Compounds useful as inhibitors of Helios protein

Abstract

Chemical Formula 1 below: TIFF2023503052000086.tif3455 [wherein Z is CR6R6 or C=O; ring A is TIFF2023503052000087.tif45153, wherein R1, R2, R3, R4, R5, m, and n are defined herein, or a salt thereof. Also disclosed are methods of using such compounds that inhibit Helios protein, and pharmaceutical compositions containing such compounds. These compounds are useful for treating proliferative diseases such as viral infections and cancer.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 937,350, filed November 19, 2019, which is incorporated herein in its entirety.

[0002] The present invention generally relates to compounds that inhibit Helios protein.Compounds, compositions containing such compounds, and methods of using them are provided herein.The present invention further relates to pharmaceutical compositions that contain at least one compound according to the present invention, which are useful for treating proliferative diseases such as cancer and viral infection. [Background technology]

[0003] Regulatory T cells (Tregs) play a key role in controlling self-tolerance and immune homeostasis through the maintenance of inhibitory activity and anergy during active immune and inflammatory responses. By maintaining a stable, anergic and suppressive phenotype, Tregs attenuate excessive immune responses and prevent or ameliorate autoimmunity. Numerous reports have demonstrated the presence of Tregs within human tumor tissues. Studies have demonstrated a clear negative correlation between the number of Tregs and T cell infiltration into tumors and survival rate (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 a potential important role of Tregs in preventing the development of effective antitumor immunity. Accumulating evidence indicates that Foxp3+CD25+CD4+Tregs significantly infiltrate tumors and clearly impede immune responses against tumor cells in rodents and humans. Upon activation by specific antigen, Tregs suppress responder T cells in an antigen-nonspecific and bystander manner in vitro (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 involving 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 intratumoral CD25+CD4+ Tregs induced regression of established tumors, accompanied by changes in the cytokine environment at the tumor site (Yu et al., 2005, J Exp Med. 201: 779-91).Furthermore, transfer of Treg-depleted CD4+ T cells significantly enhanced antitumor immune responses compared with transfer of Treg-containing T cells (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrating Tregs activated by either tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific antitumor immune responses. Modulation of the activity of key factors controlling Treg differentiation may be a potential therapeutic strategy for the treatment of certain diseases, such as cancer and viral infections.

[0004] FoxP3+CD4Tregs are remarkably stable. Research is still evolving to understand the genetic mechanisms that ensure their phenotypic stability after expansion during inflammation, infection or autoimmunity. Transcription factors (TFs) involved in maintaining the stable immunosuppressive phenotype of Tregs likely contribute to this process. The Helios (IKZF2) gene, a member of the Ikaros family of TFs, differs from other Ikaros family members based on its selective expression by thymocytes that undergo negative selection, as well as the regulatory lineages of CD4 and CD8 T cells. Helios is expressed by two regulatory T cell lines, FoxP3+CD4+ and Ly49+CD8+Tregs, which are required to maintain self-tolerance (Kim et al., 2015, Science 350:334-339; Sebastian et al., 2016, J Immunol 196:144-155). Interestingly, in the steady state, Helios is largely dispensable for Treg activity, but recent studies suggest that in the context of inflammation, control of the genetic program of FoxP3+CD4Tregs by Helios is necessary for maintaining a stable phenotype and enhancing suppressive function (Thornton et al., 2010, J Immunol. 184:3433-3441; Kim et al., 2015). Helios expression by Tregs has been shown to be important for their ability to maintain a suppressive and anergic phenotype during intense inflammatory responses. Activation of the IL-2Rα-STAT5 pathway has been shown to be a key contributor by ensuring Treg survival and stability (Kim et al., 2015). Helios plays an essential role in maintaining the FoxP3+CD4Treg phenotype by expressing dominant lymphocyte-intrinsic inhibition to prevent autoimmune disease in the presence of highly activated autoreactive T cells from Scurfy mice lacking the FoxP3 forkhead domain. Bone marrow (BM) chimeras reconstituted with Helios- / - / Scurfy BM cells but not with Helios+ / + / Scurfy BM cells rapidly developed autoimmunity (Kim et al., 2015).These findings indicate an important contribution of Helios to autoreactive T cell selection, differentiation, and function. Immunosuppression expressed by Tregs can impede antitumor immune responses. Selective deficiency of Helios in FoxP3+CD4 Tregs results in increased Treg instability and conversion of intratumoral CD4 Tregs to effector T cells (Teff). Intratumoral Treg instability may increase the number of Teff cells in the tumor as a combined result of Treg conversion and reduced suppressive activity of Tregs. In addition, defective IL-2 responses were observed in Helios-deficient intratumoral Tregs, which may result in a reduced number of activated Tregs and contribute to increased intratumoral Teff activity. Interactions between tumor cells and infiltrating immune cells result in the secretion of inflammatory mediators such as TNF-α, IL-6, IL-17, IL-1, and TGF-β, as well as the formation of a local inflammatory environment (Kim et al., 2015).

[0005] Lineage instability of Helios-deficient Tregs is also accompanied by a decrease in FoxP3 expression, resulting in the acquisition of an effector phenotype through the production of inflammatory cytokines. Effector cell conversion of Helios-deficient Tregs within the tumor tissue microenvironment is associated with increased expression of genes controlling the Teff phenotype (Yates et al., 2018, PNAS, 2018, 115: 2162-2167). The acquisition of an unstable phenotype by Helios deficiency occurs only within the tumor microenvironment (TME), but not in peripheral lymphoid organs (Nakagawa et al., 2016, PNAS 113: 6248-6253). In chronic inflammatory TME, Helios deficiency in Tregs can significantly relieve the repressed gene program associated with T helper cell differentiation through upregulation of T helper cell-associated TFs and effector cytokines. These genetic alterations in Helios-deficient Tregs are most prominent in the Treg subpopulation with high affinity for self-antigens, as indicated by enhanced GITR / PD-1 expression and increased reactivity to self-antigens. Their combined effects, together with increased T cell receptor (TCR) ligation and co-stimulatory receptor expression by Tregs, may promote Treg-to-Teff phenotypic conversion in the TME, suggesting that gene expression changes, as a central feature of Treg conversion, are immune environment dependent (Yates et al., 2018).

[0006] Decreased Helios expression in FoxP3+CD4 Tregs may allow the conversion of memory Tregs into Teff cells expressing tumor antigen-specific autoreactive T cell receptors. Alterations in Treg signatures may be selectively induced in chronic inflammatory conditions where tumors grow. Helios-deficient Tregs may exhibit TCR repertoires that are biased towards high affinity for self-peptides / MHC, promoting robust activation in the TME (Yates et al., 2018). Given the increased TCR autoreactivity in CD4 Tregs compared to regular T cells, Treg conversion may generate highly potent effector CD4 T cells with attenuation of Treg-mediated suppression in the TME. A more effective strategy may rely on approaches to selectively convert intratumoral Tregs into Teff cells without affecting the systemic Treg population. As a central player in maintaining Treg size and functional stability in response to diverse immunological perturbations, pharmacological intervention of Helios may be relevant for strategies to enhance current tumor immunotherapies. Since the conversion of Tregs to Teffs may be restricted to the inflammatory intratumoral microenvironment, antibody or small molecule-based approaches targeting Helios may lead to improved Treg-dependent cancer immunotherapy. Importantly, the conversion of Helios-deficient Tregs occurs only in the local inflammatory environment of the tumor. This approach may not induce the autoimmune side effects associated with the systemic reduction of Tregs. Thus, strategies that specifically exploit the Helios-dependent control of intratumoral Treg phenotypes hold great promise for improving cancer immunotherapy. In addition, it has been reported that ablation of Foxp3+Tregs enhances vaccine-induced antitumor T cell responses (Nishikawa et al., 2010, Int. J. Cancer 127: 759-767), suggesting that a reduction in Helios levels may be beneficial for enhancing the efficacy of cancer vaccines.

[0007] In addition to antitumor immunotherapy, during viral infection, Treg cells may limit immunopathology resulting from excessive inflammation, albeit potentially inhibiting effective antiviral T cell responses and promoting viral persistence (Schmitz et al., 2013, PLOS Pathogens 9: e1003362). Chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus results in a marked expansion of Foxp3+Tregs, implying a potential mechanism by which certain infectious pathogens may evade host immune responses by activating and expanding Tregs (Punkosdy et al., 2011, PNAS 108: 3677-3682). In the context of chronic viral infection, therapeutic benefits may be achieved by reducing Helios levels in activated Tregs.

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

[0009] The present invention provides compounds of formula 1, or salts thereof, useful for decreasing Helios protein levels, decreasing 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 1 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 by decreasing the activity of Helios protein, comprising administering to a patient a compound of formula 1 and / or a pharma- ceutically acceptable salt thereof.

[0012] The present invention also provides processes and intermediates for making compounds of Formula 1 and / or salts thereof.

[0013] The present invention also provides compounds of Formula 1 and / or pharma- ceutically acceptable salts thereof for use in therapy.

[0014] The present invention also provides the use of the compound of formula 1 and / or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of certain diseases, such as cancer and viral infection, by decreasing Helios protein levels in cells, decreasing Helios activity levels, and / or inhibiting Helios expression levels and controlling Treg differentiation.

[0015] The compounds of Formula 1 and compositions containing the compounds of Formula 1 may be used to treat, prevent, or cure a variety of proliferative diseases, such as viral infections and cancer. Pharmaceutical compositions containing these compounds are useful for treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as viral infections and cancer.

[0016] These and other features of the invention will be described in expanded form as the disclosure continues. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0018] A first aspect of the present invention is a compound comprising at least one of the following formula 1: [ka] [In the formula, Z is CR 6 R 6 or C=O; Ring A is [ka] and; R 1 is -(CR z R z ) 1-2 NR 1a R 1b and; R 1a is hydrogen, C 1-6 Alkyl, C 1-4 Fluoroalkyl, C 1-3 Cyanoalkyl, C 1-6 Hydroxyalkyl, -(CH 2 ) 1-3 O(C 1-3 alkyl), -(CH 2 ) 1-3 S(O) 2 (C 1-3 alkyl), -(CH 2 ) 1-3 C(O)O(C 1-3 alkyl), -(CH 2 ) 1-3 NR x R x , -(CH 2 ) 1-3 C(O)NR x R x , -(CH 2 ) 1-3 NR x C(O)(C 1-3 alkyl), -C(O)(C 1-3 alkyl), -CH(phenyl)(C 1-2 Hydroxyalkyl), -CR x R x CR x (Phenyl) 2 , R 1c , -(CR x R x ) 1-3 R 1c , -(CR x R x ) 1-3 OR1c , or -C(O)R 1c and; R 1b is hydrogen, C 1-3 Alkyl or -CH 2 (phenyl); Or, R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, azocanyl, diazepanyl, dioxidothiomorpholinyl, isoindolinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyrrolidinyl, pyrrolidinonyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 2 R 1e Replaced with; R 1c is C 3-7 cycloalkyl, phenyl, oxetanyl, azetidinyl, furanyl, pyranyl, pyrrolyl, pyrrolidinyl, pyrrolidinonyl, pyrazolyl, imidazolyl, indazolyl, thiazolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxotetrahydrothiopyranyl, dioxidotetrahydrothiophenyl, benzo[d]thiazolyl, naphthalenyl, quinolinyl, or quinoxalinyl, where each ring group is F, Cl, -CN, -OH, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy, -C(O)O(C 1-3 alkyl), -NR y R y , -S(O) 2 (C 1-3 alkyl), -S(O) 2 NR x R x , -CH 2(phenyl), -NO 2 , C 3-6 substituted with 0 to 2 substituents independently selected from cycloalkyl, imidazolyl, and phenyl; R 1d is C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, -NR y R y , -NR x C(O)(C 1-3 alkyl), -C(O)(C 1-3 alkyl), -C(O)NR y R y , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl; R 1e is -CH 3 and; Each R 2 are independently halogen, -CN, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Alkoxy or C 1-3 Fluoroalkoxy;NR 2 (R=H, C 1-3 alkyl), optionally substituted with phenyl, optionally substituted with heteroaryl; R 3は R 1a and; Each R 4 are independently halogen, -CN, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Alkoxy or C 1-3is fluoroalkoxy; R 5 is hydrogen, F, or C 1-3 is alkyl; Each R 6 are independently hydrogen or C 1-3 is alkyl; Each R x are independently H or -CH 3 and; Each R y are independently H or C 1-4 is alkyl; Each R z are independently H or -CH 3 or two R z form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring; m is 0, 1, or 2; n is 0, 1, 2, or 3. or a salt thereof.

[0019] One embodiment is a compound represented by Formula 1: [In the formula, R 1a is hydrogen, C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-4 Hydroxyalkyl, -(CH 2 ) 1-3 OCH 3 , -(CH 2 ) 1-3 S(O) 2 (C 1-2 alkyl), -(CH 2 ) 1-2 C(O)O(C 1-3 alkyl), -(CH 2 ) 1-3 NR x R x , -(CH 2 ) 1-2 C(O)NR x R x , -(CH 2 ) 1-3NR x C(O)(C 1-3 alkyl), -C(O)(C 1-3 alkyl), -CH(phenyl)(C 1-2 Hydroxyalkyl), -CR x R x CR x (Phenyl) 2 , R 1c , -(CR x R x ) 1-3 R 1c , -(CR x R x ) 1-3 OR 1c , or -C(O)R 1c and; Or, R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, azocanyl, diazepanyl, dioxidothiomorpholinyl, isoindolinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 2 R 1e Replaced with; R 1c is C 3-6 cycloalkyl, phenyl, oxetanyl, furanyl, pyrrolyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, indazolyl, thiazolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxotetrahydrothiopyranyl, dioxidotetrahydrothiophenyl, benzo[d]thiazolyl, naphthalenyl, quinolinyl, or quinoxalinyl, where each ring group is F, Cl, -CN, -OH, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy, C 1-2Fluoroalkoxy, -C(O)O(C 1-2 alkyl), -NR x R y , -S(O) 2 (C 1-2 alkyl), -S(O) 2 NR x R x , -CH 2 (phenyl), -NO 2 , C 3-6 substituted with 0 to 2 substituents independently selected from cycloalkyl, imidazolyl, and phenyl; R 1d is C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, -NR x R y , -NR x C(O)(C 1-2 alkyl), -C(O)(C 1-2 alkyl), -C(O)NR y R y , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl; Each R 4 are independently F, Cl, -CN, -CH 3 , -CHF 2 , -CF 3 , -OCH 3 , or -OCF 3 and; R 5 is hydrogen, F, or -CH 3 and; m is 0 or 1; n is 0, 1, or 2. or a salt thereof.

[0020] One embodiment has the following structure: [ka] [In the formula, R 1a is hydrogen, C 1-6 Alkyl, -CH 2 CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 C(O)OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(O)NH 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)NH 2 , -CH 2 CH 2 NHC(O)CH 3 , -CH(phenyl)(CH 2 CH 2 OH), -CH 2 CH(phenyl) 2 , R 1c , -CR x R x R 1c , -CH 2 CH 2 R 1c , -CH2 CH 2 CH 2 R 1c , or -CH 2 CH 2 OR 1c and; Or, R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, diazepanyl, dioxidothiomorpholinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 1 R 1e Replaced with; R 1c is C 3-6 cycloalkyl, phenyl, oxetanyl, furanyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, indazolyl, thiazolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, benzo[d]thiazolyl, naphthalenyl, quinolinyl, or quinoxalinyl, where each ring group is selected from the group consisting of F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -C(O)OCH 3 , -NH(CH 3 ), -N(CH 3 ) 2 , -S(O) 2 CH 3 , -S(O) 2 N(CH 3 ) 2 , -CH 2 (phenyl), -NO 2 substituted with 0 to 2 substituents independently selected from , cyclopropyl, imidazolyl, and phenyl; R 1d is -CH 3 , -CH(CH3 ) 2 , -OCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -C(O)CH 3 , -C(O)NH 2 , -C(O)N(CH 2 CH 3 ) 2 , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl; R 1e is -CH 3 is] The present invention provides a compound of formula 1, or a salt thereof, having the formula:

[0021] One embodiment has the following structure: [ka] [In the formula, R 1a is hydrogen, C 1-6 Alkyl, -CH 2 CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 CH 2 OH, -CH 2 CH2 OCH 3 , -CH 2 CH 2 C(O)OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(O)NH 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)NH 2 , -CH 2 CH 2 NHC(O)CH 3 , -CH(phenyl)(CH 2 CH 2 OH), -CH 2 CH(phenyl) 2 , R 1c , -CR x R x R 1c , -CH 2 CH 2 R 1c , -CH 2 CH 2 CH 2 R 1c , or -CH 2 CH 2 OR 1c and; Or, R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, diazepanyl, dioxidothiomorpholinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 1 R 1e Replaced with; R 1c is C 3-6cycloalkyl, phenyl, oxetanyl, furanyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, indazolyl, thiazolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, benzo[d]thiazolyl, naphthalenyl, quinolinyl, or quinoxalinyl, where each ring group is selected from the group consisting of F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -C(O)OCH 3 , -NH(CH 3 ), -N(CH 3 ) 2 , -S(O) 2 CH 3 , -S(O) 2 N(CH 3 ) 2 , -CH 2 (phenyl), -NO 2 substituted with 0 to 2 substituents independently selected from , cyclopropyl, imidazolyl, and phenyl; R 1d is -CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -C(O)CH 3 , -C(O)NH 2 , -C(O)N(CH 3 ) 2 , -C(O)N(CH 2 CH 3 ) 2 , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2(methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl; R 1e is -CH 3 and; R 4 is -CH 3 and; n is 0 or 1. The present invention provides a compound of formula 1, or a salt thereof, having the formula:

[0022] In one embodiment, Z is CR 6 R 6 or a salt thereof. The compound of this embodiment has the following structure: [ka] Each R 6 are independently hydrogen or -CH 3 Included in this embodiment are compounds where each R 6 Also included in this embodiment are compounds where is hydrogen.

[0023] One embodiment provides a compound of formula 1, or a salt thereof, wherein Z is C=O. The compound of this embodiment has the following structure: [ka] has.

[0024] In one embodiment, R 1a But hydrogen, C 1-6 Alkyl, C 1-4 Fluoroalkyl, C 1-3 Cyanoalkyl, C 1-6 Hydroxyalkyl, -(CH 2 ) 1-3 O(C 1-3 alkyl), -(CH 2 ) 1-3 S(O) 2 (C 1-3 alkyl), -(CH2 ) 1-3 C(O)O(C 1-3 alkyl), -(CH 2 ) 1-3 NR x R x , -(CH 2 ) 1-3 C(O)NR x R x , -(CH 2 ) 1-3 NR x C(O)(C 1-3 alkyl), -C(O)(C 1-3 alkyl), -CH(phenyl)(C 1-2 Hydroxyalkyl), -CR x R x CR x (Phenyl) 2 , R 1c , -(CR x R x ) 1-3 R 1c , -(CR x R x ) 1-3 OR 1c , or -C(O)R 1c ;R 1b But hydrogen, C 1-3 Alkyl or -CH 2 (phenyl), or a salt thereof.

[0025] In one embodiment, R 1a But hydrogen, C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-4 Hydroxyalkyl, -(CH 2 ) 1-3 OCH 3 , -(CH 2 ) 1-3 S(O) 2 (C 1-2 alkyl), -(CH 2 ) 1-2 C(O)O(C 1-3 alkyl), -(CH 2 ) 1-3 NR x Rx , -(CH 2 ) 1-2 C(O)NR x R x , -(CH 2 ) 1-3 NR x C(O)(C 1-3 alkyl), -C(O)(C 1-3 alkyl), -CH(phenyl)(C 1-2 Hydroxyalkyl), -CR x R x CR x (Phenyl) 2 , R 1c , -(CR x R x ) 1-3 R 1c , -(CR x R x ) 1-3 OR 1c , or -C(O)R 1c ;R 1b But hydrogen, C 1-3 Alkyl or -CH 2 (phenyl), or a salt thereof.

[0026] In one embodiment, R 1a But hydrogen, C 1-6 Alkyl, -CH 2 CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 C(O)OCH 3 , -CH 2 CH 2 N(CH3 ) 2 , -CH 2 C(O)NH 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)NH 2 , -CH 2 CH 2 NHC(O)CH 3 , -CH(phenyl)(CH 2 CH 2 OH), -CH 2 CH(phenyl) 2 , R 1c , -CR x R x R 1c , -CH 2 CH 2 R 1c , -CH 2 CH 2 CH 2 R 1c , or -CH 2 CH 2 OR 1c ;R 1b But hydrogen, C 1-3 Alkyl or -CH 2 (phenyl), or a salt thereof.

[0027] In one embodiment, R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, azocanyl, diazepanyl, dioxidothiomorpholinyl, isoindolinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyrrolidinyl, pyrrolidinonyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 2 R 1e R is substituted with1d But, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, -NR x R y , -NR x C(O)(C 1-2 alkyl), -C(O)(C 1-2 alkyl), -C(O)NR y R y , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 Included in this embodiment are compounds that are R(methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl. 1d But -CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -C(O)CH 3 , -C(O)NH 2 , -C(O)N(CH 2 CH 3 ) 2 , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 Also included in this embodiment are compounds which are (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl.

[0028] In one embodiment, R 1a and R 1b are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, azocanyl, diazepanyl, dioxidothiomorpholinyl, isoindolinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 2 R 1e R is substituted with 1d But, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, -NR x R y , -NR x C(O)(C 1-2 alkyl), -C(O)(C 1-2 alkyl), -C(O)NR y R y , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 Included in this embodiment are compounds that are R(methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl. 1d But -CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -C(O)CH3 , -C(O)NH 2 , -C(O)N(CH 2 CH 3 ) 2 , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 Also included in this embodiment are compounds which are (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl.

[0029] In one embodiment, R 1a and R 1b together with the nitrogen atom to which they are attached form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, diazepanyl, dioxidothiomorpholinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 1 R 1e R is substituted with 1d But, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, -NR x R y , -NR x C(O)(C 1-2 alkyl), -C(O)(C 1-2 alkyl), -C(O)NR y R y , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2(benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 Included in this embodiment are compounds that are R(methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl. 1d But -CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , -C(O)CH 3 , -C(O)NH 2 , -C(O)N(CH 2 CH 3 ) 2 , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 Also included in this embodiment are compounds which are (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl.

[0030] In one embodiment, ring A is: [ka] or a salt thereof.

[0031] In one embodiment, ring A is: [ka] or a salt thereof.

[0032] In one embodiment, ring A is: [ka] R 1a But hydrogen, C 1-6 Alkyl, -CH 2 CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 C(O)OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 C(O)NH 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)NH 2 , -CH 2 CH 2 NHC(O)CH 3 , -CH(phenyl)(CH 2 CH 2 OH), -CH 2 CH(phenyl) 2 , R 1c , -CR x R x R 1c , -CH 2 CH 2 R 1c , -CH 2 CH2 CH 2 R 1c , or -CH 2 CH 2 OR 1c or R 1a and R 1b together with the nitrogen atom to which they are attached form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, diazepanyl, dioxidothiomorpholinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R 1d and 0 to 1 R 1e Replaced by;R 1c But, C 3-6 cycloalkyl, phenyl, oxetanyl, furanyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, indazolyl, thiazolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, benzo[d]thiazolyl, naphthalenyl, quinolinyl, or quinoxalinyl, where each ring group is selected from the group consisting of F, Cl, -CN, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -C(O)OCH 3 , -NH(CH 3 ), -N(CH 3 ) 2 , -S(O) 2 CH 3 , -S(O) 2 N(CH 3 ) 2 , -CH 2 (phenyl), -NO 2 , cyclopropyl, imidazolyl, and phenyl; R 1d But -CH 3 , -CH(CH 3 ) 2 , -OCH(CH 3 ) 2, -N(CH 3 ) 2 , -NHC(O)CH 3 , -C(O)CH 3 , -C(O)NH 2 , -C(O)N(CH 2 CH 3 ) 2 , -CH 2 (phenyl), -CH 2 (Methylpyrrolidinyl), -CH 2 (benzo[d][1,3]dioxolyl), -CH(phenyl) 2 , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) 2 (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl; R 1e But -CH 3 Included in this embodiment are compounds where:

[0033] In one embodiment, ring A is: [ka] or a salt thereof.

[0034] In one embodiment, ring A is: [ka] or a salt thereof.

[0035] In one embodiment, ring A is: [ka] or a salt thereof.

[0036] In one embodiment, each R 4 are independently F, Cl, -CN, C 1-2 Alkyl, C 1-2Fluoroalkyl, C 1-2 Alkoxy or C 1-2 The compound of formula 1 or a salt thereof is provided, wherein each R is fluoroalkoxy. 4 are independently F, Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , or -OCF 3 Included in this embodiment are compounds where each R 4 are independently F, -CN, -CH 3 , or -CF 3 Also included in this embodiment are compounds where:

[0037] In one embodiment, R 5 However, hydrogen, deuterium, C 1-2 or F.

[0038] In one embodiment, R 5 However, hydrogen, deuterium, -CH 3 or F, or a salt thereof.

[0039] In one embodiment, R 5 is hydrogen, deuterium, or -CH 3 or a salt thereof.

[0040] In one embodiment, R 5 is hydrogen, deuterium, or F, or a salt thereof.

[0041] In one embodiment, R 5 is F, or a salt thereof.

[0042] In one embodiment, R 5 Ga-CH 3 or a salt thereof.

[0043] In one embodiment, R 5is hydrogen or deuterium, or a salt thereof.

[0044] In one embodiment, R 5 is deuterium.

[0045] In one embodiment, each R 6 are independently hydrogen or C 1-2 wherein each R is an alkyl group; 6 are independently hydrogen or -CH 3 Included in this embodiment are compounds where each R 6 Also included in this embodiment are compounds where is hydrogen.

[0046] One embodiment provides a compound of formula 1 or a salt thereof, wherein m is 0, 1, or 2. Included in this embodiment are compounds where m is 0 or 1. Also included in this embodiment are compounds where m is 0.

[0047] One embodiment provides a compound of formula 1 or a salt thereof, wherein n is 0, 1, or 2. Included in this embodiment are compounds where n is 0 or 1. Also included in this embodiment are compounds where n is 0.

[0048] In one embodiment, the compound is selected from the group consisting of 3-(5-{4-[(dimethylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (1); 3-(5-(4-((benzylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2); 3-(5-(4-((methyl(propyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3); 3-(5-(4-((ethyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4); 3-(5-(4-((ethyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5); 3-(5-(4-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7); 3-(5-(4-((butyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9); 3-(5-(4-(((cyclopropylmethyl)(propyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10); 3-(5-(4-((methyl(2-(pyridin-2-yl)ethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (16); 3-(5-(4-((benzyl(isopropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (19); 3-(5-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21); 3-(5-(4-((ethyl(pyridin-4-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (22);3-(5-(4-((methyl(1-methylpyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (29); 2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)(methyl)amino)-N,N-dimethylacetamide (34); 3-(5-(4-((methyl(1-methylpyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (49); 3-(5-(4-((diethylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50); 3-(5-(4-(((cyclohexylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (54); 3-(1-oxo-5-(4-(((1-phenylethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (55); 3-(5-(4-(((2-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (56); 3-(5-(4-(((3-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (57); 3-(5-(4-(((4-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (58); 3-(5-(4-(((cyclohexylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (59); 3-(5-(4-((butylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (61); 3-(1-oxo-5-(4-((propylamino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (62);3-(1-oxo-5-(4-((phenethylamino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (63); 3-(5-(4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (64); 3-(5-(4-((neopentylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (65); 3-(1-oxo-5-(4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (66); 3-(5-(4-(((4-methoxybenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (67); 3-(5-(4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68); 3-(5-(4-(((1-cyclopropylcyclobutyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (77); 3-(5-(4-(((2-methyltetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80); 3-(1-oxo-5-(4-(((1R,2R)-2-phenylcyclopentyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (84); 3-(5-(4-((cyclopentylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86); 3-(5-(4-((cyclohexylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87); 3-(5-(4-(((2-morpholinoethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (88);3-(5-(4-((tert-butylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (89); 3-(5-(4-(((2,2-diphenylethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90); N-(2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)ethyl)acetamide (91); 3-(5-(4-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (92); 3-(5-(4-(((2-chlorophenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (93); 3-(5-(4-(((4-chlorophenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94); 3-(5-(4-(((4-methoxyphenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95); 3-(5-(4-(((4-hydroxyphenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96); 3-(5-(4-((isopentylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (97); 3-(1-oxo-5-(4-(((3-phenylpropyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (98); 2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)acetonitrile (99); 2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)acetamide (100);3-(5-(4-(((4-hydroxycyclohexyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (101); 3-(5-(4-(((3-chlorophenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (102); 3-(1-oxo-5-(4-(((2-phenoxyethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (103); 3-(5-(4-(((1-benzylpyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (104); 3-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)propanamide (105); 3-(5-(4-(((2-(benzo[d]thiazol-2-yl)ethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (106); 3-(5-(4-(((4-(dimethylamino)cyclohexyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (107); 3-(5-(4-((cyclobutylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (108); 3-(5-(4-((cyclopropylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (109); 3-(1-oxo-5-(4-(((2-phenylthiazol-4-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (110); 3-(1-oxo-5-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (111);Methyl 3-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)propanoate (112); 3-(5-(4-(((3-(1H-imidazol-1-yl)propyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (113); 3-(5-(4-(((3-morpholinopropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (114); 3-(1-oxo-5-(4-(((3-(2-oxopyrrolidin-1-yl)propyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (115); 3-(5-(4-((ethylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (116); 3-(1-oxo-5-(4-((((R)-1-phenylethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (122); 3-(1-oxo-5-(4-((((S)-1-phenylethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (123); 3-(5-(4-(((1-hydroxycyclohexyl)methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (124); 3-(5-(4-(((2-methyltetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (126); 3-(5-(4-(((4-hydroxybutyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (128); 3-(5-(4-(((oxetan-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129);3-(5-(4-((((R)-3-hydroxy-1-phenylpropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (131); 3-(5-(4-((methyl((S)-1-phenylethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (136); 3-(5-(4-((methyl((R)-1-phenylethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (137); 3-(5-(4-((methyl((1R,2R)-2-(methylamino)cyclohexyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140); 3-(5-(4-((methyl(2-phenylpropan-2-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (142); 3-(1-oxo-5-(4-((3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (144); 3-(5-{4-[(methylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (145); 4-{[({2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridin-4-yl}methyl)(methyl)amino]methyl}-N,N-dimethylbenzene-1-sulfonamide (146); 3-(5-(4-(((4-fluorobenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147); 3-(5-(4-((methyl(3-(trifluoromethyl)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (148); 3-(5-(4; -((Methyl(4-(trifluoromethyl)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (149); 4-((((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)(methyl)amino)methyl)benzonitrile (150); 3-(5-(4-((Methyl(4-nitrobenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (151); 3-(5-(4-(((3,4-difluorobenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (152); Methyl 4-((((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)(methyl)amino)methyl)benzoate (153); 3-(5-(4-(((4-chlorobenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (154); 3-(5-(4-((methyl(quinolin-8-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (155); 3-(5-(4-((methyl(3-(trifluoromethoxy)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (156); 3-(5-(4-((methyl(4-(methylsulfonyl)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (157); 3-(5-(4-(((3-methoxybenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (158); 3-(5-(4-((methyl(pyridin-3-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (159);3-(5-(4-((methyl(pyridin-4-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (160); 3-(5-(4-((methyl(4-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (161); 3-(5-(4-((methyl(naphthalen-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (162); 3-(5-{4-[(dibenzylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (163); 3-[5-(4-{[benzyl(methyl)amino]methyl}pyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (164); 3-{5-[4-({[(6-methoxypyridin-3-yl)methyl](methyl)amino}methyl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (168); 3-(5-(4-((((1H-indazol-4-yl)methyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (169); 3-(5-(4-((methyl(1-methylpiperidin-4-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (170); 3-(5-(4-((methyl(phenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (171); 3-(5-(4-(((furan-3-ylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (172); 3-(5-(4-(((cyclopropylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (173);3-(5-(4-((methyl((1-methyl-1H-imidazol-5-yl)methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (174); 3-(5-(4-(((cyclopentylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (175); 3-(5-(4-((methyl(thiazol-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (176); 3-(5-(4-(((4-(1H-imidazol-1-yl)benzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (177); 3-(5-(4-(((cyclobutylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (178); 3-(5-(4-((isobutyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (179); 3-(5-(4-((isopentyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180); 3-(5-(4-(((1-hydroxypropan-2-yl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (181); 3-(5-(4-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (182); 3-(5-(4-((methyl (quinoxalin-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (183); 3-(5-(4-((methyl(3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (184);The compound of formula 1 or a salt thereof is provided, which is 3-(5-(4-(((4-hydroxybutan-2-yl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185); or 3-(5-(4-((dimethylamino)methyl)pyridin-2-yl)-6-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (194).

[0049] In one embodiment, the compound is 3-(5-(4-((ethyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (6); 3-(1-oxo-5-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (8); 3-(1-oxo-5-(4-((4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (11); 3-(5-(4-((4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-N,N-diethylpiperidine-3-carboxamide (13); 3-(5-(4-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (14); 3-(1-oxo-5-(4-((4-(pyridin-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (15); 3-(5-(4-([1,4'-bipiperidine]-1'-ylmethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (17); 3-(1-oxo-5-(4-((4-(pyrimidin-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (18); 3-(5-(4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20); 3-(1-oxo-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (23);3-(5-(4-((4-(furan-2-carbonyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24); 3-(1-oxo-5-(4-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (25); 3-(1-oxo-5-(4-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (26); 3-(5-(4-((3-methyl-4-(m-tolyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (27); 3-(5-(4-((4-acetylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28); 3-(5-(4-((2-(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30); N-((3S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidin-3-yl)acetamide (31); 3-(1-oxo-5-(4-((4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (32); 3-(5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33); 3-(5-(4-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35); 3-(5-(4-((4-benzylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (36);3-(1-oxo-5-(4-((3-oxopiperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (37); 3-(5-(4-((4-benzylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38); 3-(5-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39); 3-(5-(4-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)piperidine-4-carboxamide (41); 3-(5-(4-((4-benzhydrylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (42); 3-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (43); 3-(5-(4-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (44); 3-(5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (45); 3-(5-(4-((2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46); 3-(5-(4-((3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (47); 3-(5-(4-(azepan-1-ylmethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (48);3-(5-(4-((3,3-dimethylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (51); 3-(5-(4-((2,2-dimethylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (52); 3-(5-(4-((2,6-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (53); 3-(5-(4-((hexahydrocyclopenta[b]pyrrole-1(2H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60); 3-(5-(4-(((S)-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69); 3-(5-(4-(((R)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70); 3-(5-(4-(((R)-2-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (71); 3-(5-(4-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72); 3-(5-(4-(((S)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (73); 3-(5-(4-(((S)-2-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (74); 3-(5-(4-(((R)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (75); 3-(1-oxo-5-(4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (76);3-(5-(4-(((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (78); 3-(5-(4-((2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (79); 3-(5-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (81); 3-(5-(4-((4,4-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82); 3-(1-oxo-5-(4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (83); 3-(5-(4-((3,3-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (85); 3-(5-(4-((2,2-dimethylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (117); 3-(5-(4-((3,3-dimethylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (118); 3-(5-(4-((2,5-dimethylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (119); 3-(5-(4-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120); 3-(5-(4-((4-(4-aminophenyl)-4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (121);3-(5-(4-(((R)-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (125); 3-(5-(4-((6-azaspiro[2.5]octan-6-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127); 3-(5-(4-((3-isopropoxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130); 3-(1-oxo-5-(4-((4-tosylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (132); 3-(1-oxo-5-(4-(((S)-2-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (133); 3-(1-oxo-5-(4-(((R)-2-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (134); 3-(1-oxo-5-(4-(((S)-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (135); 3-(1-oxo-5-(4-(((R)-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (138); 3-(1-oxo-5-(4-(((S)-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (139); 3-(1-oxo-5-(4-((4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (141); 3-(1-oxo-5-(4-((3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (143);3-(5-{4-[(azetidin-1-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (165); 3-(5-{4-[(morpholin-4-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (166); 4-({2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridin-4-yl}methyl)-1λ6-thiomorpholine-1,1-dione (167); 3-(5-(5-chloro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (186); 3-(5-(5-chloro-4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (187); 3-(5-(5-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (188); 3-(5-(5-fluoro-4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (189); 3-(5-(5-fluoro-4-((3-(pyridin-3-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (190); 3-(5-(3-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (191); 3-(5-(3-fluoro-4-((3-(pyridin-3-yl)azetidin-1-yl)methyl)pyridine; 3-(5-(3-fluoro-4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (193); 3-(1-oxo-5-(4-((3-(pyridin-4-yl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (195); 3-(5-(4-((3-methoxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (196); 3-(5-(4-((3-methoxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (197); 3-(5-(4-((3-ethoxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (198); 3-(1-oxo-5-(4-((4-(p-tolyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (199); 3-(5-(4-(((S)-2-benzylaziridin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200); 3-(5-(4-((2-methylaziridin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (201); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-N,N-dimethylazetidine-3-carboxamide (202); 3-(1-oxo-5-(4-((3-(pyridin-3-yl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (203); 3-(1-oxo-5-(4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (204-205);The compound of formula 1 or a salt thereof is provided, which is 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxamide (206); 3-(5-(4-((4-methoxy-3,3-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (207); or 3-(4-fluoro-1-oxo-5-(4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (208).

[0050] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses 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 can be combined with any other embodiment to describe additional embodiments. It is also understood that each element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0051] definition 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 recognized that certain features of the present invention that are described above and below in the context of separate embodiments for clarity may also be combined to form a single embodiment. Conversely, various features of the present invention that are described in the context of a single embodiment for brevity may also be combined to form subcombinations thereof. The embodiments deemed exemplary or preferred herein are intended to be illustrative and not limiting.

[0052] Unless otherwise stated herein, references in the singular may also include the plural. For example, "a" and "an" may refer to either one or more than one.

[0053] As used herein, the term "compound and / or salt thereof" refers to at least one compound, at least one salt of said compound, or a combination thereof. For example, a compound of formula 1 and / or salt thereof includes one compound of formula 1; two compounds of formula 1; a salt of one compound of formula 1; one compound of formula 1 and one or more salts of compounds of formula 1; and a salt of two or more compounds of formula 1.

[0054] Unless otherwise specified, any atom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0055] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or patent application publications incorporated herein by reference.

[0056] Set forth below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification (unless limited in specific instances) either individually or as part of a larger group.

[0057] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds.

[0058] According to the convention used in the art, [ka] is used in structural formulas herein to indicate the bond that is the point of attachment from a moiety or substituent to a core or backbone structure.

[0059] The terms “halo” and “halogen” as used herein refer to F, Cl, Br, and I.

[0060] The term "cyano" refers to the group -CN.

[0061] The term "amino" means -NH 2 Refers to the base.

[0062] The term "oxo" refers to the group ═O.

[0063] The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups, e.g., containing 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 is presented in subscript after the symbol "C," the subscript more specifically defines 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 from 1 to 4 carbon atoms.

[0064] The term "fluoroalkyl," as used herein, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" refers to a group of alkyl groups substituted with one or more fluorine atoms, C 1 , C 2 , C 3 , and C 4 Representative examples of fluoroalkyl groups include -CF 3 and -CH 2 CF 3 These include, but are not limited to:

[0065] 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.

[0066] 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 It is intended to include fluoroalkoxy groups.

[0067] 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 defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" means a cycloalkyl group having from 3 to 6 carbon atoms.

[0068] The compounds of the present invention include all isotopes of atoms occurring in the compounds. Isotopes include those 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 Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, substituting an appropriate isotopically labeled reagent for an otherwise utilized non-labeled reagent.

[0069] The term "pharmacologically acceptable" is used herein to refer to those compounds, substances, compositions, and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or nuisance and are equivocal to a reasonable risk-benefit ratio.

[0070] Compounds of formula 1 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 acidic and / or basic salts formed with inorganic and / or organic acids and bases. Additionally, the term "salt" may include zwitterions (internal salts), for example, compounds of formula 1 may contain both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, for example, in isolation or purification steps that may be performed during formulation, and are therefore contemplated within the scope of the present invention. Salts of compounds of formula 1 may be formed by reacting compounds of formula 1 with an amount of acid or base, such as an equal amount, in a solvent in which the salt precipitates, or by reaction in an aqueous solvent followed by lyophilization.

[0071] Representative acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), hydroiodide, and the like. Salts include, for example, salts such as, for example, salts of, for example, maleates (formed with maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0072] Representative base salts include alkali metal salts, such as ammonium, sodium, lithium, and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (e.g., organic amines), such as trialkylamines, such as 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 salts with amino acids, such as arginine, lysine, and the like. Basic nitrogen-containing groups may be quaternized with such chemicals as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0073] The compound of formula 1 may be provided as an amorphous solid or a crystalline solid. Lyophilization may be utilized to provide the compound of formula 1 as a solid.

[0074] It should further be understood that solvates (e.g., hydrates) of the compounds of formula 1 are also within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula 1 with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0075] Various types of prodrugs are known in the art and are described in the following references: a)The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); b)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c)Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); and d)Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 203); e) Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587, (2018) It is described in.

[0076] Additionally, after its preparation, the compound of Formula 1 may be isolated and purified to obtain a composition comprising 99% or more by weight of the compound of Formula 1 (substantially pure), which composition is then used or formulated as described herein. Such "substantially pure" compounds of Formula 1 are also contemplated herein as part of the invention.

[0077] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive reaction mixtures, and isolation to a useful degree of purity from formulation to an effective therapeutic agent. The present invention is intended to embody stable compounds.

[0078] The term "Helios inhibitor" refers to an agent that can reduce Helios protein levels, reduce Helios activity levels and / or inhibit Helios expression levels in cells and control Treg differentiation. Helios inhibitors can be reversible or irreversible inhibitors.

[0079] 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 protein, subfamily 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 shown below. Isoform 1 (UniProt Q9UKS7-1) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 1) Isoform 2 (UniProt Q9UKS7-2) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 2) Isoform 4 (UniProt Q9UKS7-4) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 3) Isoform 6 (UniProt Q9UKS7-6) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHDS (SEQ ID NO: 4) Isoform 7 (UniProt Q9UKS7-7) METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 5) The "Helios" isoforms 1, 2, 4, 6, and 7 listed above contain the degron FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (underlined). A degron is a part of a protein that plays a role in controlling the rate of protein degradation.

[0080] 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 exists in two human isoforms 1 (Q9H2S9-1) and 2 (Q9H2S9-2): Isoform 1 (UniProt Q9H2S9-1) MHTPPALPRRFQGGGRVRTPGSHRQGKDNLERDPSGGCVPDFLPQAQDSNHFIMESLFCESSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAAHHSLEPGFGSLAFFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 7) Isoform 2 (UniProt Q9H2S9-2) MDSRYLQLQLYLPSCSLLQGSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAAHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 8) This includes isoforms encoded by The above "Eos" protein isoforms 1 and 2 contain a degron FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (underlined), which is identical to the degron of the "Helios" protein.

[0081] As used herein, "Ikaros" protein is encoded by 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 protein includes isoforms encoded by amino acid sequences Q13422-1, Q13422-2, Q13422-3, Q13422-4, Q13422-7, and Q13422-8. Ikaros protein also includes isoforms encoded by amino acid sequences Q13422-5 and Q13422-6.

[0082] As used herein, "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 amino acid sequences Q9UKT9-1, Q9UKT9-3, Q9UKT9-4, Q9UKT9-6, Q9UKT9-7, Q9UKT9-8, Q9UKT9-9, and Q9UKT9-14. Aiolos protein also includes isoforms encoded by amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12, and Q9UKT9-13, Q9UKT9-15, and Q9UKT9-16.

[0083] 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.

[0084] As used herein, the term "contacting" refers to the joining of the indicated components in an in vitro system or in vivo system. For example, "contacting" a Helios protein with a compound of formula 1 includes administering a compound of the invention to an individual or patient, such as a human, that has a Helios protein, as well as introducing a compound of formula 1 to a sample, including, for example, a cell preparation or purified preparation that contains a Helios protein.

[0085] The terms "treat," "treating," and "treatment," as used herein, refer to any type of therapeutic intervention or process undertaken or in which an active agent is administered to a patient to reverse, alleviate, ameliorate, inhibit, slow, or prevent the progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease. "Treat," "treating," and "treatment" do not encompass prophylaxis or prevention.

[0086] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or a combination of the claimed compounds, or a compound of the invention in combination with other active ingredients, effective to reduce Helios protein levels, reduce Helios activity levels, and / or inhibit Helios expression levels in a cell, or to prevent proliferative diseases such as viral infections and cancer.

[0087] As used herein, the term "cell" is intended to refer to a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as 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, such as a mammal.

[0088] The term "patient" includes human and other mammalian subjects receiving either therapeutic or prophylactic treatment.

[0089] The term "subject" includes any human or non-human animal. For example, the methods and compositions disclosed herein can be used to treat a patient with cancer. Non-human animals include all vertebrates, mammals and non-mammals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, reptiles, etc. In one embodiment, the patient is a human patient.

[0090] The term "pharmaceutically acceptable carrier" as used herein means a pharma- ceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulant, involved in carrying or transporting a compound of interest 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 of the formulation, i.e., ingredients such as adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, and dispensing agents, depending on the mode of administration and the nature of the dosage form; and must not be harmful to the patient.

[0091] The term "pharmaceutical composition" means a composition comprising a compound of the present invention together with at least one additional pharma- ceutically acceptable carrier.

[0092] usefulness The compounds of formula 1 are useful in the treatment of cancer.

[0093] In one embodiment, the present invention provides a combination preparation of a compound of formula 1, and / or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, and an additional therapeutic agent, for simultaneous, separate or sequential use in the treatment and / or prevention of various diseases or disorders associated with the activity of Helios protein, which may be used to reduce Helios protein levels, Helios activity levels, and / or Helios expression levels in cells and to control Treg differentiation.

[0094] The compounds of formula 1 and pharmaceutical compositions comprising at least one compound of formula 1 are useful for the treatment or prevention of any disease or condition associated with the activity of the Helios protein. These include viral and other infectious diseases (e.g., skin infections, GI infections, urinary tract infections, genitourinary infections, systemic infections), as well as proliferative diseases (e.g., cancer). The compounds of formula 1 and pharmaceutical compositions comprising at least one compound of formula 1 may be administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to a patient. In some embodiments, the compounds of formula 1 or pharmaceutical compositions comprising at least one compound of formula 1 are administered orally. In other embodiments, the compounds of formula 1 or pharmaceutical compositions comprising at least one compound of formula 1 are administered parenterally.

[0095] The compound of formula 1 can selectively reduce Helios protein levels, reduce Helios activity levels, and / or inhibit Helios expression levels in cells, and control Treg differentiation. For example, the compound of formula 1 can be used to selectively reduce Helios activity levels and / or inhibit Helios expression levels in cells and control Treg differentiation in cells or individuals requiring reduced Helios protein levels, reduced Helios activity levels, and / or inhibited Helios expression levels, by administering an inhibitory amount of the compound of formula 1 or a salt thereof.

[0096] In one embodiment, the compound of formula 1 is administered sequentially prior to administration of the immunological anti-cancer agent. In another embodiment, the compound of formula 1 is administered simultaneously with the immunological anti-cancer agent. In yet another embodiment, the compound of formula 1 is administered sequentially after administration of the immunological anti-cancer agent.

[0097] In another embodiment, the compound of Formula 1 may be formulated with an immunological anti-cancer agent.

[0098] Immune anti-cancer agents include, for example, small molecule drugs, antibodies, or other biomolecules or small molecules. Examples of biological immune anti-cancer 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.

[0099] In one embodiment, the immune anti-cancer agent is (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in enhancement of antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0100] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, including 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 co-inhibitory receptors is the TNF family of molecules that bind to the cognate TNF receptor family members, 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, LIG Examples include HT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0101] In one embodiment, T cell responses may be stimulated by a combination of a compound of Formula 1 and one or more of (i) antagonists (e.g., immune checkpoint inhibitors) of proteins that inhibit T cell activation, 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.

[0102] Other agents that can be combined with the compound of formula 1 for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compound of formula 1 can be combined with antagonists of KIR, such as lirilumab.

[0103] Further agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including, but 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).

[0104] In another embodiment, the compound of formula 1 may be combined with one or more agonist agents that bind positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immune suppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., with anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that activate innate immune activation and / or inflammation at the tumor site.

[0105] In one embodiment, the immunological anti-cancer agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0106] In another embodiment, the immuno-anticancer agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-anticancer agent may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is a recombinant protein called AMP-224, which is composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0107] In another embodiment, the immunological anti-cancer agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), and MSB0010718C (WO2013 / 79174).

[0108] In another embodiment, the immunological anti-cancer agent is a LAG-3 antagonist, such as an antagonist 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).

[0109] In another embodiment, the immunological anti-cancer 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).

[0110] In another embodiment, the immunological anti-cancer agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0111] In another embodiment, the immune anticancer 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).

[0112] In another embodiment, the immunological anti-cancer agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0113] In another embodiment, the immunological anti-cancer agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0114] In another embodiment, the immunological anti-cancer agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immunological anti-cancer agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0115] In another embodiment, the immunological anti-cancer agent is a CD27 agonist, such as an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0116] In another embodiment, the immunological anti-cancer agent is MGA271 (anti-B7H3) (WO11 / 109400).

[0117] Combination therapy is intended to include sequential administration of these therapeutic agents, i.e., each therapeutic agent is administered at a different time, as well as substantially simultaneous administration of these therapeutic agents, or at least two of the therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form having a fixed ratio of each therapeutic agent, or by administering multiple single dosage forms of each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or different routes. For example, the first therapeutic agent of the combination selected may be administered by intravenous injection, while the other therapeutic agent of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally and all therapeutic agents may be injected intravenously. Combination therapy can also include administering the therapeutic agents as described above in further combination with other biologically active ingredients and non-pharmaceutical therapies (e.g., surgery or radiation therapy). When the combination therapy further includes a non-drug therapy, the non-drug therapy may be administered at any suitable time, so long as a beneficial effect of the interaction of the combination of the therapeutic agent and the non-drug therapy is achieved, e.g., where deemed appropriate, a beneficial effect may be achieved even when the non-drug therapy is temporarily removed from administration of the therapeutic agent, perhaps for days or even weeks.

[0118] The types of cancer that may be treated with the compounds of formula 1 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 intestinal cancer such as neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer, esophageal cancer, labia 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, brain tumors such as melanoma, glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, These include 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.

[0119] For example, one or more additional pharmaceutical agents or treatment methods, such as antiviral agents, chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors, may be optionally combined with the compounds of Formula 1 for the treatment of Helios protein-associated diseases, disorders or conditions. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0120] Suitable chemotherapeutic or other anti-cancer agents include, for example, uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and alkylating agents (including, but not limited to, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes), such as temozolomide.

[0121] Suitable agents for use in combination with the compounds of formula 1 in the treatment of melanoma include: dacarbazine (DTIC) optionally in combination with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin and tamoxifen; the combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY. The compounds of formula 1 may also be used in combination with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma.

[0122] The compounds of formula 1 may 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 viral diseases such as polio, measles, and mumps. Attenuated melanoma cells or parts of melanoma cells, called antigens, may be injected into patients to stimulate the body's immune system to destroy the melanoma cells.

[0123] Melanomas confined to the arms or legs may be treated with a combination of drugs, including one or more compounds of Formula I, using hyperthermic isolated limb perfusion therapy. This treatment protocol involves temporarily isolating the blood circulation of the involved limb from the rest of the body and injecting high doses of chemotherapy drugs into the arteries that feed the limb, thus providing a high dose to the tumor without exposing the internal organs to doses that might otherwise cause severe side effects. The perfusion fluid is usually warmed to 38.9°C to 40°C. Melphalan is the drug most commonly used in this chemotherapy. It may be administered with another drug called tumor necrosis factor (TNF).

[0124] Suitable chemotherapeutic or other anti-cancer agents include, for example, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and antimetabolites (including, but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) such as gemcitabine.

[0125] Suitable chemotherapeutic or other anti-cancer agents 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, ara-C, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.

[0126] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and droloxafine.

[0127] Also suitable are cytotoxic agents such as epidophyllotoxin; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes, such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutics; leucovorin; tegafur; and hematopoietic growth factors.

[0128] Other anti-cancer agents include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies against costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies against cytokines (IL-10 or TGF-β).

[0129] Other anti-cancer drugs include those that block immune cell migration, such as antagonists against chemokine receptors CCR2 and CCR4.

[0130] Other anti-cancer agents include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0131] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0132] 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 functioning of cancer cells, thus resulting in apoptosis. Suitable STIs include: (i) bcr / abl kinase inhibitors, such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, such as, for example, 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, such as, for example, farnesyltransferase inhibitors (FTIs), such as, for example, L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513 (1995)); (v) cell cycle kinase inhibitors, such as, for example, flavopiridol and UCN-01 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203)); and (vi) phosphatidylinositol kinase inhibitors, such as, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one compound of formula 1 may be in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one compound of formula 1 and at least one STI may be administered to a patient simultaneously or sequentially.In other words, the at least one compound of Formula 1 may be administered first, the at least one STI may be administered first, or the at least one compound of Formula 1 and the at least one STI may be administered simultaneously. Furthermore, when more than one compound of Formula 1 and / or STI is used, the compounds may be administered in any order.

[0133] The present invention further provides a pharmaceutical composition for treating a chronic viral infection in a patient, comprising at least one compound of Formula 1, optionally comprising at least one chemotherapeutic agent, and optionally comprising at least one antiviral agent, in a pharma- ceutically acceptable carrier.

[0134] Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of said pharmaceutical composition.

[0135] In certain embodiments of the present invention, at least one compound of formula 1 and at least one chemotherapeutic agent are administered to a patient simultaneously or sequentially. In other words, at least one compound of formula 1 may be administered first, at least one chemotherapeutic agent may be administered first, or at least one compound of formula 1 and at least one STI may be administered simultaneously. Furthermore, when more than one compound of formula 1 and / or chemotherapeutic agent are used, the compounds may be administered in any order. Similarly, any antiviral agent or STI may be administered at any time point compared to the administration of the compound of formula 1.

[0136] Chronic viral infections that may be treated using the present 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).

[0137] Suitable antiviral agents contemplated for use in combination with the compounds of Formula 1 may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

[0138] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C, named beta-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (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. Exemplary suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0139] Combination therapy is intended to include sequential administration of these therapeutic agents, i.e., each therapeutic agent is administered at a different time, as well as substantially simultaneous administration of these therapeutic agents, or at least two of the therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form having a fixed ratio of each therapeutic agent, or by administering multiple single dosage forms of each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or different routes. For example, the first therapeutic agent of the combination selected may be administered by intravenous injection, while the other therapeutic agent of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally and all therapeutic agents may be injected intravenously. Combination therapy can also include administering the therapeutic agents as described above in further combination with other biologically active ingredients and non-pharmaceutical therapies (e.g., surgery or radiation therapy). When the combination therapy further includes a non-drug therapy, the non-drug therapy may be administered at any suitable time, so long as a beneficial effect of the interaction of the combination of the therapeutic agent and the non-drug therapy is achieved, e.g., where deemed appropriate, a beneficial effect may be achieved even when the non-drug therapy is temporarily removed from administration of the therapeutic agent, perhaps for days or even weeks.

[0140] Pharmaceutical Compositions The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of Formula 1 formulated with one or more pharma- ceutically acceptable carriers (excipients) and / or diluents, and, optionally, one or more additional therapeutic agents described above.

[0141] The compound of formula 1 may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The compound and the composition of the compound of formula 1 may be administered by any suitable means for any of the uses described herein, including, for example, oral administration such as tablets, capsules (each of which includes sustained or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingual administration; buccal administration; parenteral administration such as subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasal administration, such as administration to the nasal mucosa, for example, by inhalation spray; topical administration, such as in the form of a cream or ointment; or rectal administration, such as in the form of a suppository. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0142] 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 made in the form of a dosage unit containing 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 for humans or other mammals may vary widely depending on the condition of the patient and other factors, but can be determined by routine methods.

[0143] Any pharmaceutical composition contemplated herein can be delivered orally, for example, by any acceptable suitable oral formulation. Representative 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 pharma-ceutical palatable formulation, pharmaceutical compositions according to the present invention can include at least one agent selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0144] Tablets can be prepared, for example, by mixing at least one compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof with at least one non-toxic pharma- ceutically acceptable excipient suitable for tablet manufacture. Representative excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid; binding agents such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Furthermore, tablets can be uncoated or coated by known techniques, either to mask the unpleasant taste of unpleasant-tasting medicines or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effect of the active ingredient for a longer period of time. Representative water-soluble taste-masking substances include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0145] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of Formula 1 and / or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0146] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of Formula 1 and / or at least one pharma- ceutically acceptable salt thereof with at least one water-soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0147] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof with at least one additive suitable for the preparation of aqueous suspensions.Typical additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phospholipids, e.g., lecithin; condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide and long chain aliphatic alcohols, such as heptadecaethyleneoxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, such as, for example, but not limited to, sucrose, saccharin, and aspartame.

[0148] Oil suspensions can be prepared, for example, by suspending at least one compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof in either vegetable oil, for example, peanut oil; olive oil; sesame oil; and coconut oil; or in mineral oil, for example, liquid paraffin. Oil suspensions can also contain at least one thickening agent, for example, beeswax; solid paraffin; and cetyl alcohol. To provide a palatable oil suspension, at least one sweetener and / or at least one flavoring agent, as already described herein above, can be added to the oil suspension. Oil suspensions can further contain at least one preservative, for example, but not limited to, an antioxidant, for example, butylated hydroxyanisole, and alpha-tocopherol.

[0149] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative.Suitable dispersing agents, wetting agents, and suspending agents are as already described above.Representative preservatives include, but are not limited to, antioxidants, such as ascorbic acid.In addition, dispersible powders and granules can also include at least one additive, such as, but not limited to, sweeteners; flavoring agents; and coloring agents.

[0150] The emulsion of at least one compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof may be prepared, for example, as an oil-in-water emulsion. The oily phase of the emulsion containing the compound of formula 1 may be composed of known ingredients in a known manner. The oily phase may be provided by, but is not limited to, vegetable oils, such as olive oil and peanut oil; mineral oils, such as liquid paraffin; and mixtures thereof. While the phase may comprise a simple emulsifier, the phase may comprise a mixture of at least one emulsifier with a fat or oil, or with both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phospholipids, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensates of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and fat. Combined, the emulsifier, with or without stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. The emulsion may also contain 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 in combination with wax, or other materials known in the art.

[0151] The compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof may also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly, by any suitable pharma- ceutically acceptable injection form. Representative injection forms include, but are not limited to, sterile aqueous solutions, including acceptable vehicles and solvents, such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0152] 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 using one or more of the carriers or diluents mentioned for use in preparations for oral administration, or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and methods of administration are well known in the pharmaceutical art. The active ingredient may also be administered by injection in a composition with a suitable carrier such as saline, dextrose, or water, or with cyclodextrins (i.e., Captisol), cosolvent solubilizers (i.e., propylene glycol) or micellar solubilizers (i.e., Tween 80).

[0153] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending agents. For this purpose, any sterile fixed oil can be used, including synthetic mono- or diglycerides, for example. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0154] Sterile injectable oil-in-water microemulsions can be prepared, for example, by 1) dissolving at least one compound of Formula 1 in an oily phase, such as a mixture of soybean oil and lecithin; 2) combining the compound of Formula 1 containing oily phase with a mixture of water and glycerol; and 3) treating the combination to form a microemulsion.

[0155] Sterile aqueous or oily suspension can be prepared according to the method known in the art.For example, sterile aqueous solution or suspension can be prepared with non-toxic, parenterally acceptable diluent or solvent, such as 1,3-butanediol; sterile oily suspension can be prepared with sterile non-toxic acceptable solvent or suspending agent, such as sterile fixed oil, for example, synthetic mono- or diglyceride; for example, oleic acid and fatty acid.

[0156] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the scope of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the patient to whom the drug-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic index being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may contain a number of different components and additives in addition to the active agent, such additional components being included in the formulation for a variety of reasons, including, for example, stabilizers for the active agent, binders, and the like, which are well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as, for example, Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd Edition (2012), Pharmaceutical Press.

[0157] 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) such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween, polyethoxylated castor oil such as CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, 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. Chemically modified derivatives such as cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrin, or hydroxyalkyl cyclodextrins, such as 2- and 3-hydroxypropyl-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance delivery of the compounds of Formula 1 described herein.

[0158] The pharmacoactive compounds of the present invention can be processed according to conventional methods of pharmacy to produce medicaments intended for administration to patients, such as humans and other mammals.The pharmaceutical compositions can be subjected to conventional pharmaceutical processes, such as sterilization, and / or contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.Tablets and pills can be further prepared with enteric coatings.Such compositions can also contain adjuvants, such as wetting agents, sweeteners, flavoring agents, and perfumes.

[0159] For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants that are suitable for the indicated administration route.For oral administration, the compound may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets may contain controlled release formulations, such as those that can be provided with the active compound dispersed in hydroxypropylmethylcellulose.

[0160] The amount of compound administered and the dosing schedule for treating a condition with the compounds and / or compositions of the present invention are determined by various factors, including age, weight, sex, medical condition of the patient, type of disease, severity of disease, 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 and about 50 mg / kg body weight, most preferably between about 0.005 and 10 mg / kg body weight, may be appropriate. The daily dose may be administered in one to four separate doses per day. Other dosing schedules include administration once a week and once every two-day cycle.

[0161] The pharmaceutical compositions of the present invention comprise at least one compound of formula 1 and / or at least one pharma- ceutically acceptable salt thereof, and optionally include additional agents selected from any pharma- ceutically acceptable carrier, adjuvant, and vehicle. Alternative compositions of the present invention comprise a compound of formula 1, or a prodrug thereof, as described herein, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0162] The present invention also includes pharmaceutical kits useful for treating or preventing Helios protein-associated diseases or disorders, and other diseases mentioned herein, including, for example, one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1. Such kits may optionally further include one or more of a variety of conventional pharmaceutical kit components, as would be readily apparent to one of skill in the art, such as, for example, a container with one or more pharma- ceutically acceptable carriers, additional containers, etc. Instructions, either as a package insert or label, indicating the amounts of components to be administered, administration guidelines, and / or mixing guidelines of the components, may also be included in the kit.

[0163] Dosing regimens for the compounds of the invention will, of course, vary depending on known factors such as the pharmacodynamic properties of the particular drug 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 therapy; frequency of treatment; route of administration, renal and hepatic function of the patient, and the effect desired.

[0164] By way of general guidance, the daily oral dose of each active ingredient, when used for the indicated effects, will range from about 0.001 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day, and most preferably from about 0.1 to about 250 mg per day. For intravenous administration, the most preferred dose will range from about 0.01 to about 10 mg / kg / min during a constant rate infusion. The compound of formula 1 may be administered in a single daily dose, or the total daily dose may be administered in two, three, or four divided doses per day.

[0165] The compounds are normally administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected for the intended dosage form, e.g., oral tablets, capsules, elixirs, and syrups, and in accordance with conventional pharmaceutical practice.

[0166] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 200 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0167] A typical capsule for oral administration contains at least one compound of Formula 1 (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0168] A typical injectable formulation is prepared by aseptically placing at least one compound of Formula 1 (250 mg) into a vial, aseptically lyophilizing, and sealing the vial. Upon use, the contents of the vial are mixed with 2 mL of saline to form the injectable formulation.

[0169] The present invention includes within its scope pharmaceutical compositions containing as an active ingredient a therapeutically effective amount of at least one compound of formula 1, alone or in combination with a pharmaceutical carrier. Where appropriate, the compound of formula 1 may be used alone, in combination with other compounds of formula 1, or in combination with one or more other therapeutic agents, e.g., anti-cancer agents, or other pharma- ceutical active substances.

[0170] Regardless of the route of administration selected, the compounds of formula 1, which may be used in the form of a suitable hydrate, and / or pharmaceutical compositions of the present invention are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0171] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may vary so long as they obtain an amount of the active ingredient that is effective to achieve the desired therapeutic effect for a particular patient, composition, and method of administration, and which is not toxic to the patient.

[0172] The selected dose level will depend on a variety of factors, including the activity of the particular compound of Formula 1, or esters, salts, or amides thereof, being employed, the route of administration, the time of administration, the rate of excretion or metabolism, rate and extent of absorption of the particular compound being employed, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular compound being employed, the age, sex, weight, condition, overall health and medical history of the patient being treated, and similar factors well known in the medical arts.

[0173] A physician or veterinarian having ordinary skill in the art can easily 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 1 utilized in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0174] In general, a suitable daily dose of the compound of formula 1 will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective amount will generally be determined by the factors described above. In general, oral, intravenous, intracerebroventricular and subcutaneous doses of the compound of formula 1 for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.

[0175] If desired, an effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In some embodiments of the invention, dosing is a single daily administration.

[0176] While it is possible for a compound of formula 1 to be administered alone, it is more preferable to administer the compound as a pharmaceutical formulation (composition).

[0177] The other therapeutic agents described above, when utilized in combination with a compound of Formula 1, may be used in amounts as indicated, for example, in the Physician's Desk Reference (PDR) or as otherwise determined by one of skill in the art. In the methods of the invention, such other therapeutic agents may be administered prior to, simultaneously with, or following administration of the compounds of the invention.

[0178] Preparation method The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known to those skilled in the art of organic synthesis chemistry, or synthetic methods that are slightly modified as recognized by those skilled in the art.Preferred methods include, but are not limited to, the methods described below.All references cited herein are incorporated herein by reference in their entirety.

[0179] 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 appropriate for the reagents and materials employed and suitable for the transformations being effected. It should also be understood that in the description of the synthetic methods described below, all proposed reaction conditions, such as the choice of solvent, reaction atmosphere, reaction temperature, experimental time and work-up method, are selected to be standard conditions for the reaction and should be readily recognized by those skilled in the art. It will be understood by those skilled in the art of organic synthesis that the functionality present on the various parts of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, in which case alternative methods will need to be used. This will sometimes require the decision to change the order of synthetic steps or to select one particular process scheme over another to obtain the desired compound of the present invention. It will be recognized that another major consideration in planning any synthetic route in the art is the judicious selection of protecting groups used to protect reactive functional groups present in the compounds described in the present invention. A reliable reference that lists many options for the skilled practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, 4th ed., Wiley and Sons, 207).

[0180] Compounds of formula 1 may be prepared by reference to the methods illustrated in the following schemes. As shown therein, the final product is a compound having the same structural formula as formula 1. It will be understood that any compound of formula 1 may be prepared by the schemes by appropriate selection of reagents having suitable substituents. 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 as defined herein or elsewhere in the specification.

[0181] General routes to the compounds described in this invention are illustrated in Schemes 1-9, where R 4 , R 5 , R 6 The , Z, and A substituents are either predefined herein or functional groups that can be converted to the desired final substituent. Substituent L is a leaving group such as a halide (preferably I, Br, or Cl) or a sulfonate. 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, the general procedure for preparing the compounds of the invention involves starting with an appropriately substituted heterocycle 1. The leaving group L of 1 is converted to a suitable coupling partner M using conditions well known to those skilled in the art or methods described herein to provide intermediate 2. When M is a boronic acid or boronic ester, 2 can be converted to a suitable coupling partner M using a suitable palladium catalyst (e.g., Pd(PPh 3 ) 4 Alternatively, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)) in the presence of a suitable base (e.g., cesium carbonate, potassium phosphate, or sodium bicarbonate) can be used to couple with an appropriately substituted heterocycle 3 in a Suzuki-Miyaura coupling reaction to give 4. When M is a stannane, 2 can be coupled with a suitable catalytic system (e.g., Pd(PPh 3 ) 4 or bis(triphenylphosphine)dichloropalladium(II) / CuI) to couple with an appropriately substituted heterocycle 3 in a Stille coupling reaction to give 4. When R is tert-butyl, intermediate 4 can be converted to 5 by treatment with a protic acid such as benzenesulfonic acid. In some cases, depending on the choice of acid protecting group R, 4 can be cleaved with a base (e.g., K 2 CO 3 , K 3 PO 4, or LiHMDS) to give 5. In some cases, intermediate 4 may spontaneously cyclize to 5 under the Suzuki-Miyaura or Stille coupling conditions utilized to prepare it. [ka]

[0182] In some cases, it may be advantageous to attach the heterocycle A earlier in the synthetic sequence. In such cases, the leaving group L of 6 is converted to a suitable coupling partner M using conditions well known to those skilled in the art or methods described herein to provide intermediate 7. When M is a boronic acid or boronic ester, 7 can be coupled to a suitable palladium catalyst (e.g., Pd(PPh 3 ) 4 Alternatively, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)) in the presence of a suitable base (e.g., cesium carbonate, potassium phosphate, or sodium bicarbonate) can be used to couple with an appropriately substituted heterocycle 3 in a Suzuki-Miyaura coupling reaction to give 8. When M is a stannane, 7 can be readily reacted with a suitable catalytic system (e.g., Pd(PPh 3 ) 4 or bis(triphenylphosphine)dichloropalladium(II) / CuI) in a Stille coupling reaction with an appropriately substituted heterocycle 3 to give 8. The benzylic position can be brominated in the presence of a radical initiator such as AIBN, benzoyl peroxide, or light via the action of NBS to give bromide 9. Bromide 9 can be condensed with 3-aminopiperidine-2,6-dione (10) in the presence of a base (e.g., diisopropylethylamine or triethylamine) to give 11. [ka]

[0183] Alternatively, bromide 9 (Scheme 2) or compound 12 (where L is a leaving group such as a halide or sulfonate; Scheme 3) can be condensed with 13 (where R is a carboxylic acid protecting group such as tert-butyl, methyl, ethyl, or benzyl) in the presence of a base (e.g., diisopropylethylamine or triethylamine) as shown in Scheme 3 to give intermediate 14. [ka]

[0184] The particular choice of acid protecting group R in intermediate 4 may require different conditions to convert it to compound 5 (Scheme 4). For example, when R is methyl, ethyl, or benzyl, base-induced cyclization of 4 may be preferred to convert 4 directly to 5 using a suitable base (e.g., LiHMDS) in a suitable solvent (e.g., tetrahydrofuran). When R is tert-butyl, acid-induced cyclization of 4 may be preferred to convert 4 directly to 5 using a suitable acid (e.g., benzenesulfonic acid) in a suitable solvent (e.g., acetonitrile). In some cases, it may be more preferable to use a two-step procedure in which the free carboxylic acid 15 is first liberated using conditions appropriate for the particular acid protecting group R. Such methods are 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) may be preferred. When R is methyl, ethyl, or benzyl, basic hydrolysis using a suitable base (e.g., LiOH) may be preferred. In other cases, when R is benzyl, it may be advantageous to deprotect it by the action of palladium catalyzed hydrogenolysis. Once liberated, the carboxylic acid of 15 is activated and intramolecular attack by the pendant primary amide occurs by the action of thionyl chloride / dimethylformamide or carbonyldiimidazole / dimethylaminopyridine to give 5. [ka]

[0185] As shown in Scheme 1, heterocycles (such as compound 1) substituted with an appropriate leaving group L are useful intermediates in the synthesis of compounds of formula 1. In some cases, they may be prepared as shown in Scheme 5, where L is a leaving group such as a halide. First, the benzylic position of intermediate 6 is brominated in the presence of a radical initiator such as AIBN, benzoyl peroxide, or light through the action of NBS to give bromide 16. Bromide 16 is condensed with 3-aminopiperidine-2,6-dione (10) in the presence of a base (e.g., diisopropylethylamine or triethylamine) to give 17. Alternatively, bromide 16 is condensed with 13 in the presence of a base (e.g., diisopropylethylamine or triethylamine) to give 18. [ka]

[0186] An alternative approach to access heterocycles substituted with an appropriate leaving group L is shown in Scheme 6. First, dehydration of 19 is achieved by the action of acetic anhydride to give the anhydride 20. In some cases, this process can be accelerated by the addition of pyridine. The anhydride 20 is condensed with 3-aminopiperidine-2,6-dione (10) using a combination of acetic acid and potassium acetate to give 21. Alternatively, the anhydride 20 is condensed with 13 using a combination of acetic acid and potassium acetate to give 22. [ka]

[0187] In some cases, it may be advantageous to attach the heterocycle A earlier in the synthetic sequence. In such cases, the leaving group L of 19 is converted to a suitable coupling partner M using conditions well known to those skilled in the art or methods described herein to provide intermediate 23. When M is a boronic acid or boronic ester, 23 can be coupled to a suitable palladium catalyst (e.g., Pd(PPh 3 ) 4Alternatively, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)) in the presence of a suitable base (e.g., cesium carbonate, potassium phosphate, or sodium bicarbonate) can be used to couple with an appropriately substituted heterocycle 3 in a Suzuki-Miyaura coupling reaction to give 24. When M is a stannane, 23 can be reacted with an appropriate catalytic system (e.g., Pd(PPh 3 ) 4 or bis(triphenylphosphine)dichloropalladium(II) / CuI) to couple with an appropriately substituted heterocycle 3 in a Stille coupling reaction to give 24. Dehydration of 24 is achieved by the action of acetic anhydride to give the anhydride 25. In some cases, this process can be accelerated by the addition of pyridine. The anhydride 25 is condensed with 3-aminopiperidine-2,6-dione (10) using a combination of acetic acid and potassium acetate to give 26, as shown in Scheme 7. [ka]

[0188] As shown in the previous schemes, it is often convenient and advantageous to convert the leaving group L of 27 to a suitable coupling partner M in 28, such as a boronic acid, boronic ester, or stannane. This can then be coupled to a substituted heterocycle 3 to give 5. In some cases, it may be more preferable to reverse the coupling partners and couple 27 to a substituted heterocycle 29 to give 5 directly. When the coupling partner M of 29 is a boronic acid or boronic ester, a copper-mediated Suzuki-Miyaura coupling reaction may be preferred (see Crowley, et. al. Tetrahedron Letters, 2011, 5055). This is shown in Scheme 8. Similarly, intermediate 1 (Scheme 9) can be coupled to heterocycle 29 to give intermediate 4 directly. Further elaboration in the manner described above can alternatively give compounds of formula 1. [ka] [ka] EXAMPLES

[0189] The following examples illustrate certain embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their usual customary meanings unless otherwise specified. Additional abbreviations utilized in the examples and elsewhere in this application are defined above. Common intermediates are generally useful in the preparation of more than one example. In some cases, alternative preparations of intermediates or examples are described. Often, chemists of ordinary skill in the art of synthesis may construct alternative preparations that may be desirable based on one or more considerations, such as, for example, shorter reaction times, cheaper starting materials, ease of handling or isolation, improved yields, compatibility with catalysts, avoidance of toxic reagents, availability of specialized equipment, and reduced number of linear steps. The intention of describing alternative preparations is to further enable the preparation of examples of the present invention. In some cases, some functional groups in the examples and claims shown may be replaced by bioisosteric replacements known in the art, such as, for example, replacement of carboxylic acid groups with tetrazole or phosphate moieties. Abbreviation AIBN Azobisisobutyronitrile Boc tert-butoxycarbonyl DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide ESI Electrospray Ionization EtOAc Ethyl acetate EtOH Ethanol h time Hex HPLC High Performance Liquid Chromatography Hunig's base N,N-diisopropylethylamine LCMS Liquid Chromatography Mass Spectrometry min mL Milliliters MS mass spectrometry NBS N-Bromosuccinimide Pd(dppf)Cl 2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl 2 [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) TEA Triethylamine Analytical HPLC conditions Method A: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; 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). Method B: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 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).

[0190] Example 1 [ka] Step 1: tert-Butyl (S)-5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate To a suspension of tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (14.46 g, 60.6 mmol) in acetonitrile (231 mL) was added DIEA (20.2 mL, 115 mmol) at 0° C. After stirring for 15 min, the reaction mixture was treated with solid methyl 4-bromo-2-(bromomethyl)benzoate (22 g, 57.7 mmol) in portions over 5 min. The reaction mixture was stirred at 0° C. for 30 min and then left at room temperature overnight. Under a reflux condenser, the reaction mixture was warmed to 60° C. in an oil bath and kept at that temperature overnight. The reaction mixture was allowed to cool to room temperature while stirring. After cooling to room temperature, a precipitate formed. The flask was placed in a 0° C. bath while stirring. After 30 min, the solid was collected by filtration, washed with a minimum of cold acetonitrile, and air-dried to give 20.13 g (88% yield) as a white solid. Chiral HPLC analysis showed the material to be >98% ee. MS(ES): m / z = 397.1 [M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ 7.76-7.71 (m,1H),7.68-7.62 (m,2H),6.22 (br s,1H),5.31 (br s,1H),4.91 (dd,J=8.7,6.3 Hz,1H),4.62-4.53 (m,1H),4.51-4.40 (m,1H),2.47-2.10 (m,4H),1.44 (s,9H)

[0191] Step 2: 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 A dry flask was charged with tert-butyl (S)-5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate (10.0 g, 25.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.67 g, 30.2 mmol), and potassium acetate (7.41 g, 76 mmol) and flushed with nitrogen. The solid was suspended in dioxane (100 mL) and degassed with a stream of nitrogen while stirring for 5 min. The reaction mixture was treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.737 g, 1.007 mmol), degassed for 5 min, sealed, and heated to 60 °C for 18 h. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite, washing with additional EtOAc. The filtrate was concentrated and purified on an ISCO 220 gram silica gel column (0%→20% B / DCM, B=15% EtOH / EtOAc+0.1% TEA) to give 9.9 g (89% yield) as a white solid. MS (ES): m / z = 445.3 [M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ 7.99-7.90 (m,2H),7.88-7.83 (m,1H),6.32 (br s,1H),5.36 (br s,1H),4.97-4.88 (m,1H),4.58-4.41 (m,2H),2.48-2.13 (m,4H),1.44 (s,9H),1.39 (s,12H)

[0192] Step 3: tert-Butyl (S)-5-amino-4-(5-(4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a flask, (2-chloropyridin-4-yl)methanol (1.00 g, 6.97 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 (3.87 g, 8.71 mmol), Pd(dtbpf)Cl2 (0.136 g, 0.209 mmol), dioxane (50 mL) and aqueous K3PO4 (3M, 11.61 mL, 34.8 mmol) were added. The vessel was sealed and the air was replaced with nitrogen. The reaction mixture was heated at 70 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine and separated. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on a 120 gram ISCO column eluting with 0-100% B / DCM [B=15% EtOH / EtOAc+0.1% triethylamine] to give 1.38 g (47%). MS (ES): m / z = 426.4 [M+H] +

[0193] Step 4: 3-(5-(4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To a solution of tert-butyl (S)-5-amino-4-(5-(4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.00 g, 2.35 mmol) in DCM (15 mL) was added thionyl chloride (0.511 mL, 7.05 mmol) dropwise at 0° C. After 5 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. The resulting residue was dissolved in acetonitrile (15 mL). To this was added benzenesulfonic acid (0.818 g, 5.17 mmol). The reaction mixture was heated at 130° C. for 30 min in a microwave. The reaction mixture was concentrated to dryness. To this was added 20 mL of 2M HCl in diethyl ether and the resulting mixture was stirred for 30 min. The mother liquor was decanted and discarded. The remaining solid was dried under vacuum to give 708 mg (81%) of the hydrochloride salt. MS(ES): m / z = 370.2 [M+H] +

[0194] Step 5: 3-(5-{4-[(dimethylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione To a vial was added 3-(5-(4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (71 mg, 0.175 mmol), dimethylamine hydrochloride (42.8 mg, 0.524 mmol), and DMF (1 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.304 mL, 1.748 mmol). The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and treated with acetic acid (0.5 mL). The product was purified by preparative HPLC to give 40 mg (52%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.37-10.73 (m,1H),8.66 (d,J=5.0 Hz,1H),8.33 (s,1H),8.25 (dd,J=8.0,1.4 Hz,1H),7.98 (s,1H),7.84 (d,J=8.1 Hz,1H),7.36 (dd,J=5.3,1.0 Hz,1H),5.21-5.11 (m,1H),4.61-4.39 (m,2H),3.02-2.87 (m,1H),2.71-2.59 (m,1H),2.53 (m,2H),2.47-2.38 (m,1H),2.22 (s,6H),2.12-2.00 (m,1H) LCMS (Method B): Retention time 1.09 min, [M+H] + 379.3

[0195] Example 2-143 The compounds in Table 1 were prepared following the procedure described in Example 1, substituting the appropriate primary or secondary amine for dimethylamine: [ka] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0196] Example 144 [ka] Step 1: tert-Butyl ((2-chloropyridin-4-yl)methyl)carbamate To the vial was added (2-chloropyridin-4-yl)methanamine, 2HCl (300 mg, 1.39 mmol), DCM (8 mL), and di-tert-butyl dicarbonate (365 mg, 1.670 mmol). After stirring for 5 min at room temperature, triethylamine (0.775 mL, 5.57 mmol) was added and the reaction mixture was stirred for 3 h. The reaction mixture was concentrated and purified by ISCO on a 24 g silica gel column eluted with 5-100% EtOAc / Hexanes to give 325 mg (96%). MS (ES): m / z = 243.1 [M+H] +

[0197] Step 2: 3-{5-[4-(aminomethyl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione In a 2 mL microwave vial, add tert-butyl ((2-chloropyridin-4-yl)methyl)carbamate (24 mg, 0.099 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 (54.9 mg, 0.124 mmol), Pd(dtbpf)Cl 2 (1.933 mg, 2.97 μmol), 1,4-dioxane (1 mL) and aqueous K3PO4 (0.165 mL, 0.494 mmol) were added. The reaction vial was sealed and the air was replaced with nitrogen. The reaction mixture was heated in a microwave for 10 min at 120 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over sodium sulfate and concentrated. PhSO 3 The crude product was dissolved in a solution of H solution (0.5 mL, 1.44 g in 40 mL) and heated in a microwave for 30 min at 130° C. The reaction mixture was concentrated to dryness. The resulting residue was purified by preparative HPLC to give 34.6 mg (30%). 1 H NMR (500 MHz, DMSO-d 6) δ 11.02 (s,1H),8.75 (d,J=4.9 Hz,1H),8.42 (br s,2H),8.31 (s,1H),8.22 (br d,J=8.1 Hz,1H),8.14 (br s,1H),7.90 (d,J=8.1 Hz,1H),7.48 (br d,J=4.7 Hz,1H),5.17-5.07 (m,1H),4.63-4.53 (m,1H),4.49-4.39 (m,1H),4.19 (br s,2H),2.97-2.86 (m,1H),2.64 (br d,J=16.7 Hz,1H),2.49-2.36 (m,1H),2.11-2.01 (m,1H) LCMS (Method A): Retention time 0.74 min, [M+H] + 351.1

[0198] Example 145 [ka] Step 1: tert-Butyl ((2-chloropyridin-4-yl)methyl)(methyl)carbamate To the vial was added tert-butyl ((2-chloropyridin-4-yl)methyl)carbamate (40 mg, 0.165 mmol), DMF (1.5 mL), and iodomethane (35.1 mg, 0.247 mmol). After stirring for 5 min at room temperature, sodium hydride (26.4 mg, 0.659 mmol) was added and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with brine. The mixture was concentrated and purified by preparative HPLC to give 29 mg (69%). MS (ES): m / z = 257.1 [M+H] +

[0199] Step 2: 3-(5-{4-[(methylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione In a microwave vial, add tert-butyl ((2-chloropyridin-4-yl)methyl)(methyl)carbamate (25 mg, 0.097 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 (54.1 mg, 0.122 mmol), Pd(dtbpf)Cl 2 (1.90 mg, 2.92 μmol), 1,4-dioxane (1 mL) and aqueous K3PO4 (0.162 mL, 0.487 mmol) were added. The vial was sealed and the air was replaced with nitrogen. The reaction mixture was heated in a microwave for 10 min at 120 °C. The reaction mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate and concentrated. PhSO 3 The resulting residue was dissolved in a solution of H solution (0.5 mL, 1.44 g in 40 mL) and heated in a microwave for 10 min at 120° C. The mixture was purified by preparative HPLC to give the product (15.1 mg, 43%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.64 (d,J=4.9 Hz,1H),8.32 (s,1H),8.24 (d,J=7.9 Hz,1H),8.03 (s,1H),7.86 (d,J=7.9 Hz,1H),7.39 (br d,J=4.9 Hz,1H),5.14 (dd,J=13.3,5.3 Hz,1H),4.61-4.51 (m,1H),4.49-4.39 (m,1H),3.80 (s,2H),2.98-2.87 (m,1H),2.69-2.60 (m,1H),2.49-2.39 (m,1H),2.33 (s,3H),2.07 (br d,J=5.5 Hz,1H) LCMS (Method A): Retention time 0.55 min, [M+H] + 365.5

[0200] Example 146 [ka] Step 1: 3-(5-(4-((methylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bishydrochloride To a flask was added tert-butyl (S)-5-amino-4-(5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.0 g, 3.71 mmol), benzenesulfonic acid (1.762 g, 11.14 mmol), and acetonitrile (60 mL). The resulting mixture was heated to reflux and held at that temperature for 4 h. The reaction mixture was concentrated. The resulting residue was treated with 50 mL of 2M HCl in diethyl ether and stirred for 15 min. The resulting solid was collected by filtration, washed with diethyl ether, and air-dried to give the product as the bis-HCl salt (1.4 g, 78%). MS (ES): m / z = 365.2 [M+H] +

[0201] Step 2: 4-{[({2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridin-4-yl}methyl)(methyl)amino]methyl}-N,N-dimethylbenzene-1-sulfonamide To a vial was added 3-(5-(4-((methylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bishydrochloride (20 mg, 0.046 mmol), 4-(bromomethyl)-N,N-dimethylbenzenesulfonamide (25.4 mg, 0.091 mmol), and DMF (1 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (35.5 mg, 0.274 mmol). The reaction mixture was warmed to 50° C. and held at that temperature for 4 hours. The reaction mixture was quenched by the addition of acetic acid (0.2 mL). The reaction mixture was purified by HPLC to give the product (12.1 mg, 46%). 1 H NMR (500 MHz, DMSO-d 6) δ 11.02 (s,1H),8.66 (d,J=4.9 Hz,1H),8.30 (s,1H),8.22 (br d,J=7.9 Hz,1H),8.01 (s,1H),7.86 (d,J=7.9 Hz,1H),7.75-7.69 (m,2H),7.69-7.63 (m,2H),7.45 (d,J=4.3 Hz,1H),5.12 (br dd,J=13.1,4.9 Hz,1H),4.62-4.52 (m,1H),4.49-4.39 (m,1H),3.61 (br s,4H),2.98-2.85 (m,1H),2.65 (br d,J=16.2 Hz,1H),2.52 (br s,6H),2.44 (qd,J=13.1,4.4 Hz,1H),2.19 (s,3H),2.11-2.00 (m,1H) LCMS (Method A): Retention time 1.10 min,[M+H] + 562.1

[0202] Examples 147-162 The compounds in Table 2 were prepared following the procedure described in Example 146, substituting the appropriate bromide for 4-(bromomethyl)-N,N-dimethylbenzenesulfonamide: [ka] [Table 13]

[0203] Example 163 [ka] Step 1: N,N-Dibenzyl-1-(2-chloropyridin-4-yl)methanamine To a solution of (2-chloropyridin-4-yl)methanamine, 2HCl (40 mg, 0.186 mmol) dissolved in DMF (1 mL) was added sodium hydride (29.7 mg, 0.742 mmol) and (bromomethyl)benzene (69.8 mg, 0.408 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with brine. The organics were concentrated and purified by preparative HPLC to give the product (31 mg, 52%). MS (ES): m / z = 323.2 [M+H] +

[0204] Step 2: 3-(5-{4-[(dibenzylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione Example 163 was prepared following the general procedure used to prepare 3-(5-{4-[(methylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.02 (br d,J=4.0 Hz,1H),8.67 (d,J=4.9 Hz,1H),8.28 (s,1H),8.21 (br d,J=7.9 Hz,1H),8.00 (s,1H),7.86 (d,J=7.9 Hz,1H),7.49 (br d,J=4.6 Hz,1H),7.47-7.42 (m,4H),7.38 (t,J=7.5 Hz,4H),7.31-7.24 (m,2H),5.17 (br dd,J=13.3,5.0 Hz,1H),4.63-4.53 (m,1H),4.51-4.39 (m,1H),3.67 (s,2H),3.61 (s,4H),3.00-2.89 (m,1H),2.71-2.60 (m,1H),2.46 (td,J=13.3,9.2 Hz,1H),2.07 (br dd,J=10.8,5.6 Hz,1H) LCMS (Method B): Retention time 2.36 min,[M+H] + 531.2

[0205] Example 164 [ka] Step 1: N-benzyl-1-(2-chloropyridin-4-yl)-N-methylmethanamine To a solution of (2-chloropyridin-4-yl)methanamine, 2HCl (43.4 mg, 0.201 mmol) in DMF (1 mL) was added sodium hydride (32.2 mg, 0.805 mmol) and (bromomethyl)benzene (36.1 mg, 0.211 mmol). The resulting mixture was stirred at room temperature for 1 h. To this was added iodomethane (30 mg, 0.211 mmol). The reaction mixture was stirred overnight. The product was isolated by preparative HPLC to give 23 mg (46%). MS (ES): m / z = 247.1 [M+H] +

[0206] Step 2: 3-[5-(4-{[benzyl(methyl)amino]methyl}pyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione Example 164 was prepared following the general procedure used to prepare 3-(5-{4-[(methylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione. 1 H NMR (500 MHz, DMSO-d 6) δ 11.03 (s,1H),8.81 (d,J=4.9 Hz,1H),8.32 (s,1H),8.24 (d,J=8.2 Hz,1H),8.21 (s,1H),7.90 (d,J=7.9 Hz,1H),7.60-7.53 (m,3H),7.51-7.45 (m,3H),5.14 (dd,J=13.4,5.2 Hz,1H),4.63-4.54 (m,1H),4.50-4.35 (m,4H),3.62-3.48 (m,1H),2.98-2.87 (m,1H),2.68-2.61 (m,4H),2.49-2.37 (m,1H),2.13-2.02 (m,1H) LCMS (Method B): Retention time 1.66 min, [M+H] + 455.1

[0207] Example 165 [ka] Step 1: 4-(azetidin-1-ylmethyl)-2-chloropyridine To the vial was added 2-chloro-4-(chloromethyl)pyridine (44 mg, 0.187 mmol), THF (1.5 mL) and azetidine (13.44 mg, 0.234 mmol). After stirring for 5 min, N-ethyl-N-isopropylpropan-2-amine (0.130 mL, 0.749 mmol) was added. The reaction mixture was warmed to 40° C. and kept at that temperature for 3 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate and concentrated to give the product (31 mg, 91%). MS (ES): m / z = 182.9 [M+H] +

[0208] Step 2: 3-(5-{4-[(azetidin-1-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione In a microwave vial, add 4-(azetidin-1-ylmethyl)-2-chloropyridine (17.4 mg, 0.095 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 (52.9 mg, 0.119 mmol), Pd(dtbpf)Cl 2 (1.863 mg, 2.86 μmol), 1,4-dioxane (1 mL), and aqueous K3PO4 (0.159 mL, 0.476 mmol) were added. The vial was sealed and the air was replaced with nitrogen. The reaction mixture was heated in a microwave for 10 min at 120 °C. The reaction mixture was cooled, diluted with EtOAc, and washed with brine. The organics were dried over sodium sulfate and concentrated. PhSO in acetonitrile was added. 3 The resulting residue was dissolved in a solution of H solution (0.5 mL, 1.44 g in 40 mL) and heated in a microwave for 10 min at 120° C. The reaction mixture was concentrated and purified by preparative HPLC to give Example 165 (8.1 mg, 18%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.61 (d,J=4.9 Hz,1H),8.29 (s,1H),8.21 (br d,J=7.6 Hz,1H),7.90 (s,1H),7.84 (d,J=8.1 Hz,1H),7.31 (br d,J=4.9 Hz,1H),5.17-5.08 (m,1H),4.60-4.39 (m,2H),3.65 (br s,2H),3.20 (t,J=7.0 Hz,3H),2.96-2.85 (m,1H),2.68-2.60 (m,1H),2.48-2.35 (m,2H),2.11-1.96 (m,3H) LCMS (Method A): Retention time 0.91 min, [M+H] + 390.9

[0209] Example 166 [ka] Example 166 was prepared following the general procedure used to prepare 3-(5-{4-[(azetidin-1-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.01 (s,1H),8.64 (d,J=5.0 Hz,1H),8.30 (s,1H),8.22 (br d,J=8.0 Hz,1H),7.97 (s,1H),7.84 (d,J=8.0 Hz,1H),7.38 (d,J=4.5 Hz,1H),5.19-5.05 (m,1H),4.62-4.35 (m,2H),3.56-3.54 (m,6H),2.97-2.84 (m,1H),2.67-2.59 (m,1H),2.46-2.34 (m,5H),2.12-1.99 (m,1H) LCMS (Method B): Retention time 1.23 min, [M+H] + 421.1

[0210] Example 167 [ka] Example 167 was prepared following the general procedure used to prepare 3-(5-{4-[(azetidin-1-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione. 1 H NMR (500 MHz, DMSO-d 6) δ 11.01 (s,1H),8.66 (d,J=5.0 Hz,1H),8.32 (br s,1H),8.24 (br d,J=8.0 Hz,1H),8.02 (br s,1H),7.85 (d,J=8.0 Hz,1H),7.41 (d,J=4.8 Hz,1H),5.18-5.07 (m,1H),4.60-4.38 (m,2H),3.17 (br s,3H),2.94 (br s,4H),2.63 (br d,J=15.3 Hz,1H),2.51 (br s,4H),2.48-2.36 (m,1H),2.12-1.99 (m,1H) LCMS (Method B): Retention time 1.13 min, [M+H] + 469.0

[0211] Example 168 [ka] To a vial was added 3-(5-(4-((methylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione bishydrochloride (20 mg, 0.046 mmol), 6-methoxynicotinaldehyde (18.8 mg, 0.137 mmol), and DMF (1 mL). After stirring for 10 min at room temperature, sodium triacetoxyborohydride (29.1 mg, 0.137 mmol) was added. The reaction mixture was warmed to 50° C. and kept at that temperature overnight. The reaction mixture was filtered and purified by preparative HPLC to give 2.5 mg (11%). 1 H NMR (500 MHz, DMSO-d 6) δ 11.00 (s,1H),8.73 (d,J=4.8 Hz,1H),8.27 (s,1H),8.22 (s,1H),8.19 (d,J=8.0 Hz,1H),8.08 (s,1H),7.87 (d,J=8.0 Hz,1H),7.79 (dd,J=8.6,2.3 Hz,1H),7.49 (d,J=4.6 Hz,1H),6.86 (d,J=8.6 Hz,1H),5.09 (br dd,J=13.1,5.1 Hz,1H),4.56 (d,J=17.6 Hz,1H),4.48-4.37 (m,1H),3.80-3.78 (m,7H),2.88 (ddd,J=18.0,13.3,5.1 Hz,1H),2.69-2.61 (m,1H),2.49 (br s,3H),2.42 (br dd,J=12.7,4.1 Hz,1H),2.11-2.01 (m,1H) LCMS (Method A): Retention time 1.02 min, [M+H] + 486.3

[0212] Examples 169-185 The compounds in Table 3 were prepared following the general procedure described in Example 168, substituting the appropriate aldehyde or ketone for 6-methoxynicotinaldehyde: [ka] [Table 14] [Table 15]

[0213] Example 186 [ka] Step 1: 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 aqueous K3PO4 (1.873 mL, 5.62 mmol) were added. The vial was sealed and the air was replaced with nitrogen. It 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 separated. The organics were 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, eluting with 0-100% DCM-20% methanolic ammonia in DCM) 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] +

[0214] Step 2: 3-(5-(5-chloro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 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) was added dropwise thionyl chloride (0.132 mL, 1.826 mmol). 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 in a microwave oven for 25 min at 120° C. The reaction mixture was concentrated to dryness, 2 mL of 3M HCl in MeOH was added, and stirred at 0° C. (ice-water bath) until complete dissolution. Then, 8 mL of EtOAc was added and 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 HCl salt. MS (ES): m / z = 404.3, 406.3 [M+H] +

[0215] Step 3: 3-(5-(5-chloro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 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-phenylazetidine, HCl (17.71 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 using the following conditions: column: XBridge C18, 200 mm x 19 mm, 5-μm particles; 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, 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 to give 3-(5-(5-chloro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15.5 mg, 0.030 mmol, 33.1% yield). LCMS (Method A): Retention time 1.28 min; MS (ES): m / z = 501.17 [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)

[0216] Example 187 The compounds in Table 4 were prepared following the general procedure described in Example 186, substituting the appropriate amine for 3-phenylazetidine. [ka] [Table 16]

[0217] Example 188 [ka] Step 1: 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 (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. It 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 separated. The organics were 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, eluting with 0-100% DCM-20% methanolic ammonia in DCM) 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 this material and subsequent intermediates was not determined. MS(ES): m / z = 444.04 [M+H] +

[0218] Step 2: 3-(5-(5-fluoro-4-(chloromethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a cooled (0° C.) solution 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) was added dropwise thionyl chloride (0.319 mL, 4.40 mmol). 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 (0.510 g, 3.22 mmol) was added, and the reaction mixture was heated at 120° C. in a microwave for 25 min. The reaction mixture was concentrated to dryness, 4 mL of 3M HCl in MeOH was added, and stirred at 0° C. (ice-water bath) until complete dissolution. Then, 12 mL of EtOAc was added and 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-(4-(chloromethyl)-5-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (480 mg, 1.238 mmol, 84% yield) as the HCl salt. MS (ES): m / z = 388.2 [M+H] +

[0219] Step 3: 3-(5-(5-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 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 3-phenylazetidine, HCl (25.4 mg, 0.149 mmol) followed by Hunig's base (136 μL, 0.780 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 using the following conditions: column: XBridge C18, 200 mm x 19 mm, 5-μm particles; 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, 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 to give 3-(5-(5-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7.1 mg, 0.015 mmol, 11.28% yield). LCMS (Method A): Retention time 1.78 min; MS (ES): m / z = 485.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.1 (s,1H),8.9 (s,1H),8.43 (s,1H),8.30 (m,m 1H),8.01 (s,1H),7.81 (d,J=8.0 Hz,1H),7.5-7.38 (m,5H),7.26-7.20 (m,1H),5.3 (m,1H),4.61 (d,J=17.4 Hz,1H),4.51(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)

[0220] Examples 189-190 The compounds in Table 5 were prepared according to the procedures described herein, substituting the appropriate amine for 3-phenylazetidine: [ka] [Table 17]

[0221] Example 191 [ka] Step 1: tert-Butyl 5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate In a 20 mL vial, add 2-chloro-3-fluoropyridin-4-yl)methanol (400 mg, 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 (1.650 g, 3.71 mmol), Pd(dtbpf)Cl 2 (0.048 g, 0.074 mmol), 1,4-dioxane (12.38 mL) and K 3 PO 4(4.13 mL, 12.38 mmol) of 3M aqueous solution was added. The vial was sealed and the air was replaced with nitrogen. It was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), washed with brine, and separated. The organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by ISCO column chromatography on a silica gel column (40 g Gold, eluting with 0-100% DCM-20% methanolic ammonia in DCM) to give tert-butyl 5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (630 mg, 1.421 mmol, 57.4% yield) as a brown solid. The enantiomeric excess of this material and subsequent intermediates was not determined. MS(ES): m / z = 444.4 [M+H] +

[0222] Step 2: 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a cooled (0° C.) solution of tert-butyl 5-amino-4-(5-(3-fluoro-4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.62 g, 1.398 mmol) in DCM (7.5 mL) was added dropwise thionyl chloride (0.304 mL, 4.19 mmol). 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 (4 mL), benzenesulfonic acid (0.486 g, 3.08 mmol) was added, and the reaction mixture was heated at 120° C. in a microwave for 30 min. The reaction mixture was concentrated to dryness, 4 mL of 3M HCl in MeOH was added, and stirred at 0° C. (ice-water bath) until complete dissolution. Then, 12 mL of EtOAc was added and 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-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (465 mg, 1.199 mmol, 86% yield) as the HCl salt. MS (ES): m / z = 388.2 [M+H] +

[0223] Step 3: 3-(5-(3-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To 3-(5-(4-(chloromethyl)-3-fluoropyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (35 mg, 0.082 mmol) dissolved in DMF (30 mL) was added 3-phenylazetidine, HCl (16.10 mg, 0.095 mmol) followed by Hunig's base (0.086 mL, 0.495 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 using the following conditions: column: XBridge C18, 200 mm x 19 mm, 5-μm particles; 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, 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 to give 3-(5-(3-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (15.4 mg, 0.032 mmol, 38.5% yield). LCMS (Method A): Retention time 1.12 min; MS (ES): m / z = 485.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.6 (s,1H),8.3 (s,1H),8.21 (m,1H),8.11 (m,1H),7.81 (s,1H),7.6 (m,1H),7.5-7.38 (m,5H),7.26-7.20 (m,1H),5.2 (m,1H),4.51 (d,J=17.4 Hz,1H),4.34(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)

[0224] Examples 192-193 The compounds in Table 6 were prepared following the general procedure described in Example 196, substituting the appropriate amine for 3-phenylazetidine: [ka] [Table 18]

[0225] Example 194 [ka] Step 1: tert-Butyl (S)-5-amino-4-(6-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-5-oxopentanoate A 40 mL pressure vial was charged with tert-butyl (S)-5-amino-4-(5-bromo-6-methyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 0.729 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (278 mg, 1.094 mmol), and potassium acetate (215 mg, 2.188 mmol) and flushed with nitrogen. The solid was suspended in dioxane (10 mL) and degassed with a stream of nitrogen while stirring for approximately 5 min. The reaction mixture was diluted with PdCl 2 (dppf) 2 (16.01 mg, 0.022 mmol), degassed again for 5 min, and heated to 95 °C under nitrogen for 3 h. The reaction mixture was diluted with EtOAc, washed with brine, and treated with MgSO 4 The filtrate was concentrated and purified on an ISCO 24 gram silica gel column eluted with 0-40% B / DCM (B=15% EtOH / EtOAc+0.1% TEA) to give the title compound in 95% yield.

[0226] Step 2: 3-(5-(4-((dimethylamino)methyl)pyridin-2-yl)-6-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione In a 2 mL microwave vial, add 1-(2-chloropyridin-4-yl)-N,N-dimethylmethanamine (13 mg, 0.076 mmol), tert-butyl (S)-5-amino-4-(6-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-5-oxopentanoate (38.4 mg, 0.084 mmol), PdCl 2 (dtbpf) (1.490 mg, 2.286 μmol), dioxane (1.5 mL) and 3M aqueous K3PO4 (0.102 mL, 0.305 mmol) were added. It was sealed and purged with nitrogen, then heated in a microwave oven for 10 min at 120° C. The reaction mixture was diluted with EtOAc, washed with brine, separated and the organics were concentrated. The crude material was purified using preparative HPLC Method 1 to give 4.1 mg of the title compound. Analytical HPLC Method B: Retention time 0.89 min; [M+H] + 393.3; 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.62 (d,J=5.0 Hz,1H),7.68 (s,1H),7.60 (s,1H),7.47 (s,1H),7.35 (d,J=4.8 Hz,1H),5.13 (dd,J=13.2,5.0 Hz,1H),4.47 (d,J=17.2 Hz,1H),4.35 (d,J=17.1 Hz,1H),3.51 (s,1H),3.46-3.42 (m,1H),2.97-2.88 (m,1H),2.62 (br d,J=16.4 Hz,1H),2.45-2.40 (m,1H),2.39 (s,3H),2.20 (s,6H),2.13 (s,1H),2.07-1.99 (m,1H)

[0227] Example 195 The compounds in Table 7 were prepared following the general procedures described herein using commercially available amines: [ka] [Table 19]

[0228] Examples 196-201 The compounds in Table 8 were prepared according to the procedures described herein, substituting tert-butyl (4-((7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)carbamate with the appropriate primary or secondary amine: [ka] [Table 20]

[0229] Examples 202-207 Following the general procedures described herein, the compounds in Table 9 were prepared: [ka] [Table 21] Analytical HPLC conditions Method A: ACQUITY UPLC(TM) BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile phase A: 95:5 Water: 2.5 mM NH 4 OAc in acetonitrile; mobile phase B: 5:95 water: 2.5 mM NH 4 Acetonitrile containing OAc; Temperature: 40°C; Gradient: 20% B to 100% B over 2 min; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm) Method B: Column: XBridge BEH XP C18 (50 x 2.1) mm, 2.5 μm; Mobile phase A: 95:5 Water: 10 mM NH 4 OAc in acetonitrile; mobile phase B: 5:95 water: 10 mM NH4 Acetonitrile containing OAc; Temperature: 50°C; Gradient: 0% B to 100% B over 3 min; Flow rate: 1.1 mL / min; Detection: MS and UV (220 nm) Method C: XBridge BEH XP C18 (50 x 2.1) mm, 2.5 μm; Mobile phase A: 95:5 water:acetonitrile with 0.1% trifluoroacetic acid; Mobile phase B: 5:95 water:acetonitrile with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min; Flow rate: 1.1 mL / min; Detection: MS and UV (220 nm). Method D: Column - Kinetex XB-C18 (75 X 3 mm - 2.6 μm); Mobile phase A: 5 mM NH 4 COOH in water; Mobile phase B: acetonitrile; Gradient: 10% B to 50% B over 3 min, flow rate: 1.0 mL / min; 50% B to 100% B until 4.1 min, flow rate: 1.0 mL / min; Hold until 4.5 min; 90% B from 4.5 min to 5.0 min, flow rate: 1.5 mL / min; Detection: MS and UV (220 nm). Method E: Column - Kinetex XB-C18 (75 x 3 mm-2.6 μm); Mobile phase A: 0.1% TFA in water; Mobile phase B: acetonitrile; Gradient: 20% B to 100% B over 4.6 min; Flow rate: 1.0 mL / min; Detection: MS and UV (220 nm). Method F: Column - Kinetex XB-C18 (75 x 3 mm-2.6 μm); Mobile phase A: 0.1% TFA in water; Mobile phase B: Acetonitrile; Gradient: 5% B to 40% B over 4 min, flow rate: 1.0 mL / min; 40% B to 100% B until 4.6 min, flow rate: 1.5 mL / min; Hold until 4.7 min; 5% B from 4.7 min to 5.0 min, flow rate: 1.5 mL / min; Detection: MS and UV (220 nm). Method G: Column - Kinetex XB-C18 (75 X 3 mm - 2.6 μm); Mobile phase A: 10 mM NH 4COOH in water; Mobile phase B: acetonitrile; Gradient: 20% B to 100% B over 4 min, flow rate: 1.0 mL / min; hold until 4.6 min, then 20% B from 4.7 min to 5.0 min, flow rate: 0.7 mL / min; Detection: MS and UV (220 nm).

[0230] Example 208 [ka] [ka] Step 1: (2-(trimethylstannyl)pyridin-4-yl)methanol A stirred solution of (2-chloropyridin-4-yl)methanol (200 mg, 1.393 mmol) and hexamethylditin (0.433 mL, 2.090 mmol) in toluene (10 mL) was purged with argon for 5 min, then [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (45.4 mg, 0.070 mmol) was added. The reaction mixture was stirred at 100° C. for 2 h, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to give (2-(trimethylstannyl)pyridin-4-yl)methanol (350 mg, 74% yield). LCMS (Method A): Retention time 1.72 min; [M+H] + 274.2

[0231] Step 2: tert-Butyl (S)-5-amino-4-(4-fluoro-5-(4-(hydroxyethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate [ka] A stirred solution of tert-butyl (S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate (229 mg, 0.552 mmol) and (2-(trimethylstannyl)pyridin-4-yl)methanol (150 mg, 0.552 mmol) in dioxane (20 mL) was purged with argon for 5 min and bis(triphenylphosphine)palladium(II) chloride (38.7 mg, 0.055 mmol) was added. The reaction mixture was heated to 100° C. and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (SiO 2 Purification on a 80 g column, 0-100% B (B=15% EtOH, 0.5% TEA in EtOAc) / chloroform) gave tert-butyl (S)-5-amino-4-(4-fluoro-5-(4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (180 mg, 66% yield). LCMS (Method A): Retention time 1.04 min; [M+H] + 444.3

[0232] Step 3: tert-Butyl (S)-5-amino-4-(5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate [ka] To a stirred solution of tert-butyl (S)-5-amino-4-(4-fluoro-5-(4-(hydroxymethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.180 g, 0.406 mmol) in dichloromethane (10 mL), add SOCl 2(0.089 mL, 1.218 mmol) was added at 0° C. The reaction mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure to give tert-butyl (S)-5-amino-4-(5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.175 g, 74.7% yield). LCMS (Method A): Retention time 1.48 min; [M+H] + 462.3

[0233] Step 4: 3-(5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a stirred solution of tert-butyl (S)-5-amino-4-(5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate (175 mg, 0.379 mmol) in acetic acid (2 mL) was added benzenesulfonic acid (120 mg, 0.758 mmol). The reaction mixture was heated to 120° C. and stirred for 2 h. The volatiles were removed under reduced pressure to give 3-(5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130 mg, 66% yield). LCMS (Method A): Retention time 1.12 min; [M+H] + 388.3

[0234] Step 5: 3-(4-fluoro-1-oxo-5-(4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione To a stirred solution of 3-(5-(4-(chloromethyl)pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.080 g, 0.206 mmol) and 3-phenylazetidine HCl (0.082 g, 0.619 mmol) in DMF (2 mL) was added DIPEA (0.216 mL, 1.238 mmol) at 25° C. The reaction mixture was heated to 80° C. and stirred for 3 h. Volatiles were removed under reduced pressure and the resulting crude product was purified by preparative HPLC using the following conditions: Column: Gemini NX C18 (250 mm x 21 mm ID, 5 μm); Mobile phase A = 10 mM aqueous ammonium acetate pH 4.5; Mobile phase B = acetonitrile:MeOH (1:1); Flow rate: 19 mL / min; Gradient time: 20-70% B over 20 min. The fractions were lyophilized to give 3-(4-fluoro-1-oxo-5-(4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (23 mg, 22% yield). LCMS (Method G): Retention time 1.60 min; [M+H] + 485.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.03 (br s,1H),8.69 (d,J = 5.0 Hz,1H),8.09 (t,J = 7.3 Hz,1H),7.83 (s,1H),7.71 (d,J = 8.0 Hz,1H),7.44-7.28 (m,5H),7.25-7.20 (m,1H),5.16 (dd,J = 13.1,5.0 Hz,1H),4.76-4.38 (m,2H),3.79 (s,2H),3.75-3.63 (m,3H),3.22 (br t,J = 5.3 Hz,2H),3.02-2.90 (m,1H),2.66-2.60 (m,1H),2.43 (br d,J = 4.5 Hz,1H),2.11-2.02 (m,1H)

[0235] Biological assays The pharmacological properties of the compounds of the invention may be confirmed by a number of biological assays. The following exemplified biological assays have been carried out with the compounds of the invention.

[0236] Helios cytolysis assay Jurkat cells were seeded in 384-well cell culture plates at 80,000 cells / well in 40 μL RPMI + 10% FBS, and then compounds of interest were added using ultrasonic dispensing technique. Cell cultures were maintained at 37°C and 5% CO 2 The cells were incubated at 4°C for 72 hours. To facilitate analysis, the cell cultures were spun down at 200 rpm for 5 minutes and the supernatant was discarded. After shaking the plate to remove the cell pellet, the cells were resuspended in 50 μL of Fixation Buffer (eBioScience FoxP3 Buffer Set 00-5523-00) for 60 minutes at room temperature. After centrifugation and discarding the supernatant, the cells were permeabilized with 50 μL of Permeabilization buffer (eBioScience FoxP3 Buffer Set 00-5523-00) for 10 minutes at room temperature. Following permeabilization, cells were spun down and the supernatant replaced with 20 μL of fluorescently labeled antibodies against Helios and Ikaros or the corresponding isotype controls (Ikaros-Alexa488 [Biolegend, Catalog No. #368408, 1:50], Helios-PE [CST, Catalog No. #29360, 1:50]) in 1x Permeabilization buffer and the staining reaction was incubated for 1 h at room temperature; protected from light. Afterwards, 30 μL of 1x Permeabilization buffer was added, then the cells were centrifuged and the supernatant was discarded. Stained cells were resuspended in 25 μL of flow cytometry staining buffer (PBS + 0.2% BSA) and analyzed using an Intellicyt Ique Plus flow cytometer. [Table 22] [Table 23]

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Claims

1. The structure: 【Chemistry 1】 [In the formula, R １ａ is hydrogen, C １－６ Alkyl, -CH ２ CH ２ CF ３ , -CH ２ CN, -CH ２ CH ２ OH, -CH(CH ３ ) CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ ) CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ , -CH ２ CH ２ C(O)OCH ３ , -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ C(O)NH ２ , -CH ２ C(O)N(CH ３ ) ２ , -CH ２ CH ２ C(O)NH ２ , -CH ２ CH ２ NHC(O)CH ３ , -CH(phenyl)(CH ２ CH ２ OH), -CH ２ CH (phenyl) ２ , R １ｃ , -CR ｘ R ｘ R １ｃ , -CH ２ CH ２ R １ｃ , -CH ２ CH ２ CH ２ R １ｃ , or -CH ２ CH ２ OR １ｃ and R 1b is hydrogen, C 1-3 alkyl, or —CH 2 (phenyl); Or, R １ａ and R １ｂ are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, diazepanyl, dioxidothiomorpholinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R １ｄ and 0 to 1 R １ｅ is replaced by; R １ｃ is C ３－６ cycloalkyl, phenyl, oxetanyl, furanyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, indazolyl, thiazolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, benzo[d]thiazolyl, naphthalenyl, quinolinyl, or quinoxalinyl, where each ring group is selected from the group consisting of F, Cl, —CN, —OH, —CH ３ , -CF ３ , -OCH ３ , -OCF ３ , -C(O)OCH ３ , -NH(CH ３ ), -N(CH ３ ) ２ , -S(O) ２ CH ３ , -S(O) ２ N (CH ３ ) ２ , -CH ２ (phenyl), -NO ２ substituted with 0 to 2 substituents independently selected from , cyclopropyl, imidazolyl, and phenyl; R １ｄ is -CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -N(CH ３ ) ２ , -NHC(O)CH ３ , -C(O)CH ３ , -C(O)NH ２ , -C(O)N(CH ３ ) ２ , -C(O)N(CH ２ CH ３ ) ２ , -CH ２ (phenyl), -CH ２ (methylpyrrolidinyl), -CH ２ (benzo[d][1,3]dioxolyl), -CH(phenyl) ２ , -C(O)(tetrahydrofuranyl), -C(O)(furanyl), -S(O) ２ (methylphenyl), phenyl, methylphenyl, aminophenyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, or dihydrobenzo[d]imidazolonyl; R １ｅ is -CH ３ and R ４ is -CH ３ and Each R ｘ are independently H or -CH ３ and n is 0 or 1. or a salt thereof.

2. R １ａ is hydrogen, C １－６ Alkyl, -CH ２ CH ２ CF ３ , -CH ２ CN, -CH ２ CH ２ OH, -CH(CH ３ ) CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ ) CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ , -CH ２ CH ２ C(O)OCH ３ , -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ C(O)NH ２ , -CH ２ C(O)N(CH ３ ) ２ , -CH ２ CH ２ C(O)NH ２ , -CH ２ CH ２ NHC(O)CH ３ , -CH(phenyl)(CH ２ CH ２ OH), -CH ２ CH (phenyl) ２ , R １ｃ , -CR ｘ R ｘ R １ｃ , -CH ２ CH ２ R １ｃ , -CH ２ CH ２ CH ２ R １ｃ , or -CH ２ CH ２ OR １ｃ and R 1b is hydrogen, C 1-3 alkyl, or —CH 2 (phenyl); wherein R 1c and R x are as defined in claim 1 ; 2. The compound according to claim 1, or a salt thereof.

3. R １ａ and R １ｂ are joined together with the nitrogen atom to which they are attached to form a ring group selected from azaspiro[2.5]octanyl, azepanyl, azetidinyl, diazepanyl, dioxidothiomorpholinyl, morpholinyl, octahydrocyclopenta[b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazabicyclo[2.2.1]heptanyl, piperazinonyl, piperazinyl, piperidinyl, pyrrolidinyl, and tetrahydroisoquinolinyl, wherein each ring group is selected from 0 to 1 R １ｄ and 0 to 1 R １ｅ is replaced by; wherein R 1d and R 1e are as defined in claim 1 ; 2. The compound according to claim 1, or a salt thereof.

4. The compound comprising: 3-(5-{4-[(dimethylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (1); 3-(5-(4-((benzylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2); 3-(5-(4-((methyl(propyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3); 3-(5-(4-((ethyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4); 3-(5-(4-((isopropyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5); 3-(5-(4-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7); 3-(5-(4-((butyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9); 3-(5-(4-(((cyclopropylmethyl)(propyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10); 3-(5-(4-((methyl(2-(pyridin-2-yl)ethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (16); 3-(5-(4-((benzyl(isopropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (19); 3-(5-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21); 3-(5-(4-((ethyl(pyridin-4-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (22); 3-(5-(4-((methyl(1-methylpyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (29); 2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)(methyl)amino)-N,N-dimethylacetamide (34); 3-(5-(4-((methyl(1-methylpyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (49); 3-(5-(4-((diethylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50); 3-(5-(4-(((cyclohexylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (54); 3-(1-oxo-5-(4-(((1-phenylethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (55); 3-(5-(4-(((2-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (56); 3-(5-(4-(((3-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (57); 3-(5-(4-(((4-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (58); 3-(5-(4-(((cyclohexylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (59); 3-(5-(4-((butylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (61); 3-(1-oxo-5-(4-((propylamino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (62); 3-(1-oxo-5-(4-((phenethylamino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (63); 3-(5-(4-(((cyclopropylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (64); 3-(5-(4-((neopentylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (65); 3-(1-oxo-5-(4-((((tetrahydrofuran-2-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (66); 3-(5-(4-(((4-methoxybenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (67); 3-(5-(4-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (68); 3-(5-(4-(((1-cyclopropylcyclobutyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (77); 3-(5-(4-(((2-methyltetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80); 3-(1-oxo-5-(4-((((1R,2R)-2-phenylcyclopentyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (84); 3-(5-(4-((cyclopentylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86); 3-(5-(4-((cyclohexylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (87); 3-(5-(4-(((2-morpholinoethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (88); 3-(5-(4-((tert-butylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (89); 3-(5-(4-(((2,2-diphenylethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90); N-(2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)ethyl)acetamide (91); 3-(5-(4-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (92); 3-(5-(4-(((2-chlorophenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (93); 3-(5-(4-(((4-chlorophenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94); 3-(5-(4-(((4-methoxyphenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95); 3-(5-(4-(((4-hydroxyphenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96); 3-(5-(4-((isopentylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (97); 3-(1-oxo-5-(4-(((3-phenylpropyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (98); 2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)acetonitrile (99); 2-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)acetamide (100); 3-(5-(4-(((4-hydroxycyclohexyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (101); 3-(5-(4-(((3-chlorophenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (102); 3-(1-oxo-5-(4-(((2-phenoxyethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (103); 3-(5-(4-(((1-benzylpyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (104); 3-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)propanamide (105); 3-(5-(4-(((2-(benzo[d]thiazol-2-yl)ethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (106); 3-(5-(4-(((4-(dimethylamino)cyclohexyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (107); 3-(5-(4-((cyclobutylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (108); 3-(5-(4-((cyclopropylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (109); 3-(1-oxo-5-(4-((((2-phenylthiazol-4-yl)methyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (110); 3-(1-oxo-5-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (111); Methyl 3-(((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)amino)propanoate (112); 3-(5-(4-(((3-(1H-imidazol-1-yl)propyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (113); 3-(5-(4-(((3-morpholinopropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (114); 3-(1-oxo-5-(4-(((3-(2-oxopyrrolidin-1-yl)propyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (115); 3-(5-(4-((ethylamino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (116); 3-(1-oxo-5-(4-((((R)-1-phenylethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (122); 3-(1-oxo-5-(4-((((S)-1-phenylethyl)amino)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (123); 3-(5-(4-((((1-hydroxycyclohexyl)methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (124); 3-(5-(4-(((2-methyltetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (126); 3-(5-(4-(((4-hydroxybutyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (128); 3-(5-(4-(((oxetan-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129); 3-(5-(4-((((R)-3-hydroxy-1-phenylpropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (131); 3-(5-(4-((methyl((S)-1-phenylethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (136); 3-(5-(4-((methyl((R)-1-phenylethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (137); 3-(5-(4-((methyl((1R,2R)-2-(methylamino)cyclohexyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (140); 3-(5-(4-((methyl(2-phenylpropan-2-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (142); 3-(1-oxo-5-(4-((3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (144); 3-(5-{4-[(methylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (145); 4-{[({2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridin-4-yl}methyl)(methyl)amino]methyl}-N,N-dimethylbenzene-1-sulfonamide (146); 3-(5-(4-(((4-fluorobenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (147); 3-(5-(4-((methyl(3-(trifluoromethyl)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (148); 3-(5-(4-((methyl(4-(trifluoromethyl)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (149); 4-((((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)(methyl)amino)methyl)benzonitrile (150); 3-(5-(4-((methyl(4-nitrobenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (151); 3-(5-(4-(((3,4-difluorobenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (152); Methyl 4-((((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)(methyl)amino)methyl)benzoate (153); 3-(5-(4-(((4-chlorobenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (154); 3-(5-(4-((methyl(quinolin-8-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (155); 3-(5-(4-((methyl(3-(trifluoromethoxy)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (156); 3-(5-(4-((methyl(4-(methylsulfonyl)benzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (157); 3-(5-(4-(((3-methoxybenzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (158); 3-(5-(4-((methyl(pyridin-3-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (159); 3-(5-(4-((methyl(pyridin-4-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (160); 3-(5-(4-((methyl(4-methylbenzyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (161); 3-(5-(4-((methyl(naphthalen-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (162); 3-(5-{4-[(dibenzylamino)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (163); 3-[5-(4-{[benzyl(methyl)amino]methyl}pyridin-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (164); 3-{5-[4-({[(6-methoxypyridin-3-yl)methyl](methyl)amino}methyl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (168); 3-(5-(4-((((1H-indazol-4-yl)methyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (169); 3-(5-(4-((methyl(1-methylpiperidin-4-yl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (170); 3-(5-(4-((methyl(phenethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (171); 3-(5-(4-(((furan-3-ylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (172); 3-(5-(4-(((cyclopropylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (173); 3-(5-(4-((methyl((1-methyl-1H-imidazol-5-yl)methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (174); 3-(5-(4-(((cyclopentylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (175); 3-(5-(4-((methyl(thiazol-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (176); 3-(5-(4-(((4-(1H-imidazol-1-yl)benzyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (177); 3-(5-(4-(((cyclobutylmethyl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (178); 3-(5-(4-((isobutyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (179); 3-(5-(4-((isopentyl(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180); 3-(5-(4-(((1-hydroxypropan-2-yl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (181); 3-(5-(4-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (182); 3-(5-(4-((methyl(quinoxalin-2-ylmethyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (183); 3-(5-(4-((methyl(3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (184); 3-(5-(4-(((4-hydroxybutan-2-yl)(methyl)amino)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (185); or 3-(5-(4-((dimethylamino)methyl)pyridin-2-yl)-6-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (194) 2. The compound of claim 1, wherein:

5. The compound is 3-(1-oxo-5-(4-piperidin-1-ylmethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (6); 3-(1-oxo-5-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (8); 3-(1-oxo-5-(4-((4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (11); 3-(5-(4-((4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-N,N-diethylpiperidine-3-carboxamide (13); 3-(5-(4-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (14); 3-(1-oxo-5-(4-((4-(pyridin-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (15); 3-(5-(4-([1,4'-bipiperidine]-1'-ylmethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (17); 3-(1-oxo-5-(4-((4-(pyrimidin-2-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (18); 3-(5-(4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20); 3-(1-oxo-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (23); 3-(5-(4-((4-(furan-2-carbonyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24); 3-(1-oxo-5-(4-((4-(pyridin-4-yl)piperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (25); 3-(1-oxo-5-(4-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (26); 3-(5-(4-((3-methyl-4-(m-tolyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (27); 3-(5-(4-((4-acetylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28); 3-(5-(4-((2-(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30); N-((3S)-1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)pyrrolidin-3-yl)acetamide (31); 3-(1-oxo-5-(4-((4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (32); 3-(5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33); 3-(5-(4-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35); 3-(5-(4-((4-benzylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (36); 3-(1-oxo-5-(4-((3-oxopiperazin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (37); 3-(5-(4-((4-benzylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38); 3-(5-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39); 3-(5-(4-((4-(dimethylamino)piperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)piperidine-4-carboxamide (41); 3-(5-(4-((4-benzhydrylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (42); 3-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (43); 3-(5-(4-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (44); 3-(5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (45); 3-(5-(4-((2-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46); 3-(5-(4-((3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (47); 3-(5-(4-(azepan-1-ylmethyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (48); 3-(5-(4-((3,3-dimethylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (51); 3-(5-(4-((2,2-dimethylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (52); 3-(5-(4-((2,6-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (53); 3-(5-(4-((hexahydrocyclopenta[b]pyrrol-1(2H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60); 3-(5-(4-(((S)-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69); 3-(5-(4-(((R)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70); 3-(5-(4-(((R)-2-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (71); 3-(5-(4-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72); 3-(5-(4-(((S)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (73); 3-(5-(4-(((S)-2-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (74); 3-(5-(4-(((R)-3-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (75); 3-(1-oxo-5-(4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (76); 3-(5-(4-(((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (78); 3-(5-(4-((2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (79); 3-(5-(4-(((3S,5R)-3,5-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (81); 3-(5-(4-((4,4-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82); 3-(1-oxo-5-(4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (83); 3-(5-(4-((3,3-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (85); 3-(5-(4-((2,2-dimethylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (117); 3-(5-(4-((3,3-dimethylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (118); 3-(5-(4-((2,5-dimethylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (119); 3-(5-(4-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120); 3-(5-(4-((4-(4-aminophenyl)-4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (121); 3-(5-(4-(((R)-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (125); 3-(5-(4-((6-azaspiro[2.5]octan-6-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127); 3-(5-(4-((3-isopropoxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130); 3-(1-oxo-5-(4-((4-tosylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (132); 3-(1-oxo-5-(4-(((S)-2-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (133); 3-(1-oxo-5-(4-(((R)-2-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (134); 3-(1-oxo-5-(4-(((S)-3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (135); 3-(1-oxo-5-(4-(((R)-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (138); 3-(1-oxo-5-(4-(((S)-3-phenylpyrrolidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (139); 3-(1-oxo-5-(4-((4-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (141); 3-(1-oxo-5-(4-((3-phenylpiperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (143); 3-(5-{4-[(azetidin-1-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (165); 3-(5-{4-[(morpholin-4-yl)methyl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (166); 4-({2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]pyridin-4-yl}methyl)-1λ6-thiomorpholine-1,1-dione (167); 3-(5-(5-chloro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (186); 3-(5-(5-chloro-4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (187); 3-(5-(5-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (188); 3-(5-(5-fluoro-4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (189); 3-(5-(5-fluoro-4-((3-(pyridin-3-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (190); 3-(5-(3-fluoro-4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (191); 3-(5-(3-fluoro-4-((3-(pyridin-3-yl)azetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (192); 3-(5-(3-fluoro-4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (193); 3-(1-oxo-5-(4-((3-(pyridin-4-yl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (195); 3-(5-(4-((3-methoxy-3-methylazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (196); 3-(5-(4-((3-methoxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (197); 3-(5-(4-((3-ethoxyazetidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (198); 3-(1-oxo-5-(4-((4-(p-tolyl)piperidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (199); 3-(5-(4-(((S)-2-benzylaziridin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200); 3-(5-(4-((2-methylaziridin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (201); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)-N,N-dimethylazetidine-3-carboxamide (202); 3-(1-oxo-5-(4-((3-(pyridin-3-yl)azetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (203); 3-(1-oxo-5-(4-((2-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (204-205); 1-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyridin-4-yl)methyl)azetidine-2-carboxamide (206); 3-(5-(4-((4-methoxy-3,3-dimethylpiperidin-1-yl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (207); or 3-(4-Fluoro-1-oxo-5-(4-((3-phenylazetidin-1-yl)methyl)pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione (208) 2. The compound according to claim 1, which is selected from the group consisting of:

6. 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

7. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer.

8. 8. The pharmaceutical composition of claim 7, 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.

9. 6. An agent for decreasing Helios protein levels, Helios activity levels, or Helios expression levels in a cell, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof.

10. The method of claim 9, wherein the Helios protein is an amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, or 5.

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