, 1 H) 4.53-4.62 (m, 2 H) 4.40-4.49 (m, 2 H) 4.14 (br t, J=7.17 Hz, 1 H) 2.89-2.98 (m, 1H) 2.64 (br d, J=16.17 Hz, 1 H) 2.39-2.49 (m, 2 H) 2.04-2.16 (m, 2 H) 1.85-1.94 (m, 1 H) 1.76-1.84 (m, 1 H) 0.95-1.00 (m, 9 H).

[0407] Examples 189 to 197 The compounds in Table 24 were prepared following the general method described in Example 188, substituting the appropriate amine for N-(tert-butyl)pyrrolidine-2-carboxamide. [Table 40] [Table 41]

[0408] Example 198 3-(5-(3-fluoro-4-((4-fluoro-4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] A 1-dram vial was charged with Intermediate 149B (20 mg, 0.047 mmol), 4-fluoro-4-methylpiperidine,HCl (10.86 mg, 0.071 mmol), DMF (1 mL) and N-ethyl-N-isopropylpropan-2-amine (0.082 mL, 0.471 mmol) and heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and AcOH (0.5 mL) was added. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particle size; Mobile phase A: 5:95 acetonitrile:water (with ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with ammonium acetate); Gradient: 16% B at 0 min hold, 16-56% B at 25 min hold, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. The product yield was 16.2 mg with an estimated purity of 100% by LCMS analysis. Analytical HPLC was used to determine the final purity. HPLC method conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). HPLC result: Purity: 100%; Found: 469.10; Retention time: 1.54 min. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 11.01 (s, 1 H) 8.54 (d, J=4.56 Hz, 1 H) 8.12 (s, 1 H) 8.04 (br d, J=7.80 Hz, 1 H) 7.87 (d, J=7.88 Hz, 1 H) 7.53-7.57 (m, 1 H) 5.16 (dd, J=13.39, 5.10 Hz, 1 H) 4.56 (d, J=17.42 Hz, 1 H) 4.44 (d, J=17.25 Hz, 1 H) 3.70 (br s, 1 H) 2.89-3.00 (m, 1 H) 2.59-2.67 (m, 2 H) 2.51 (br d, J=1.33 Hz, 3 H) 2.32-2.48 (m, 3 H) 2.02-2.09 (m, 1 H) 1.73-1.80 (m, 3 H) 1.64-1.72 (m, 1 H) 1.28-1.38 (m, 3 H).

[0409] Example 199 3-(5-(4-((2-acetyltetrahydropyridazin-1(2H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] A 1-dram vial was charged with Intermediate 149B (20 mg, 0.047 mmol), hexahydropyridazine (5.68 mg, 0.066 mmol) dissolved in DMF (1 mL), and N-ethyl-N-isopropylpropan-2-amine (0.082 mL, 0.471 mmol) and stirred at 80° C. for 90 min. The reaction mixture was cooled to room temperature. Acetic anhydride (9.63 mg, 0.094 mmol) was added and the reaction mixture was stirred at room temperature for 30 min and acidified with a few drops of AcOH. The mixture was purified by preparative HPLC method 1 to give the title compound in 34% yield. HPLC method A result: Purity: 100%; Found: 480.20; Retention time: 1.21 min. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 11.02 (br s, 1 H) 8.52-8.61 (m, 1 H) 8.08-8.16 (m, 1 H) 8.02 (br d, J=7.63 Hz, 1 H) 7.86-7.93 (m, 1 H) 7.54 (br s, 1 H) 5.12-5.20 (m, 1 H) 4.54-4.64 (m, 1 H) 4.40-4.49 (m, 1 H) 4.16-4.31 (m, 3 H) 3.08-3.18 (m, 1 H) 2.88-3.07 (m, 3 H) 2.63 (br d, J=16.78Hz, 1H) 2.37-2.47 (m, 1 H) 1.99-2.10 (m, 2 H) 1.76-1.83 (m, 3 H) 1.73 (br d, J=11.90 Hz, 1 H) 1.33-1.51 (m, 2 H).

[0410] Example 200 3-(5-(4-((4-(1,1-difluoropropyl)piperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 200A: 4-(1,1-difluoropropyl)piperidine To a solution of 1-(pyridin-4-yl)propan-1-one (1.g, 7.40 mmol) in DCM (30 mL) was added N,N-diethyl-1,1,1-trifluoro-4-sulfanamine (2.172 mL, 14.80 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 days. A 5% aqueous solution of sodium bicarbonate was added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, brine, then dried over sodium sulfate, filtered and concentrated to give a 5:1 mixture of 4-(1,1-difluoropropyl)pyridine and 1-(pyridin-4-yl)propan-1-one. The resulting mixture was dissolved in methanol (10 mL) and then 1M hydrochloric acid (10 mL) was added followed by catalytic platinum oxide (50 mg). The resulting suspension was hydrogenated on a Parr shaker at approximately 40 psi for 4 days. The mixture was filtered through Celite and concentrated to give a mixture containing approximately 20% of the title compound as the HCl salt.

[0411] Example 200: To 4-(1,1-difluoropropyl)piperidine,HCl (8.47 mg, 0.042 mmol), Intermediate 149B (18 mg, 0.042 mmol), DMF (1 mL) and N-ethyl-N-isopropylpropan-2-amine (0.074 mL, 0.424 mmol) were added and stirred at 90° C. for 1 h. The mixture was purified by preparative HPLC method 1 to give the title compound in 14% yield. HPLC method A results: Purity: 100%; Found: 515.20; Retention time: 1.84 min. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 11.02 (br s, 1 H) 8.54 (br s, 1 H) 8.12 (br s, 1 H) 8.04 (br d, J=5.80 Hz, 1 H) 7.87 (br d, J=6.71 Hz, 1 H) 7.54 (br s, 1 H) 5.12-5.19 (m, 1 H) 4.53-4.61 (m, 1 H) 4.41-4.48 (m, 1 H) 2.90-2.97 (m, 2 H) 2.60-2.67 (m, 1 H) 2.37-2.47 (m, 1 H) 2.06 (br t, J=9.31 Hz, 3H) 1.77-1.93 (m, 3 H) 1.67-1.76 (m, 2 H) 1.39-1.51 (m, 2 H) 0.94 (br t, J=7.02 Hz, 3 H).

[0412] Example 201 tert-Butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,5-diazaspiro[3.5]nonane-5-carboxylate [ka] A 2-dram vial was charged with Intermediate 149B (60 mg, 0.141 mmol), tert-butyl 2,5-diazaspiro[3.5]nonane-5-carboxylate, 0.5 equivalents of oxalate (46.0 mg, 0.170 mmol), acetonitrile (1 mL) and N-ethyl-N-isopropylpropan-2-amine (0.246 mL, 1.414 mmol) and stirred at 75° C. for 2 hours. The mixture was purified by preparative HPLC Method 1 to give the title compound in 67% yield. HPLC Method A results: Purity: 97.9%; Found: 578.20; Retention time: 1.8 min. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 8.53 (d, J=4.73 Hz, 1 H) 8.11 (s, 1 H) 8.03 (br d, J=7.78 Hz, 1 H) 7.87 (d, J=7.93 Hz, 1 H) 7.50 (t, J=4.69 Hz, 1 H) 5.15 (dd, J=13.31, 4.84 Hz, 1 H) 4.56 (d, J=17.32 Hz, 1 H) 4.43 (d, J=17.32 Hz, 1 H) 3.01-3.10 (m, 2 H) 2.87-2.99 (m, 1 H) 2.63 (br d, J=15.87 Hz, 1 H) 2.37-2.48 (m, 1 H) 2.01-2.09 (m, 1 H) 1.76-1.85 (m, 2 H) 1.68 (br s, 2 H) 1.38 (s, 9 H) 1.28-1.34 (m, 2 H).

[0413] Example 202 3-(5-(4-((1-acetyl-1,8-diazaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 202A: 3-(5-(4-((1,8-diazaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A 2-dram vial was charged with Intermediate 149B (65 mg, 0.153 mmol), tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate (44.2 mg, 0.184 mmol), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.267 mL, 1.532 mmol) and heated at 75° C. for 2 h. The mixture was concentrated to dryness and 1:1 TFA / DCM (5 mL) was added. The mixture was stirred at room temperature. After 1 h, the mixture was concentrated to dryness to provide the TFA salt of the title compound.

[0414] Example 202: A 1-dram vial was charged with 3-(5-(4-((1,8-diazaspiro[4.5]decane-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, TFA (25 mg, 0.041 mmol), acetic anhydride (12.64 mg, 0.124 mmol), DMF (1.5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.072 mL, 0.413 mmol) and stirred at room temperature for 1 hour. The mixture was purified by preparative HPLC Method 1 to give the title compound in 63% yield. HPLC Method A Results: Purity: 99.2%; Observed Mass: 534.20; Retention Time: 1.39 min. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 11.01 (s, 1 H) 8.54 (d, J=4.58 Hz, 1 H) 8.12 (s, 1 H) 8.04 (br d, J=7.63 Hz, 1 H) 7.87 (d, J=7.93 Hz, 1 H) 7.54 (t, J=4.88 Hz, 1 H) 5.15 (dd, J=13.28, 5.04 Hz, 1 H) 4.57 (br d, J=17.09 Hz, 1 H) 4.44 (br d, J=17.70 Hz, 1 H) 2.84-2.97 (m, 3 H) 2.79 (br d, J=11.29 Hz, 2 H) 2.63 (br d, J=16.17 Hz, 1 H) 2.38-2.48 (m, 1 H) 2.14 (br t, J=11.60 Hz, 2 H) 2.03-2.10 (m, 1 H) 1.92 (s, 3 H) 1.81-1.87 (m, 2 H) 1.71-1.78 (m, 2 H) 1.20 (br d, J=11.60 Hz, 2 H).

[0415] Example 203 Methyl 8-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,8-diazaspiro[4.5]decane-1-carboxylate [ka] To a 1-dram vial was added 3-(5-(4-((1,8-diazaspiro[4.5]decane-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, TFA (25 mg, 0.041 mmol), dimethyl dicarbonate (16.61 mg, 0.124 mmol), DMF (1.5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.072 mL, 0.413 mmol) and stirred at room temperature for 1 hour. The mixture was purified by preparative HPLC Method 1 to give the title compound in 81% yield. HPLC Method A Results: Purity: 100%; Found: 550.10; Retention Time: 1.08 min. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 11.00 (s, 1 H) 8.55 (d, J=4.88 Hz, 1 H) 8.12 (s, 1 H) 8.04 (m, J=7.93 Hz, 1 H) 7.95 (s, 1 H) 7.87 (m, J=7.93 Hz, 1 H) 7.54 (t, J=4.58 Hz, 1 H) 5.15 (dd, J=13.28, 5.04 Hz, 1 H) 4.57 (d, J=17.70 Hz, 1 H) 4.44 (d, J=17.40 Hz, 1 H) 3.36 (br t, J=6.87 Hz, 1 H) 2.91-2.97 (m, 1 H) 2.90 (s, 2 H) 2.81 (br d, J=10.99 Hz, 2 H) 2.74 (s, 2 H) 2.60-2.72 (m, 3 H) 2.55 (s, 2 H) 2.36-2.48 (m, 2 H) 2.12-2.20 (m, 2 H) 2.02-2.09 (m, 1 H) 1.91 (s, 3 H) 1.84 (br s, 2 H) 1.71 (quin, J=6.64 Hz, 2 H) 1.25 (br d, J=11.29 Hz, 2 H).

[0416] Examples 204 to 275 The compounds in Table 25 were prepared following the general method described for Example 203, substituting the appropriate amine for 4-fluoro-4-methylpiperidine. Compounds with acetate or methyl formate were prepared following the general methods of Examples 202 and 203, respectively. [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51]

[0417] Example 276 3-(4-fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 276A: 5-Bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one To a stirred solution of 2,2,6,6-tetramethylpiperidine (7.07 mL, 41.6 mmol) in THF (150 mL) was added 2.5M n-BuLi / hexane solution (16 mL, 40.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. To this reaction mixture was added a solution of 4-bromo-3-fluorobenzoic acid (3.5 g, 15.98 mmol) in anhydrous THF (100 mL) dropwise at −50° C. The reaction mixture was stirred at the same temperature for 3 h. Anhydrous DMF (2.48 mL, 32.0 mmol) was added at −50° C. and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with 1.5N HCl (100 mL). The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine and anhydrous Na 2 SO 4 The residue was purified by flash chromatography (SiO 2 Purification on a 120 g column, 0~50% EtOAc / petroleum ether) afforded 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (1.0 g, 23% yield) as a yellow solid. LCMS (Method A): Retention time 0.48 min, [M+H] + 245.1, 247.1; 1 H NMR (400 MHz, acetonitrile-d 3 ) δ 7.93 (dd, J = 8.0, 5.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 6.74 (br s, 1H), 5.94 (br s, 1H).

[0418] Intermediate 276B: tert-butyl (s)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate To a stirred solution of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (15.0g, 60.7 mmol) in DMF (200 mL) was added tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (14.50 g, 60.7 mmol) and sodium triacetoxyborohydride (32.2 g, 152 mmol) at 0°C. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with ice water (250 mL). The solid precipitate was filtered, washed with water and then dried under reduced pressure to give the title compound in 79% yield. ESI MS (M+H) + = 415.1.

[0419] Intermediate 276C: tert-butyl (s)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-5-oxopentanoate A dry 500 mL round bottom flask was charged with tert-butyl (S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate (5.0 g, 12.04 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.67 g, 14.45 mmol) and potassium acetate (3.55 g, 36.1 mmol) and purged with nitrogen. The solid was suspended in dioxane (80 mL) and degassed with a stream of nitrogen for 5 min with stirring. The reaction mixture was cooled to 100° C. for 10 min with Pd(dppf)Cl. 2 (0.352 g, 0.482 mmol), degassed for 5 min, sealed and heated to 60 °C under nitrogen for 18 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine and diluted with MgSO 4 The mixture was dried over ice and the filtrate was concentrated. The yield was taken as the theoretical yield. ESI MS (M+H) + = 463.2.

[0420] Intermediate 276D: tert-Butyl (S)-5-amino-4-(4-fluoro-5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 100 mL flask, tert-butyl (S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-5-oxopentanoate (1.85 g, 4.00 mmol) dissolved in dioxane (40 mL) was added to a 100 mL flask containing (2-chloro-3-fluoropyridin-4-yl)methanol (0.679 g, 4.20 mmol), Pd(dtbpf)Cl 2 (0.078 g, 0.120 mmol) and K 3 PO 4 Aqueous solution (6.67 mL, 20.01 mmol) was added. The reaction mixture was sealed, purged with nitrogen, and then heated at 75 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and the organic layer was separated and diluted with MgSO 4 After drying over high pressure and concentration, the mixture was purified using a 120 g silica gel column by ISCO eluting with 0-10% DCM / MeOH to give the title compound in 68% yield.

[0421] Intermediate 276E: 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl To tert-butyl 5-amino-4-(4-fluoro-5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.240 g, 2.69 mmol) dissolved in DCM (35 mL) and cooled in an ice-water bath was added thionyl chloride (0.585 mL, 8.06 mmol) (dropwise). After 10 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 0.5 h, the mixture was concentrated to dryness. The resulting residue was dissolved in acetic acid (18 mL) and diluted with PhSO 3H (0.935 g, 5.91 mmol) was added and refluxed for 3 h. The mixture was concentrated to dryness and 3M HCl / MeOH (30 mL) was added and stirred at 0° C. until complete dissolution. Then EtOAc (70 mL) was added and the reaction mixture was stirred for about 5 min. The mixture was placed in an ice-water bath for about 0.5 h. The precipitate was filtered, washed with EtOAc, and air-dried to give the title product in 58% yield.

[0422] Example 276: To a 2-dram vial was added 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (20 mg, 0.045 mmol), 2-(piperidin-4-yl)propan-2-ol, HCl (10.16 mg, 0.057 mmol), DMF (1 mL) and N-ethyl-N-isopropylpropan-2-amine (0.079 mL, 0.452 mmol). The reaction mixture was heated at 80° C. for 1.5 h. The mixture was cooled to room temperature and acidified with a few drops of AcOH before being purified using preparative HPLC method 1 to give the title compound in 39% yield. HPLC method A result: Purity: 95.7%; Found: 513.20; Retention time: 0.92 min. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 11.03 (s, 1 H) 8.56 (br d, J=4.27 Hz, 1 H) 7.73-7.82 (m, 2 H) 7.61 (br t, J=4.27 Hz, 1 H) 5.11-5.20 (m, 1 H) 4.63-4.71 (m, 1 H) 4.46-4.55 (m, 1 H) 2.91 (br d, J=10.68 Hz, 2 H) 2.59-2.68 (m, 1 H) 2.43-2.49 (m, 1 H) 2.03-2.10 (m, 1 H) 1.93-2.01 (m, 2 H) 1.67 (br d, J=10.68 Hz, 2 H) 1.23-1.33 (m, 2 H) 1.14-1.21 (m, 1 H) 1.04 (s, 6 H).

[0423] Examples 277 to 284 The compounds in Table 26 were prepared following the general method described in Example 276, substituting the appropriate amine for 2-(piperidin-4-yl)propan-2-ol. [Table 52] [Table 53]

[0424] Example 285 3-(5-(6-amino-5-((8-benzoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 285A: tert-Butyl 3-((2-amino-6-chloropyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of 2-amino-6-chloronicotinaldehyde (500 mg, 3.19 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (678 mg, 3.19 mmol) in THF (20 mL) was added acetic acid (0.548 mL, 9.58 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 30 minutes, followed by addition of sodium triacetoxyborohydride (1354 mg, 6.39 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction, the reaction mixture was cooled to 0° C. The reaction was quenched with saturated NH 4 The reaction mixture was then poured into water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography ((SiO2 Purification on a 25 g column, 0~100% EtOAc / petroleum ether afforded tert-butyl (1R,5S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (620 mg, 1.207 mmol, 38% yield) as a light brown solid. LCMS (Method B): Retention time 2.74 min, [M+H] + 353.2.

[0425] Intermediate 285B: 3-((3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-6-chloropyridin-2-amine To a well-stirred solution of tert-butyl (1R,5S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.700 mmol) in anhydrous DCM (8 mL) was added TFA (2 mL) at ambient temperature under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mass was concentrated to give the crude product 3-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-6-chloropyridin-2-amine (550 mg, 1.696 mmol, 100% yield) as a thick brown syrup. LCMS (Method B): Retention time 0.34 min, [M+H] + 253.2.

[0426] Intermediate 285C: (3-((2-amino-6-chloropyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone To a well-stirred solution of 3-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-6-chloropyridin-2-amine (400 mg, 1.583 mmol) in DCM (10 mL) at 0° C., TEA (1.324 mL, 9.50 mmol) and benzoic anhydride (537 mg, 2.374 mmol) were added under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 16 h. The solvent was concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography (SiO 2 , 25 g column, 0~100% EtOAc / petroleum ether) to give ((1R,5S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone (560 mg, 1.048 mmol, 66% yield) as an off-white solid. LCMS (Method B): Retention time 2.07 min, [M+H] + 357.2.

[0427] Intermediate 285D: tert-butyl 5-amino-4-(5-(6-amino-5-((8-benzoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate Sodium bicarbonate (88 mg, 1.051 mmol) was added to a 30 mL microwave vial containing a well-stirred solution of ((1R,5S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(phenyl)methanone (150 mg, 0.420 mmol) and tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (205 mg, 0.462 mmol) in 1,4-dioxane (7 mL) and water (1 mL) under nitrogen at ambient temperature. The reaction mixture was degassed by bubbling nitrogen gas through it for 20 minutes. Pd(PPh 3 )4 (24.29 mg, 0.021 mmol) was added to the reaction mixture. The reaction mixture was heated to 120° C. under microwave irradiation for 2 h. The reaction vessel was cooled to ambient temperature, diluted with ethyl acetate (50 mL), filtered through a bed of celite, and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (SiO 2 , 25 g column, 0~10% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(6-amino-5-(((1R,5S)-8-benzoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (120 mg, 0.163 mmol, 39% yield) as an off-white solid. LCMS (Method B): Retention time 1.88 min, [M+H] + 639.2.

[0428] Example 285: To a stirred solution of tert-butyl 5-amino-4-(5-(6-amino-5-((8-benzoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (120 mg, 0.188 mmol) in acetonitrile (3.0 mL) in a microwave vial, add N 2Benzenesulfonic acid (44.6 mg, 0.282 mmol) was added under atmosphere. The reaction mixture was sealed and irradiated in microwave at 130° C. for 2 h. After completion of the reaction, the reaction mixture was concentrated to give the crude product. It was purified using preparative HPLC (Diluent: THF:acetonitrile (50:50); Column: XBridge C18 (250 x 19) mm, 5μ; Mobile phase A: 10 mM ammonium acetate in water; Mobile phase B: acetonitrile; Gradient: 30% A + 70% B to 70% A + 30% B over 15 min: Flow rate: 15 mL / min). Fractions containing the desired product were lyophilized to give 3-(5-(6-amino-5-((8-benzoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione (32 mg, 0.055 mmol, 29% yield) as a white solid. LCMS (Method D): Retention time: 1.32, 565.2 [M+H] + ;HPLC (Method A);Retention time: 5.80 min;Purity: 96.38%; 1 HNMR:400 MHz (DMSO) δ 10.99 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 7.20 Hz, 1H), 7.78 (d, J = 7.20 Hz, 1H), 7.55-7.40 (m, 6H), 7.20 (d, J = 6.40 Hz, 1H), 6.22 (s, 2H), 5.14 (br d, J = 13.20 Hz, 1H), 4.62 (br s, 1H), 4.46 (dd, J = 17.20, 51.40 Hz, 2H), 3.98 (br s, 1H), 3.46 (m, 2H), 2.93 (br t, J = 13.60 Hz, 1H), 2.75 (m, 1H), 2.68-2.55 (m, 2H), 2.43 (m, 1H), 2.38-2.12 (m, 2H), 2.10-1.98 (m, 1H), 1.93-1.75 (m, 4H).

[0429] Example 286 3-(5-(5-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Intermediate 286A: 3-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-chloropyridin-2-amine To a stirred solution of 2-azaspiro[3.3]heptane hydrochloride (256 mg, 1.916 mmol) and 2-amino-6-chloronicotinaldehyde (300 mg, 1.916 mmol) in THF (15 mL) was added acetic acid (0.329 mL, 5.75 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 30 min, followed by addition of sodium triacetoxyborohydride (812 mg, 3.83 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the reaction was concentrated to give the crude product. The residue was purified by flash chromatography (SiO 2 , 25 g column, 0~100% EtOAc / petroleum ether) to give 3-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-chloropyridin-2-amine (220 mg, 0.772 mmol, 40% yield) as a pale yellow solid. LCMS (Method B): Retention time -0.50 min, [M+H] + 238.0.

[0430] Intermediate 286B: tert-Butyl 4-(5-(5-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate To a well-stirred solution of 3-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-chloropyridin-2-amine (100 mg, 0.421 mmol) and tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate (206 mg, 0.463 mmol) in 1,4-dioxane (7.5 mL) and water (1.5 mL) in a 30 mL microwave vial was added sodium bicarbonate (88 mg, 1.052 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was degassed by bubbling nitrogen gas through it for 15 minutes. Pd(PPh 3 ) 4 (24.30 mg, 0.021 mmol) was added to the reaction mixture and the resulting reaction mixture was heated to 120° C. under microwave irradiation for 90 min. The reaction vessel was cooled to ambient temperature, diluted with ethyl acetate (~100 mL), filtered through a bed of celite, and concentrated in v...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Z is CR 6 R 6 or C=O; Ring A is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydropyridazinyl, 1,4-azaphosphinane 4-oxide, pyrazolyl, isoindolinyl, dihydropyrrolo[3,4-c]pyridinyl, decahydroquinolinyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, hexahydrocyclopenta[c]pyrrolyl, hexahydrofuro[3,4-c]pyrrolyl, tetrahydropyrazolo[4,3-c]pyridinyl, tetrahydroisoxazolo[4,5-c]pyridinyl, tetrahydro[1,2,4]thiazolo ... riazolo[4,3-a]pyrazinyl, octahydroisoindolyl, octahydropyrrolo[3,4-b]pyridinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, oxazabicyclo[3.1.1]heptanyl, diazaspiro[3.4]octanyl, oxazaspiro[3. 4]octanyl, azaspiro[3.5]nonanyl, oxazaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, oxaazaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, oxadiazaspiro[4.5]decanyl, spiro[indoline-3,4'-piperidinyl], 2H-spiro[benzofuran-3 ,4'-piperidinyl], 3H-spiro[isobenzofuran-1,4'-piperidinyl], 2,3-dihydrospiro[indene-1,4'-piperidinyl], azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, oxazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl or oxazabicyclo[3.2.1]octanyl; R 1 are F, -CN, -OH, C 1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, -CH 2 OCH 3 , -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NR y R y , -CH 2 NR x C(O)OC(CH 3 ) 3 , -NR x C(O)OCH 3 , -NR x C(O)OC(CH 3 ) 3 , -C(O)NR x (cyclohexyl), -S(O) 2 CH 3 , -P(O)(OH)O(phenyl), -CH 2 (phenyl), -C(O)(cyclopropyl), -C(O)(phenyl), -NR x (phenyl), -CH 2 NR x C(O)(phenyl), -NR x C(O)(phenyl), -CH 2 O(fluorophenyl), -CH 2 O(chloropyridinyl), -NR x S(O) 2 CH 3 , -NR x S(O) 2 (phenyl), cyclopropyl, methyl oxadiazolyl, methylisoxazolyl, thiophenyl, -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl), or 0, 1 or 2 R 1a is phenyl substituted with; Each R 1a are independently F, Cl, -OH, -CH 3 , -CHF 2 , -CF 3 or -S(O) 2 CH 3 and Each R 2 are independently F, -CN, -OH, -CH 3 , -CF 3 , -C(CH 3 ) 2 OH or -C(O)C(CH 3 ) 3 and Each R 3 are independently F, Cl, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 or -NH 2 and Each R 4 are independently F, Cl or -CH 3 and Each R 6 are independently hydrogen or C 1 - 3 is alkyl; R x is hydrogen or -CH 3 and Each R y are independently hydrogen or C 1-4 is alkyl; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1, 2 or 3; however, (1) When ring A is azetidinyl, pyrrolidinyl, or piperidinyl, m is 1; (2) Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; m is 1; and R 1 But, C 1-4 Alkyl, C 1-2 Fluoroalkyl, -C(O)(C 1-3 alkyl), -C(O)NR y R y , -CH 2 (phenyl), phenyl or methylphenyl; R 2 are F, -CN, -OH, -CF 3 , -C(CH 3 ) 2 OH or -C(O)C(CH 3 ) 3 is] or a salt thereof.

2. Z is CR 6 R 6 2. The compound according to claim 1, wherein:

3. 2. The compound of claim 1, or a salt thereof, wherein Z is C=O.

4. R 1 F, -CN, -OH, -CH 3 , -C(CH 3 ) 3 , -CF 2 CH 2 CH 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OCH 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OCH 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 , -C(O)NHC(CH 3 ) 3 , -C(O)NH(cyclohexyl), -S(O) 2 CH 3 , -P(O)(OH)O(phenyl), -CH 2 (phenyl), -C(O)(cyclopropyl), -C(O)(phenyl), -NH(phenyl), -N(CH 3 )(phenyl), -CH 2 NHC(O)(phenyl), -CH 2 N(CH 3 )C(O)(phenyl), -N(CH 3 )C(O)(phenyl), -CH 2 O(fluorophenyl), -CH 2 O(chloropyridinyl), -N(CH 3 )S(O) 2 CH 3 , -N(CH 3 )S(O) 2 (phenyl), cyclopropyl, methyl oxadiazolyl, methylisoxazolyl, thiophenyl, -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl), or 0, 1 or 2 R 1a 2. The compound of claim 1, or a salt thereof, wherein the phenyl is substituted with

5. Ring A is azetidinyl, pyrrolidinyl or piperidinyl; m is 1; R 1 F, -CN, -OH, -CH 3 , -C(CH 3 ) 3 , -CF 2 CH 2 CH 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)CH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OCH 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OCH 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 , -C(O)NHC(CH 3 ) 3 , -C(O)NH(cyclohexyl), -S(O) 2 CH 3 , -P(O)(OH)O(phenyl), -CH 2 (phenyl), -C(O)(cyclopropyl), -C(O)(phenyl), -NH(phenyl), -N(CH 3 )(phenyl), -CH 2 NHC(O)(phenyl), -CH 2 N(CH 3 )C(O)(phenyl), -N(CH 3 )C(O)(phenyl), -CH 2 O(fluorophenyl), -CH 2 O(chloropyridinyl), -N(CH 3 )S(O) 2 CH 3 , -N(CH 3 )S(O) 2 (phenyl), cyclopropyl, methyl oxadiazolyl, methylisoxazolyl, thiophenyl, -O(phenyl), -O(tert-butoxycarbonyl)phenyl), -O((tert-butoxycarbonyl)amino)phenyl), or 0, 1 or 2 R 1a phenyl substituted with; and R 2 F, -CN, -OH, -CF 3 , -C(CH 3 ) 2 OH or -C(O)C(CH 3 ) 3 That is, 2. The compound according to claim 1 or a salt thereof.

6. 2. The compound according to claim 1, or a salt thereof, wherein ring A is azetidinyl.

7. 2. The compound according to claim 1, or a salt thereof, wherein ring A is pyrrolyl.

8. 2. The compound according to claim 1, or a salt thereof, wherein Ring A is piperidinyl.

9. R 1 But -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -CH 2 OCH 3 , -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 3 , -C(O)NH 2 , -CH 2 NHC(O)OC(CH 3 ) 3 , -NHC(O)OC(CH 3 ) 3 , -N(CH 3 )C(O)OC(CH 3 ) 3 , -S(O) 2 CH 3 or -P(O)(OH)O(phenyl); and 2. The compound according to claim 1, wherein m is 1, or a salt thereof.

10. R 1 but 0, 1 or 2 R 1a 2. The compound of claim 1, wherein m is phenyl substituted with ; and m is 1, or a salt thereof.

11. R 1 but, 【Chemistry 2】 2. The compound according to claim 1, wherein:

12. The compound is: 3-(5-(5-chloro-4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1); 3-(5-(5-fluoro-4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2); 3-(5-(4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3); 3-(5-(5-fluoro-4-((3-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4); 3-(5-(5-fluoro-4-((3-hydroxy-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5); 3-(5-(4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (6); 3-(5-(3-fluoro-4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7); 3-(5-(3-fluoro-4-((2-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (8); 3-(5-(3-fluoro-4-((3-hydroxy-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9); 3-(5-(4-((2-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10); 3-(5-(4-((3-(3-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (11); 3-(5-(4-((3-(2-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12); 3-(5-(4-((3-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (13); 3-(5-(4-((3-(2-chlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (14); 3-(5-(4-((3-(3-chlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15); 3-(5-(4-((3-(4-chlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (16); 3-(1-oxo-5-(4-((3-(2-(trifluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (17); 3-(1-oxo-5-(4-((3-(3-(trifluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (18); 3-(1-oxo-5-(4-((3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (19); 3-(5-(4-((3-(3-(difluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20); 3-(5-(4-((3-(4-(difluoromethyl)phenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21); 3-(5-(4-((3-(2,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (22); 3-(5-(4-((3-(2,3-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (23); 3-(5-(4-((3-(3,5-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24); 3-(5-(4-((3-(3,4-dichlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25); 3-(5-(4-((3-(3,5-dichlorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (26); 3-(1-oxo-5-(4-((3-(thiophen-3-yl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (27); tert-Butyl (1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)carbamate (28); 3-(1-oxo-5-(4-((3-(phenylamino)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (29); 3-(5-(4-((3-(methyl(phenyl)amino)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30); 3-(5-(4-((3-fluoro-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (31); tert-Butyl (4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate (32); 3-(5-(4-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33); 3-(5-(4-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (34); 3-(5-(4-(((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35); 3-(5-(4-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (36); 3-(5-(4-((3-hydroxy-3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (37); 3-(1-oxo-5-(4-((3-phenoxyazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (38); 3-(5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39); 3-(5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40); 3-(5-(4-(((S)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (41); 3-(5-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (42); 3-(5-(4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (43); 3-(1-oxo-5-(4-((1-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (44); tert-Butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (45); 3-(1-oxo-5-(4-((3-phenoxypyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (46); 3-(5-(4-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (47); 3-(5-(4-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (48); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-4-phenylpiperidine-4-carbonitrile (49); 3-(1-oxo-5-(4-((4-phenoxypiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (50); 3-(1-oxo-5-(4-(spiro[indoline-3,4'-piperidine]-1'-ylmethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (51); 3-(5-(4-((2H-spiro[benzofuran-3,4'-piperidine]-1'-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (52); 3-(5-(4-((2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (53); 3-(5-(4-((4-hydroxypiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (54); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55); 3-(5-(4-((2-hydroxy-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (56); 3-(5-(4-((4-(4-(methylsulfonyl)phenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (57); 3-(5-(4-((4-(3-hydroxyphenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (58); 3-(1-oxo-5-(4-((4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (59); 3-(5-(4-((4-(3-chlorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60); 3-(5-(4-((4-(4-chlorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (61); 3-(5-(4-((4-(2-fluorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (62); 3-(5-(4-((4-(3-fluorophenyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (63); 3-(5-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (64); 3-(5-(4-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (65); 3-(5-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (66); Methyl 4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)benzoate (67); 3-(5-(4-((6-oxa-2,9-diazaspiro[4.5]decan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68); 3-(5-(4-((9-benzoyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69); 3-(5-(4-((2-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70); 3-(5-(4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (71); 3-(5-(4-((3,6-dihydropyridin-1(2H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72); Phenyl hydrogen(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-yl)phosphonate (73); 3-(5-(4-((4-methyl-4-oxido-1,4-azaphosphinan-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (74); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxylic acid (75); 3-(5-(4-((3,3-difluoro-2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (76); 3-(5-(4-((2-(4-fluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (77); 3-(5-(4-((3-(3,4-difluorophenyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (78); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxamide (79); Methyl 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxylate (80); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (81); 3-(5-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82); 3-(5-(4-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (83); 3-(5-(4-((3-(methylsulfonyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (84); tert-Butyl ((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)carbamate (85); tert-Butyl (1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)(methyl)carbamate (86); 3-(5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (88); 3-(5-(3-fluoro-4-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (89); 3-(5-(3-fluoro-4-(((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90); 3-(5-(3-fluoro-4-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (91); 3-(5-(5-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (92); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (93); 3-(5-(3-chloro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94); 3-(5-(3-chloropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95); 3-(5-(3-chloro-4-(((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96); 3-(5-(3-chloro-4-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (97); tert-Butyl (4-((7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate (98); 3-(5-(4-((3-(methoxymethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (99); 3-(5-(4-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100); 3-(5-(4-(((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (101); 3-(5-(4-(((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (102); 3-(5-(4-((6-chloro-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (103); 3-(5-(4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (104); 3-(5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (105); 3-(5-(4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (106); 3-(5-(4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (107); 3-(5-(4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (108); 3-(5-(3-fluoro-4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (109); 3-(5-(3-fluoro-4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (110); 3-(5-(3-fluoro-4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (111); 3-(5-(3-fluoro-4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (112); 3-(5-(3-fluoro-4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (113); 3-(5-(3-fluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (114); 3-(5-(3-fluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (115); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)isoindoline-1,3-dione (116); 3-(5-(4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (117); 3-(5-(4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (118); 3-(5-(4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (119); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120); 3-(5-(4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (121); 3-(5-(4-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (122); 3-(5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (123); 3-(5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (124); 3-(5-(4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (125); 3-(5-(4-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (126); (R)-3-((R)-4-fluoro-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127); (S)-3-((R)-4-fluoro-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (128); (S)-3-((R)-4-fluoro-5-(4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129); (S)-3-((R)-4-fluoro-5-(4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130); (S)-3-((R)-4-fluoro-5-(4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (131); (S)-3-((R)-4-fluoro-5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (132); (S)-3-((R)-4-fluoro-5-(4-(((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (133); (3S)-3-((3R)-4-fluoro-5-(4-((3-(1-hydroxyethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (134); (3S)-3-((3R)-4-fluoro-5-(4-((4-(1-hydroxyethyl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (135); (S)-3-((R)-5-(4-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (136); (S)-3-((R)-4-fluoro-5-(4-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (137); (S)-3-((R)-4-fluoro-5-(4-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (138); (3S)-3-((3R)-4-fluoro-5-(4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (139); (3S)-3-((3R)-4-fluoro-5-(4-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140); (S)-3-((R)-4-fluoro-3-methyl-1-oxo-5-(4-(((R)-3-phenoxypyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (141); (S)-3-((R)-4-fluoro-5-(4-(((S)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (142); 3-((R)-4-fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (143); (S)-3-((R)-4-fluoro-5-(3-fluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (144); (S)-3-(5-(4-((6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (145); (3S)-3-(5-(4-((5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (146); (3S)-3-(5-(4-((5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147); (3S)-3-(5-(4-((5-methyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (148); (3S)-3-(5-(3-fluoro-4-(((3aR,7aS)-5-hydroxyoctahydro-2H-isoindol-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (149); (S)-3-(5-(3-fluoro-4-((1-oxo-2,8-diazaspiro[4.5]decan-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150); (S)-3-(5-(3-fluoro-4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (151); (S)-3-(1-oxo-5-(4-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (152); (S)-3-(5-(3-fluoro-4-((6-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (153); tert-Butyl (3aS,6aS)-5-((2-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (154); (3S)-3-(5-(3-fluoro-4-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (155); tert-Butyl (3aR,6aS)-5-((2-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (156); 3-(5-(4-((2-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (157); (S)-3-(5-(4-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (158); N-((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)benzamide (159); (S)—N-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)-N-methylbenzamide (160); (S)—N-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)-N-methylmethanesulfonamide (161); (S)—N-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)-N-methylbenzenesulfonamide (162); Methyl (S)-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)(methyl)carbamate (163); (S)—N-((1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidin-3-yl)methyl)-N-methylbenzamide (164); 3-(5-(4-((1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (165); (S)-3-(5-(4-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (166); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (167); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (168); 3-(5-(4-((3-cyclopropylpyrrolidin-1-yl)methyl)-5-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (169); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (170); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methylpyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (171); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (172); 3-(5-(4-((3-cyclopropylpyrrolidin-1-yl)methyl)-3-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (173); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (174); 3-(5-(4-((3-cyclopropylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (175); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (176); 3-(5-(4-((3-(methoxymethyl)azetidin-1-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (177); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (178); 3-(5-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (179); 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180); 3-(5-(4-((3-(methoxymethyl)azetidin-1-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (181); 3-(5-(3-fluoro-4-((4-(trifluoromethoxy)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (182); 3-(5-(3-fluoro-4-((3-(trifluoromethoxy)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (183); 3-(5-(3-fluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (184); 3-(5-(3-fluoro-4-((3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185); 3-(5-(3-fluoro-4-((4-fluoroisoindolin-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (186); 3-(5-(4-((5-chloroisoindolin-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (187); N-(tert-butyl)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide (188); 3-(5-(4-((1-(methoxymethyl)-2-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (189); (2S)-N-cyclohexyl-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide (190); 3-(5-(4-(((R)-2-(((6-chloropyridin-3-yl)oxy)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (191); 3-(5-(4-((2-((4-fluorophenoxy)methyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (192); Ethyl 3-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (193); 3-(5-(4-((2-azabicyclo[3.1.0]hexan-2-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (194); tert-Butyl (((2S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-yl)methyl)carbamate (195); 3-(5-(4-((2-(isopropoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (196); 3-(5-(4-((3-fluoro-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (197); 3-(5-(3-fluoro-4-((4-fluoro-4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (198); 3-(5-(4-((2-acetyltetrahydropyridazin-1(2H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (199); 3-(5-(4-((4-(1,1-difluoropropyl)piperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200); tert-Butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,5-diazaspiro[3.5]nonane-5-carboxylate (201); 3-(5-(4-((1-acetyl-1,8-diazaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (202); Methyl 8-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,8-diazaspiro[4.5]decane-1-carboxylate (203); tert-Butyl 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (204); 3-(5-(3-fluoro-4-((3-fluoropiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (205); 3-(5-(4-((6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (206); tert-Butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (207); tert-Butyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (208); 3-(5-(3-fluoro-4-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (209); 3-(5-(4-((8-azaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (210); 3-(5-(3-fluoro-4-((4-hydroxy-2-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (211-212); tert-Butyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (213); tert-Butyl (2S,4R)-4-(tert-butoxy)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)pyrrolidine-2-carboxylate (214-215); tert-Butyl 6-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,6-diazaspiro[3.5]nonane-1-carboxylate (216); 3-(5-(3-fluoro-4-(((R)-2-((R)-1-hydroxy-1-phenylethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (217); 3-(5-(3-fluoro-4-(((R)-2-((S)-1-hydroxy-1-phenylethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (218); 3-(5-(3-fluoro-4-((6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (219); 3-(5-(3-fluoro-4-((4-hydroxy-4-methylazepan-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (220); 3-(5-(3-fluoro-4-((4-hydroxy-3,3-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (221); 3-(5-(3-fluoro-4-((3-hydroxy-1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (222); 3-(5-(3-fluoro-4-((3-hydroxy-2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (223); 3-(5-(3-fluoro-4-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (224); 3-(5-(3-fluoro-4-((2-hydroxy-7-azaspiro[3.5]nonan-7-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (225); 3-(5-(3-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (226); 3-(5-(4-((3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (227); Methyl 8-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (228); 3-(5-(4-((3-benzoyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (229); 3-(5-(3-fluoro-4-((3-hydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (230); 3-(5-(4-((1-(cyclopropanecarbonyl)-1,8-diazaspiro[4.5]decan-8-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (231); 3-(5-(3-fluoro-4-(((3S,4R)-3-hydroxy-4-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (232); 3-(5-(4-((5-acetyl-2,5-diazaspiro[3.5]nonan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (233); 3-(5-(3-fluoro-4-((3-(4-fluorophenyl)-3-hydroxypyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (234); 3-(5-(4-((4-benzyl-4-hydroxypiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (235); tert-Butyl ((3S,5S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-5-fluoropiperidin-3-yl)carbamate (236); 3-(5-(3-fluoro-4-((4-(4-fluorophenyl)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (237); 3-(5-(4-((3-(2-chlorophenyl)-3-hydroxypyrrolidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (238); 3-(5-(3-fluoro-4-(((4aR,8R,8aR)-8-hydroxyoctahydroquinolin-1(2H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (239); Methyl (2S,3R)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-3-hydroxypyrrolidine-2-carboxylate (240); 3-(5-(3-fluoro-4-((3-hydroxy-3-(p-tolyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (241); 3-(5-(4-((3-(3-chlorophenyl)-3-hydroxypyrrolidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (242); 3-(5-(3-fluoro-4-((4-fluoro-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (243); 3-(5-(3-fluoro-4-((2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (244); 3-(5-(3-fluoro-4-(((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (245); tert-Butyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (246); 3-(5-(3-fluoro-4-((4-hydroxy-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (247); Methyl ((3S,4S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-4-hydroxypyrrolidin-3-yl)carbamate (248); 3-(5-(4-((3H-spiro[isobenzofuran-1,4'-piperidine]-1'-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (249); 3-(5-(3-fluoro-4-((3-hydroxy-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (250); 3-(5-(4-((2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (251); Methyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (252); 3-(5-(3-fluoro-4-((3-fluoro-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (253); 3-(5-(3-fluoro-4-((1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (254); 3-(5-(3-fluoro-4-((5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (255); 3-(5-(4-((3-(2,5-dimethylphenyl)-3-hydroxypyrrolidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (256); 3-(5-(3-fluoro-4-((3-hydroxy-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (257); 3-(5-(3-fluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (258); 3-(5-(4-((6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (259); 3-(5-(3-fluoro-4-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (260); 3-(5-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (261); 3-(5-(3-fluoro-4-((3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (262); 3-(5-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (263); 3-(5-(4-((1,3-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (264); 3-(5-(4-((2,3-dimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (265); 3-(5-(3-fluoro-4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (266); 3-(5-(4-((5-chloro-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (267); 3-(5-(4-((8-chloro-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (268); 3-(5-(4-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (269); 3-(5-(4-((1-acetyl-1,7-diazaspiro[4.4]nonan-7-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (270); Methyl 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (271); 3-(5-(4-((6-acetyl-2,6-diazaspiro[3.4]octan-2-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (272); Methyl 2-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (273); 3-(5-(4-((6-acetyloctahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (274); Methyl 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropyridin-4-yl)methyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (275); 3-(4-fluoro-5-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (276); 3-(4-fluoro-5-(3-fluoro-4-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (277); 3-(4-fluoro-5-(3-fluoro-4-(((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (278); 3-(4-fluoro-5-(3-fluoro-4-(((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (279); 3-(4-fluoro-5-(3-fluoro-4-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (280); 3-(4-fluoro-5-(3-fluoro-4-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (281); 3-(4-fluoro-5-(3-fluoro-4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (282); 3-(5-(4-((5-chloro-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)methyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (283); 3-(5-(4-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3-fluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (284); 3-(5-(6-amino-5-((8-benzoyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (285); 3-(5-(5-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (286); 3-(5-(3,5-difluoro-4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (287); 3-(5-(3,5-difluoro-4-((3-(methoxymethyl)azetidin-1-yl)methyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (288); or 3-(5-(4-((2-azaspiro[3.3]heptan-2-yl)methyl)-3,5-difluoropyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (289) 2. The compound according to claim 1, which is a compound of the formula:

13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof for the treatment of cancer.

15. 15. The pharmaceutical composition of claim 14, wherein the cancer is selected from colon cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia and melanoma.

16. 13. An agent for reducing Helios protein levels, Helios activity levels, or Helios expression levels in a cell, comprising contacting a Helios protein with a compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof.

17. The method of claim 16, wherein the Helios protein is encoded by the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, or 5.

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