GSPT1 degrading agents, compositions containing the degrading agents, and methods of using the same

Abstract

Provided are compounds of formula (I), tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing, compositions comprising compounds of formula (I), tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, and methods of using same in treating diseases, disorders, or conditions mediated by, for example, degradation of G1 to S phase transition protein 1 (GSPT1). JPEG2025533108000091.jpg32170

Description

[Technical Field]

[0001] This disclosure provides compounds of Formula I, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing, compositions comprising compounds of Formula I, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, and methods of using same in treating diseases, disorders, or conditions mediated by, for example, degradation of G1 to S phase transition 1 (GSPT1) protein. [Background technology]

[0002] Abnormal protein function and misregulation of protein synthesis contribute to uncontrolled cell growth, proliferation, and migration, which can lead to cancer. Translation termination is a GTP-dependent process regulated by two key proteins, the eukaryotic release factors eRF1 and eRF3. Translation termination factor eRF3, also known as GSPT1 (G1 to S phase transition 1) protein, is a GTPase that interacts with eRF1 to promote stop codon recognition and release of the nascent peptide from the ribosome (Chauvin et al., Involvement of Human Release Factors eRF3a and eRF3b in Translation Termination and Regulation of the Termination Complex Formation, Mol Cell Biol., 2005, 25(14): 5801-5811). The GSPT1 protein activates eRF1 in a GTP-dependent manner, and its GTPase activity requires its complex with eRF1 and the ribosome to form a functional translation termination complex (Zhouravleva et al., "Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3," EMBO J., 1995, 14, pp. 4065-4072; Frolova et al., "Eukaryotic polypeptide chain release factor eRF3 is an eRF1- and ribosome-dependent guanosine triphosphatase," RNA, 1996, 2, pp. 334-341). Its role in translation termination in response to stop codons has also been discussed (Hoshino et al., "A human homologue of the yeast GST1 gene codes for a GTP-binding protein and is expressed in a proliferation-dependent manner in mammalian cells," EMBO J.In addition to these functions, GSPT1 protein is involved in cell cycle regulation, cytoskeletal organization, and apoptosis. Therefore, reduced levels of GSPT1 may impair the control of cell proliferation and facilitate cell migration and scar formation. Indeed, increased expression of GSPT1 protein has been reported in human malignancies, including acute myeloid leukemia, multiple myeloma, breast cancer, hepatocellular carcinoma, prostate cancer, lung cancer, and gastric cancer (Brito et al., Polyglycine expansions in eRF3 / GSPT1 are associated with gastric cancer susceptibility, Carcinogenesis, 2005, 26, pp. 2046-2049; Wright and Lange, Newer Potential Biomarkers in Prostate Cancer, Rev. Urol, 2007, 9(4), pp. 207-213; Malta-Vacas et al., eRF3a / GSPT1 12-GGC allele increases the susceptibility for breast cancer development, Oncol. Rep., 2009, 21(6):1551-1558; Miri et al., GGCn polymorphism of eRF3a / GSPT1 gene and breast cancer susceptibility, Med. Oncol., 2012, 29(3): pp. 1581 - 1585; Hashimoto et al., Translation termination factor eRF3 is targeted for caspase-mediated proteolytic cleavage and degradation during DNA damage-induced apoptosis, Apoptosis, 2012, 17(12): pp. 1287 - 1299; Tian, The role of miR-144 / GSPT1 axis in gastric cancer, Eur. Rev. Med. Pharmacol. Sci., 2018, 22(13): pp. 4138 - 4145; Sun et al., LncRNA DLX6-AS1 promotes the proliferation, invasion, and migration of non-small cell lung cancer cells by targeting the miR-27b-3p / GSPT1 axis, Onco. Targets Ther., 2019; 12: pp. 3945 - 3954; Zhang et al., Downregulation of microRNA-27b-3p via aberrant DNA methylation contributes to malignant behavior of gastric cancer cells by targeting GSPT1, Biomed Pharmacother., 2019, 119:109417; Powell et al., Selective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library, ACS Chem. Biol., 2020, 15(10): pp. 2722 - 2730; Nishiguchi et al., Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1 / 2 Degraders from a Focused Library of Cereblon Modulators, J.Med. Chem., 2021, 64(11):7296-7311; Surka et al., CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells, Blood, 2021,137(5):661-677). Thus, the GSPT1 protein has been identified as an oncogenic driver and a novel cancer target that can impair active translation, which contributes to the malignant phenotype of cancer cells. One mechanism for disrupting disease protein drivers is to reduce the cellular concentration of these proteins through proteolysis. Cereblon is a protein that forms an E3 ubiquitin ligase complex that ubiquitinates various other proteins for further degradation.

[0003] Although different GSPT1 degraders have been tested in clinical trials and preclinically, dose-limiting toxicities and limited efficacy have been observed. Novel GSPT1 degraders have the potential to improve clinical outcomes. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO 2013 / 075083 [Patent Document 2] WO 2013 / 075084 [Patent Document 3] WO 2013 / 078320 [Patent Document 4] WO 2013 / 120104 [Patent Document 5] WO 2014 / 124418 [Patent Document 6] WO 2014 / 151142 [Patent Document 7] WO 2015 / 023915 [Patent Document 8] U.S. Patent No. 4,938,949 [Patent Document 9] WO2021126974A1 [Patent Document 10] WO2021126973A1 [Non-patent literature]

[0005] [Non-Patent Document 1] Chauvin et al., Involvement of human Release Factors eRF3a and eRF3b in Translation Termination and Regulation of the termination complex formation, Mol Cell Biol., 2005, 25(14): pp. 5801-5811. [Non-patent document 2] Zhouravleva et al., Termination of translation in eukaryotes is governed by two interacting polypeptide chain Release Factors, eRF1 and eRF3, EMBO J., 1995, 14, pp. 4065-4072. [Non-patent document 3] Frolova et al., Eukaryotic polypeptide chain release factor eRF3 is an eRF1- and ribosome-dependent guanosine triphosphatase, RNA, 1996, 2, pp. 334-341 [Non-patent document 4] Hoshino et al., A human homologue of the yeast GST1 gene codes for a GTP-binding protein and is expressed in a proliferation-dependent manner in mammalian cells, EMBO J., 1989, 8, pp. 3807-3814. [Non-Patent Document 5] Aliouat et al., Divergent effects of Translation Termination factor eRF3A and nonsense-mediated mRNA decay factor UPF1 on the expression of uORF carrying mRNAs and ribosome protein genes, RNA Biol., 2020, 17(2):227-239 [Non-patent document 6] Brito et al., Polyglycine expansions in eRF3 / GSPT1 are associated with gastric cancer susceptibility, Carcinogenesis, 2005, 26, pp. 2046-2049 [Non-Patent Document 7] Wright and Lange, Newer Potential Biomarkers in Prostate Cancer, Rev. Urol, 2007, 9(4), pp. 207-213 [Non-patent document 8] Malta-Vacas et al., eRF3a / GSPT1 12-GGC allele increases the susceptibility for breast cancer development, Oncol. Rep., 2009, 21(6):1551-1558 [Non-Patent Document 9] Miri et al., GGCn polymorphism of eRF3a / GSPT1 gene and breast cancer susceptibility, Med. Oncol., 2012, 29(3):1581-1585 [Non-Patent Document 10] Hashimoto et al., Translation Termination factor eRF3 is targeted for caspase-mediated proteolytic cleavage and degradation during DNA damage-induced apoptosis, Apoptosis, 2012, 17(12):1287-1299 [Non-Patent Document 11] Tian, ​​The role of miR-144 / GSPT1 axis in gastric cancer, Eur. Rev. Med. Pharmacol. Sci., 2018, 22(13):4138-4145. [Non-Patent Document 12] Sun et al., LncRNA DLX6-AS1 promotes the proliferation, invasion, and migration of non-small cell lung cancer cells by targeting the miR-27b-3p / GSPT1 axis, Onco. targets Ther., 2019; 12: 3945-3954 [Non-Patent Document 13] Zhang et al., Downregulation of microRNA-27b-3p via aberrant DNA methylation contributes to malignant behavior of gastric cancer cells by targeting GSPT1, Biomed Pharmacother., 2019, 119:109417 [Non-Patent Document 14] Powell et al., Selective Degradation of GSPT1 by cereblon Modulators Identified via a Focused Combinatorial Library, ACS Chem. Biol., 2020, 15(10):2722~2730 [Non-Patent Document 15] Nishiguchi et al., Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1 / 2 Degraders from a Focused Library of cereblon Modulators, J. Med. Chem., 2021, 64(11):7296~7311 [Non-Patent Document 16] Surka et al., CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells, Blood, 2021, 137(5): pp. 661-677 [Non-Patent Document 17] Testa, Bernard and Mayer, Joachim M., Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology, Wiley-VHCA, Zurich, Switzerland 2003 [Non-Patent Document 18] SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19. [Non-Patent Document 19] Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding [Non-Patent Document 20] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia [Non-Patent Document 21] Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick [Non-Patent Document 22] J.C. Boylan, 1988–1999, Marcel Dekker, New York Summary of the Invention

[0006] One aspect of the present disclosure provides a compound selected from the compounds of formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be used in the treatment of diseases mediated by degradation of the GSPT1 protein. For example, a compound selected from the compounds of formula I below:

[0007] [ka]

[0008] a compound of the formula: (i) each R' is independently selected from hydrogen, halogen, straight-chain, branched, and cyclic alkyl groups; (ii) m and n are independently selected from 0, 1, and 2; (iii) X and Z are independently selected from: zero or a linear, branched, or cyclic alkylene group; a linear, branched, or cyclic heteroalkylene group; and a linear, branched, or cyclic alkyl group; (iv) Y and W are independently absent, —O—, —C(O)—, or —C(O)R x -, -C(S)-, -C(S)R x -, -[C(R x R y )] p -, -S-, -S(O)2-, -S(O)2R x -, NR x - and -NR x C(O)-; further wherein p is selected from 1, 2, 3, 4, 5, and 6; R x is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v) Ring A is

[0009] [ka]

[0010] (In the formula, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; each R 1 and each R 2 is hydrogen, halogen, OR z and linear, branched, and cyclic alkyl groups; z is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. Selected from; (vi) Ring B is absent or selected from optionally substituted cycloalkyl and heterocycloalkyl groups; (vii) Ring C is absent or selected from optionally substituted aryl and heteroaryl groups; (viii) Ring D is absent or selected from optionally substituted cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -C(O)N(C1-C6)2 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -S(O)2C1-C6 linear, branched and cyclic alkyl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups] is disclosed herein.

[0011] In one aspect of the disclosure, the compound of formula I is selected from compounds 1 to 24 shown below, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing.

[0012] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can comprise a compound selected from Compounds 1 to 24 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing. These compositions can further comprise an additional active pharmaceutical agent.

[0013] Another aspect of the present disclosure provides methods for treating a disease, disorder, or condition mediated by degradation of GSPT1 protein in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to a subject a therapeutically effective amount of a compound selected from compounds 1 to 24 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to a subject a therapeutically effective amount of a compound selected from compounds A to F shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0014] In some embodiments disclosed herein, methods of treatment include administering to a subject in need thereof an additional active pharmaceutical agent, either in the same pharmaceutical composition as a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments disclosed herein, methods of treatment include administering a compound selected from compounds 1 to 24 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, together with the additional active pharmaceutical agent, either in the same composition or in a separate composition. In some embodiments disclosed herein, methods of treatment include administering a compound selected from compounds A to F shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, together with the additional active pharmaceutical agent, either in the same composition or in a separate composition.

[0015] Also disclosed herein are methods for reducing GSPT1 protein activity, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the method for degrading GSPT1 protein comprises administering to a subject a compound selected from compounds 1 to 24 shown below, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, the method for degrading GSPT1 protein comprises administering to a subject a compound selected from compounds A to F shown below, a deuterated derivative of a tautomer thereof, a compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0016] The foregoing summary, as well as the following detailed description of the present disclosure, will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present disclosure, the accompanying drawings show some, but not all, alternative embodiments. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown. These drawings, which are incorporated in and constitute a part of this specification, serve to explain the principles of the present disclosure. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows a Western blot of GSPT1 degradation in HL-60 cells by compound A of the present disclosure. [Figure 2] FIG. 1 shows a Western blot of GSPT1 degradation in HL-60 cells by compounds A and 8 of the present disclosure. [Figure 3] FIG. 1 shows a Western blot of GSPT1 degradation in HL-60 cells by compound 28 of the present disclosure. [Figure 4] FIG. 1 shows a Western blot of GSPT1 degradation in HL-60 cells by compound F of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0018] I. Definition The terms "a" or "an" when used herein to refer to a noun include "at least one," and thus include both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means a single or two or more additional pharmaceutical agents.

[0019] The terms "GSPT1" or "GSPT1 protein," as used interchangeably herein, are also known as translation termination factor eRF3. G1 to S phase transition 1 (GSPT1) protein is a GTPase that interacts with eRF1 to facilitate stop codon recognition and release of the nascent peptide from the ribosome. It is involved in cell cycle regulation, cytoskeletal organization, and apoptosis.

[0020] The term "degrading agent," as used herein, refers to a molecular agent that binds to a protein kinase, such as hematopoietic precursor kinase 1, and subsequently reduces the steady-state protein levels of the kinase. In some embodiments, a degrading agent as disclosed herein reduces steady-state protein kinase levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, a degrading agent as disclosed herein reduces steady-state protein kinase levels by at least 65%. In some embodiments, a degrading agent as disclosed herein reduces steady-state protein kinase levels by at least 85%.

[0021] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variations among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown will also contain lesser amounts of isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on numerous factors, including, for example, the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as explained above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0022] As used herein, the term "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with a specified substituent group. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified groups, the substituents may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0023] The term "isotopically enriched" refers to species whose chemical structures differ only in their isotopic composition. Additionally, unless otherwise stated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms as well. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon by C, are within the scope of this disclosure.

[0024] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0025] The term "tautomer," as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the movement of an atom, e.g., a hydrogen atom or group, within the molecule.

[0026] "Stereoisomers," as used herein, refers to enantiomers and diastereomers.

[0027] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, except that one or more hydrogen atoms have been replaced with a deuterium atom ("D" or " 2"H" refers to a compound in which at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. It is recognized that some variation in natural isotopic abundance will occur in synthetic compounds depending on the origin of the chemical materials used in their synthesis. The concentration of naturally abundant stable hydrogen isotopes, despite this variation, is small and insignificant when compared to the degree of stable isotopic substitution of the deuterated derivatives disclosed herein. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium designation), at least 4500 (67.5% deuterium incorporation at each deuterium designation), at least 5000 (75% deuterium incorporation at each deuterium designation), at least 5500 (82.5% deuterium incorporation at each deuterium designation), at least 6000 (90% deuterium incorporation at each deuterium designation), at least 6333.3 (95% deuterium incorporation at each deuterium designation), at least 6466.7 (97% deuterium incorporation at each deuterium designation), or at least 6600 (99% deuterium incorporation at each deuterium designation).

[0028] The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0029] The term "alkyl," as used herein, means a straight-chain or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, alkyl groups contain 1 to 30 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 6 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms. In other embodiments, alkyl groups contain 1 to 3 alkyl carbon atoms. And in still other embodiments, alkyl groups contain 1 to 2 alkyl carbon atoms. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are straight-chain or unbranched. In some embodiments, alkyl groups are branched.

[0030] The term "cycloalkyl" refers to a fully saturated, monocyclic C 3~8 hydrocarbon or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 "cycloalkyl" refers to a hydrocarbon, wherein any individual ring in the bicyclic ring system has 3 to 7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is a C3 to C6 alkyl group. 12 In some embodiments, the cycloalkyl is a C3 to C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] The term "carbocyclyl" encompasses the term "cycloalkyl" and refers to monocyclic C alkyl groups that are fully saturated or that contain one or more units of unsaturation but are not aromatic and are therefore partially saturated. 3~8 hydrocarbon or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 "Carbocyclyl" refers to a hydrocarbon, wherein any individual ring in the bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyl includes, for example, a combination of a monocyclic carbocyclic ring fused to a phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is a C3 to C6 12 In some embodiments, the carbocyclyl is a carbocyclyl of the formula C3 to C 10 In some embodiments, the carbocyclyl is a C3 to C8 carbocyclyl. Non-limiting examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like.

[0032] The term "alkylene," as used herein, refers to a divalent alkyl group. 1~10 Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene.

[0033] The term "alkenyl," as used herein, refers to a straight or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is straight-chained, linear, or unbranched. In some embodiments, an alkenyl group is branched.

[0034] The term "alkynyl" as used herein includes, but is not limited to, C 2~8 Alkynyl refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2 to 8 carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0035] The term "heterocyclyl," as used herein, means a non-aromatic (i.e., fully saturated, or partially saturated because it contains one or more units of unsaturation but is not aromatic), monocyclic, or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system, where one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to a phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl. In some embodiments, a "heterocyclyl" group contains 3 to 14 ring members, wherein one or more ring members are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, a heterocyclic ring has at least one unsaturated carbon-carbon bond. In some embodiments, a heterocyclic ring has at least one unsaturated carbon-nitrogen bond. In some embodiments, a heterocyclic ring has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, a heterocyclic ring has one heteroatom that is a nitrogen atom. In some embodiments, a heterocyclic ring has one heteroatom that is an oxygen atom. In some embodiments, a heterocyclic ring has two heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclic ring has three heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclic ring is substituted. In some embodiments, a heterocyclic ring is unsubstituted. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl.In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, and the like.

[0036] The term "heteroatom" refers to any oxidized form of nitrogen or sulfur, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + It refers to one or more of oxygen, sulfur, and nitrogen, including (as in N-substituted pyrrolidinyl).

[0037] The term "unsaturated," as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are filled by substituents, and thus the compound contains double or triple bonds.

[0038] The term "alkoxy," as used herein, refers to an alkyl group, as defined above, where one carbon of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is linked between two carbon atoms.

[0039] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0040] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0041] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system with a delocalized pi orbital composed of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring and may be either fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, further defined as follows.

[0042] The term "aryl," used alone or as part of a larger moiety, as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic, or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, where every ring in the system is an aromatic ring containing only carbon atoms, and where each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) rings and naphthyl (C 10 ) ring. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0043] The term "heteroaryl" refers to a monocyclic, spirocyclic, fused, or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Bicyclic heteroaryls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to phenyl. In some embodiments, heteroaryl groups are substituted. In some embodiments, heteroaryl groups have one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl groups have one heteroatom. In some embodiments, heteroaryl groups have two heteroatoms. In some embodiments, heteroaryl groups are monocyclic ring systems having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0044] "Spirocyclic ring system" refers to a ring system having two or more cyclic rings, wherein any two rings share only one common atom.

[0045] The term "prodrug group" refers to a group that is covalently attached to a compound and results in a compound with improved oral bioavailability and / or tumor targeting, and / or is more active in vivo. Certain compounds of Formula I may contain a prodrug group as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (see Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be more convenient to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug group is, without limitation, a moiety in a compound, such as an ester, which is subsequently metabolically hydrolyzed to the carboxylic acid to release the active entity. Additional examples of prodrug groups include peptidyl derivatives of a compound.

[0046] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0047] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0048] Pharmaceutically acceptable salts of the disclosed compounds are disclosed herein. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0049] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0050] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts include, therefore, sulfate, pyrosulfate, bisulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-diol ... Included are oate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0051] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4(Alkyl) quaternary salts are also included. The present disclosure further contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0052] The term "subject" refers to an animal, including, but not limited to, a human.

[0053] The term "therapeutically effective amount" refers to the amount of a compound for which it is administered that produces the desired effect (e.g., an improvement in the symptoms of diseases, disorders, and conditions mediated by the degradation of GSPT1, reducing the severity of diseases, disorders, and conditions or their symptoms, and / or reducing the progression of diseases, disorders, and conditions mediated by the degradation of GSPT1 or their symptoms). The exact amount of a therapeutically effective amount will depend on the purpose of the treatment, and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0054] As used herein, the term "treatment" and its cognates refer to slowing or stopping disease progression. "Treatment" and its cognates as used herein include, but are not limited to: complete or partial remission, lower risk of diseases, disorders, and conditions mediated by GSPT1 degradation, and disease-related complications. Improvement in or reduction in the severity of any of these symptoms can be readily determined according to methods and techniques known or subsequently developed in the art.

[0055] The term "cancer" includes, but is not limited to, cancers of the epidermoid oral cavity, e.g., buccal cavity, lip, tongue, mouth, pharynx; cardiac cancers, e.g., sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers, e.g., bronchogenic lung carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis hamartoma, mesothelioma; gastrointestinal cancers, e.g., esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small bowel or small intestine intestines (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine Genitourinary cancers, including intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, e.g., hepatocellular carcinoma, bile duct adenocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone cancer, e.g., osteogenic sarcoma (bone Cancers of the nervous system, including sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers, including those of the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), and breast; blood cancers, such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders Lymphatic system disorders; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; thyroid cancers, e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, and paraganglioma; and adrenal gland cancers, such as neuroblastoma.

[0056] The compounds and compositions of the present application can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, such as conventional chemotherapeutic agents or any other anti-proliferative, anti-cancer, and / or non-drug therapies. For example, additive or synergistic effects may occur with anti-proliferative or anti-cancer agents. When the compounds of the present application are administered in conjunction with other therapies, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the specific drug used, the condition being treated, and so forth. Combination therapy includes administration of the subject compounds in further combination with one or more other biologically active components (e.g., but not limited to, conventional chemotherapeutic agents, kinase inhibitors, second and different anti-neoplastic agents), and non-drug therapies (e.g., but not limited to, surgery or radiation treatment). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. The compounds of the present application can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug therapies or treatment modalities. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or course of treatment.

[0057] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include the specified dose, amount, or weight percent value, or a range of doses, amounts, or weight percent that would be recognized by one of skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent.

[0058] II. Compounds and Compositions In a first embodiment, the compounds of the present disclosure have the following structural formula I:

[0059] [ka]

[0060] a compound of the formula: (i) each R' is independently selected from hydrogen, halogen, straight-chain, branched, and cyclic alkyl groups; (ii) m and n are independently selected from 0, 1, and 2; (iii) X and Z are independently selected from: zero or a linear, branched, or cyclic alkylene group; a linear, branched, or cyclic heteroalkylene group; and a linear, branched, or cyclic alkyl group; (iv) Y and W are independently absent, —O—, —C(O)—, or —C(O)R x -, -C(S)-, -C(S)R x -, -[C(R x R y )] p -, -S-, -S(O)2-, -S(O)2R x -, NR x - and -NR x C(O)-; further wherein p is selected from 1, 2, 3, 4, 5, and 6; R x is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (v) Ring A is

[0061] [ka]

[0062] (In the formula, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; each R 1 and each R 2 is hydrogen, halogen, OR z and linear, branched, and cyclic alkyl; further wherein R z is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. Selected from; (vi) Ring B is absent or selected from optionally substituted cycloalkyl and heterocycloalkyl groups; (vii) Ring C is absent or selected from optionally substituted aryl and heteroaryl groups; (viii) Ring D is absent or selected from optionally substituted cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -C(O)N(C1-C6)2 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -S(O)2C1-C6 linear, branched and cyclic alkyl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups] is.

[0063] In a second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is absent; all other variables not specifically defined herein are as defined in the first embodiment.

[0064] In a third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a linear alkylene group; all other variables not specifically defined herein are as defined in the first embodiment.

[0065] In a fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a methylene group; all other variables not specifically defined herein are as defined in the first embodiment.

[0066] In a fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is an ethylene group; all other variables not specifically defined herein are as defined in the first embodiment.

[0067] In a sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is absent; all other variables not specifically defined herein are as defined in the first embodiment.

[0068] In a seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is a linear alkylene group; all other variables not specifically defined herein are as defined in the first embodiment.

[0069] In an eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is a methylene group; all other variables not specifically defined herein are as defined in the first embodiment.

[0070] In a ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is an ethylene group; all other variables not specifically defined herein are as defined in the first embodiment.

[0071] In a tenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring B is selected from heterocycloalkyl groups; all other variables not specifically defined herein are as defined in the first embodiment.

[0072] In an eleventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is

[0073] [ka]

[0074] all other variables not specifically defined herein are as defined in the first embodiment.

[0075] In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is an optionally substituted aryl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0076] In a thirteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl; all other variables not specifically defined herein are as defined in the first embodiment.

[0077] In a fourteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with a halo group; all other variables not specifically defined herein are as defined in the first embodiment.

[0078] In a fifteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with fluorine; all other variables not specifically defined herein are as defined in the first embodiment.

[0079] In a sixteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with chlorine; all other variables not specifically defined herein are as defined in the first embodiment.

[0080] In a seventeenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with bromine; all other variables not specifically defined herein are as defined in the first embodiment.

[0081] In an eighteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with an alkyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0082] In a nineteenth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with a cycloalkyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0083] In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is phenyl substituted with a cyclopropyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0084] In a twenty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is an optionally substituted heteroaryl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0085] In a twenty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is pyridinyl; all other variables not specifically defined herein are as defined in the first embodiment.

[0086] In a twenty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is pyridinyl substituted with a halo group; all other variables not specifically defined herein are as defined in the first embodiment.

[0087] In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is pyridinyl substituted with fluorine; all other variables not specifically defined herein are as defined in the first embodiment.

[0088] In a twenty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is pyridinyl substituted with chlorine; all other variables not specifically defined herein are as defined in the first embodiment.

[0089] In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is pyridinyl substituted with bromine; all other variables not specifically defined herein are as defined in the first embodiment.

[0090] In a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring C is quinolyl.

[0091] In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is an optionally substituted heteroaryl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0092] In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is pyridinyl; all other variables not specifically defined herein are as defined in the first embodiment.

[0093] In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is pyridinyl substituted with a halo group; all other variables not specifically defined herein are as defined in the first embodiment.

[0094] In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is pyridinyl substituted with fluorine; all other variables not specifically defined herein are as defined in the first embodiment.

[0095] In a thirty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is pyridinyl substituted with chlorine; all other variables not specifically defined herein are as defined in the first embodiment.

[0096] In a thirty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is pyridinyl substituted with bromine; all other variables not specifically defined herein are as defined in the first embodiment.

[0097] In a thirty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is thiazolyl; all other variables not specifically defined herein are as defined in the first embodiment.

[0098] In a thirty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is thiazolyl substituted with an alkyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0099] In a thirty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring D is thiazolyl substituted with methyl; all other variables not specifically defined herein are as defined in the first embodiment.

[0100] In a thirty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, if Ring C and Ring D are absent, then X is a straight chain alkyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0101] In a thirty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a methyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0102] In a thirty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, if ring C and ring D are absent, then X is a branched alkyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0103] In a fortieth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a tert-butyl group.

[0104] In a forty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, if Ring C and Ring D are absent, then X is a cyclic alkyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0105] In a forty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, X is a cyclohexyl group; all other variables not specifically defined herein are as defined in the first embodiment.

[0106] In a forty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 1 and n is 1; all other variables not specifically defined herein are as defined in the first embodiment.

[0107] In a forty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, each R' is hydrogen; all other variables not specifically defined herein are as defined in the first embodiment.

[0108] In a forty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 2 and n is 1; all other variables not specifically defined herein are as defined in the first embodiment.

[0109] In a forty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, each R' is hydrogen; all other variables not specifically defined herein are as defined in the first embodiment.

[0110] In a forty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is

[0111] [ka]

[0112] and all other variables not specifically defined herein are as defined in the first embodiment.

[0113] In a forty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; all other variables not specifically defined herein are as defined in the first embodiment.

[0114] In a forty-ninth embodiment, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is

[0115] [ka]

[0116] and all other variables not specifically defined herein are as defined in the first embodiment.

[0117] In a 50th embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; all other variables not specifically defined herein are as defined in the first embodiment.

[0118] In a fifty-first embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is

[0119] [ka]

[0120] and all other variables not specifically defined herein are as defined in the first embodiment.

[0121] In a fifty-second embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; all other variables not specifically defined herein are as defined in the first embodiment.

[0122] In a fifty-third embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is

[0123] [ka]

[0124] and all other variables not specifically defined herein are as defined in the first embodiment.

[0125] In a fifty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; all other variables not specifically defined herein are as defined in the first embodiment.

[0126] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 35 shown in Table 1 below, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0127] [Table 1A]

[0128] [Table 1B]

[0129] [Table 1C]

[0130] [Table 1D]

[0131] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of Formula I, compounds 1 to 18, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0132] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant, hi some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0133] It will also be recognized that the pharmaceutical compositions of the present disclosure can be used in combination therapy; i.e., the pharmaceutical compositions disclosed herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from a compound of Formula I, compounds 1 to 18, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing, can be administered as a separate composition simultaneously with, before, or after a composition comprising an additional active pharmaceutical agent.

[0134] As discussed above, the pharmaceutical compositions disclosed herein include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be selected from adjuvants and vehicles. As used herein, pharmaceutically acceptable carriers can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants that are appropriate for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphate, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxylates, cellulose derivative ... sodium dimethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, perfumes, preservatives, and antioxidants.

[0135] III. Methods of Treatment and Use In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof as disclosed herein, including compounds of Formula I, compounds 1 to 35, tautomers, deuterated derivatives of the compounds or tautomers thereof, compounds A to F, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating a disease, disorder, or condition mediated by degradation of the GSPT1 protein. In another aspect, disclosed herein is the use of the compounds, tautomers, deuterated derivatives of the compounds or tautomers thereof as disclosed herein, including compounds of Formula I, compounds 1 to 24, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, compounds A to F, or pharmaceutical compositions thereof, for the manufacture of a medicament for treating a disease, disorder, or condition mediated by degradation of the GSPT1 protein. In yet another aspect, disclosed herein is a method of treating a disease, disorder, or condition mediated by degradation of GSPT1 protein in a subject, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt as disclosed herein, including a compound of Formula I, compounds 1 to 35, tautomers thereof, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, compounds A to F, or a pharmaceutical composition thereof.

[0136] In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is selected from brain cancer, breast cancer, gastric cancer, renal cancer, prostate cancer, testicular cancer, colorectal cancer, lung cancer, bladder cancer, urothelial cancer, cervical cancer, head and neck cancer, esophagogastric cancer, osteosarcoma, cervical cancer, endometrial cancer, ovarian cancer, squamous cell carcinoma, peritoneal cancer, neuroendocrine cancer, hepatocellular carcinoma, pancreatic cancer, genitourinary cancer, laryngeal cancer, skin cancer, nervous system cancer, thyroid cancer, and rhabdomyosarcoma. In some embodiments, the cancer is a hematological cancer. In some embodiments, the hematological cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0137] In some embodiments, the cancer is epidermoid oral cavity, e.g., buccal cavity, lip, tongue, mouth, or pharynx cancer; cardiac cancer, e.g., sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, e.g., bronchogenic lung carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis hamartoma, mesothelioma; gastrointestinal cancer, e.g., esophageal (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small bowel or small intestine cancer. intestines (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine Genitourinary cancers, including intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, rectum; kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, e.g., hepatocellular carcinoma, bile duct adenocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone cancer, e.g., osteogenic sarcoma (bone Cancers of the nervous system, including sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor / chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers, including those of the uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), and breast; blood cancers, such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, and polyposis lymphatic system disorders; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; cancers of the thyroid gland, e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, and paraganglioma; and cancers of the adrenal gland, such as neuroblastoma.

[0138] In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts of the foregoing, compounds as disclosed herein, including compounds A to F, of Formula I, compounds 1 to 24, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in decreasing GSPT1 activity. In another aspect, disclosed herein is the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts of the foregoing, compounds as disclosed herein, including compounds A to F, of Formula I, compounds 1 to 24, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, for the manufacture of a medicament for decreasing protein kinase activity. In yet another aspect, disclosed herein is a method of decreasing GSPT1 activity comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt as disclosed herein, including a compound of Formula I, compounds 1 to 35, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, compounds A to F, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of decreasing GSPT1 activity comprising contacting said protein kinase with a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt as disclosed herein, including a compound of Formula I, compounds 1 to 24, tautomers, deuterated derivatives of the compounds or tautomers thereof, and / or pharmaceutically acceptable salts of the foregoing, compounds A to F, or a pharmaceutical composition thereof.

[0139] The compounds of Formula I, Compounds 1 to 35, tautomers thereof, deuterated derivatives of the compounds or tautomers, Compounds A to F, and / or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered once daily, twice daily, or three times daily, for example, for the treatment of diseases, disorders, or conditions mediated by the degradation of GSPT1.

[0140] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, Compounds 1 to 35, a tautomer thereof, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of any of the foregoing, Compounds A to F, or a pharmaceutical composition thereof is administered once daily, twice daily, or three times daily.

[0141] The compounds of Formula I, Compounds 1 to 35, their tautomers, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, Compounds A to F, or pharmaceutical compositions thereof, can be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, intravaginally, transdermally, by patch, pump administration, or via an implanted reservoir, where the pharmaceutical composition is appropriately formulated. Parenteral administration includes, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can, for example, be by continuous infusion over a selected period of time. Other modes of administration contemplated in the present disclosure are as described in International Patent Application Nos. WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0142] The useful dosage or therapeutically effective amount of the compounds disclosed herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models.Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0143] Those skilled in the art will recognize that when a compound amount is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. The amounts of compounds, tautomers, pharmaceutically acceptable salts, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the compound of Formula I and its pharmaceutically acceptable salts" includes 1000 mg of the compound of Formula I and a concentration of the pharmaceutically acceptable salt of the compound of Formula I equivalent to 1000 mg of the compound of Formula I.

[0144] In another aspect of the present disclosure, the compounds and compositions disclosed herein can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, such as antiproliferative agents, anticancer agents, immunomodulatory agents, or anti-inflammatory agents, and / or non-drug therapies. For example, synergistic effects may occur with antiproliferative, anticancer, immunomodulatory, or anti-inflammatory agents. When the compounds disclosed herein are administered in conjunction with other therapies, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the specific drug used, the condition being treated, and so forth. Combination therapy includes administration of the subject compounds in further combination with one or more other biologically active components (e.g., a second kinase inhibitor, a second and different anti-neoplastic agent), and non-drug therapies (e.g., surgery or radiation treatment). For example, the compounds disclosed herein can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds disclosed herein. The compounds disclosed herein can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug treatments or treatment modalities.Combined treatment generally refers to the administration of two or more drugs in a single cycle or course of treatment.In another aspect of the present disclosure, the compounds can be administered in combination with one or more separate pharmaceutical agents, such as chemotherapeutic agents, immunotherapeutic agents, or adjunctive therapeutic agents. In some embodiments, the separate pharmaceutical agents are an anti-PD1 antibody (e.g., pembrolizumab), an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL-2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idelalisib), a PKCβ inhibitor (e.g., enzastaurin), a SYK inhibitor (e.g., fostamatinib), a JAK2 inhibitor (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), an Aurora kinase inhibitor (e.g., alisertib), an EZF12 inhibitor (e.g., tazemetostat, GSK126,CPI-1205, 3-deazaneplanocin A, EPZ005687, Ell, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOTlL inhibitors (e.g., pinometostat), FIAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMTl inhibitors (e.g., GS K3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420FU / F12 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JF1295), MEK inhibitors (e.g., trametinib, binimetinib, cobimetinib, selumetinib), PF1F19 inhibitors, PIM inhibitors (e.g., LGF1-447), IGF-IR inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), PARP inhibitors (e.g., olaparib), EGFR inhibitors (e.g., osimertinib ), HER2 / NEU inhibitors (i.e., tucatinib), SRC inhibitors (i.e., dasatinib), AKT inhibitors (i.e., ipatasertib), platinum, or chemotherapy (e.g., bendamustine, bleomycin, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, cisplatin, taxanes, or dexamethasone).

[0145] Non-limiting illustrative embodiments 1. Formula (I):

[0146] [ka]

[0147] a compound of the formula: (ix) each R' is independently selected from hydrogen, halogen, linear, branched, and cyclic alkyl groups; (x) m and n are independently selected from 0, 1, and 2; (xi) X and Z are independently selected from: zero or a linear, branched, or cyclic alkylene group; a linear, branched, or cyclic heteroalkylene group; and a linear, branched, or cyclic alkyl group; (xii) Y and W are independently absent, —O—, —C(O)—, or —C(O)R x -, -C(S)-, -C(S)R x -, -[C(R x R y )] p -, -S-, -S(O)2-, -S(O)2R x -, NR x - and -NR x C(O)-; further wherein p is selected from 1, 2, 3, 4, 5, and 6; R x is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (xiii) Ring A is

[0148] [ka]

[0149] (In the formula, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; each R 1 and each R 2 is hydrogen, halogen, OR z and linear, branched, and cyclic alkyl groups; z is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. Selected from; (xiv) Ring B is absent or selected from optionally substituted cycloalkyl groups and heterocycloalkyl groups; (xv) Ring C is absent or selected from optionally substituted aryl and heteroaryl groups; (xvi) Ring D is selected from absent or optionally substituted cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)OC1-C6 linear, branched and cyclic alkyl groups, -NHC1-C6 linear, branched and cyclic alkyl groups, -N(C1-C6 linear, branched and cyclic alkyl groups)2, -NHC(O)C1-C6 linear, branched and cyclic alkyl groups, -C(O)NHC1-C6 linear, branched and cyclic alkyl groups, -C(O)N(C1-C6)2 linear, branched and cyclic alkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -S(O)2C1-C6 linear, branched and cyclic alkyl groups, C1-C6 linear, branched and cyclic alkyl groups, C2-C6 linear, branched and cyclic alkenyl groups, C1-C6 linear, branched and cyclic hydroxyalkyl groups, C1-C6 linear, branched and cyclic aminoalkyl groups, C1-C6 linear, branched and cyclic alkoxy groups, C1-C6 linear, branched and cyclic thioalkyl groups, C1-C6 linear, branched and cyclic haloalkyl groups, C1-C6 linear, branched and cyclic haloaminoalkyl groups, C1-C6 linear, branched and cyclic halothioalkyl groups, C1-C6 linear, branched and cyclic haloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups]. 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein X is absent. 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein X is a linear alkylene group. 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 3, wherein X is a methylene group. 5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 3, wherein X is an ethylene group. 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-5, wherein Z is absent. 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-5, wherein Z is a linear alkylene group. 8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 7, wherein Z is a methylene group. 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 7, wherein Z is an ethylene group. 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-9, wherein Ring B is selected from heterocycloalkyl groups. 11. Ring B is

[0150] [ka]

[0151] 11. The compound of embodiment 10, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, selected from: 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-11, wherein Ring C is an optionally substituted aryl group. 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 12, wherein Ring C is phenyl. 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 12, wherein Ring C is phenyl substituted with a halo group. 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein Ring C is phenyl substituted with fluorine. 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein Ring C is phenyl substituted with chlorine. 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 14, wherein Ring C is phenyl substituted with bromine. 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 12, wherein Ring C is phenyl substituted with an alkyl group. 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 12, wherein Ring C is phenyl substituted with a cycloalkyl group. 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 19, wherein Ring C is phenyl substituted with a cyclopropyl group. 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-11, wherein Ring C is an optionally substituted heteroaryl group. 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 21, wherein Ring C is pyridinyl. 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 21, wherein Ring C is pyridinyl substituted with a halo group. 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 23, wherein Ring C is pyridinyl substituted with fluorine. 25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 23, wherein Ring C is pyridinyl substituted with chlorine. 26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 23, wherein Ring C is pyridinyl substituted with bromine. 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 21, wherein Ring C is quinolyl. 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-27, wherein Ring D is an optionally substituted heteroaryl group. 29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 28, wherein Ring D is pyridinyl. 30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 28, wherein Ring D is pyridinyl substituted with a halo group. 31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein Ring D is pyridinyl substituted with fluorine. 32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein Ring D is pyridinyl substituted with chlorine. 33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein Ring D is pyridinyl substituted with bromine. 34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 28, wherein Ring D is thiazolyl. 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 28, wherein Ring D is thiazolyl substituted with an alkyl group. 36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 30, wherein Ring D is thiazolyl substituted with methyl. 37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein if ring C and ring D are absent, then X is a straight chain alkyl group. 38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 37, wherein X is a methyl group. 39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein if ring C and ring D are absent, then X is a branched alkyl group. 40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 39, wherein X is a tert-butyl group. 41. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein if ring C and ring D are absent, then X is a cyclic alkyl group. 42. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 41, wherein X is a cyclohexyl group. 43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-42, wherein m is 1 and n is 1. 44. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 43, wherein each R' is hydrogen. 45. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-42, wherein m is 2 and n is 1. 46. ​​The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 45, wherein each R' is hydrogen. 47. Ring A is

[0152] [ka]

[0153] 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-46, wherein: 48. R a 48. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 47, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 49. Ring A is

[0154] [ka]

[0155] 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-46, wherein: 50. R a 50. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 49, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 51. Ring A is

[0156] [ka]

[0157] 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-46, wherein: 52. R a The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 51, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 53. Ring A is

[0158] [ka]

[0159] 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of embodiments 1-46, wherein: 54. R a 54. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 53, wherein is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups. 55.

[0160] [Table 2A]

[0161] [Table 2B]

[0162] [Table 2C]

[0163] [Table 2D]

[0164] a compound selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 56. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 53, or at least one pharmaceutically acceptable carrier. 57. A method for treating or alleviating a disease, disorder, or condition mediated by degradation of GSPT1 protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 53, or a pharmaceutical composition according to embodiment 54. 58. A method for reducing GSPT1 protein activity in a disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of embodiments 1 to 53, or a pharmaceutical composition according to embodiment 54. 59.

[0165] [Table 3]

[0166] A method for treating or alleviating a disease, disorder, or condition mediated by degradation of GSPT1 protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from: 60.

[0167] [Table 4]

[0168] A method for reducing GSPT1 protein activity in a disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from: 61. The method of any of embodiments 57-60, wherein the disease, disorder, or condition is cancer. 62. The method of embodiment 61, wherein the cancer is a solid tumor. 63. The method of embodiment 62, wherein the solid tumor is selected from brain cancer, breast cancer, gastric cancer, renal cancer, prostate cancer, testicular cancer, colorectal cancer, lung cancer, bladder cancer, urothelial cancer, cervical cancer, head and neck cancer, esophagogastric cancer, osteosarcoma, cervical cancer, endometrial cancer, ovarian cancer, squamous cell carcinoma, peritoneal cancer, neuroendocrine cancer, hepatocellular carcinoma, pancreatic cancer, genitourinary cancer, laryngeal cancer, skin cancer, nervous system cancer, thyroid cancer, and rhabdomyosarcoma. 64. The method of embodiment 61, wherein the cancer is a blood cancer. 65. The method of embodiment 64, wherein the hematological cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. 66. The method of any of embodiments 57-65, further comprising administering to the subject an existing standard of care or FDA-approved therapy. 67. The method of any of embodiments 57-65, further comprising administering to the subject at least one additional pharmaceutical agent. 68. The method of embodiment 67, wherein the at least one additional pharmaceutical agent is selected from a chemotherapeutic agent, an immunotherapeutic agent, and an adjunctive therapeutic agent. [Example]

[0169] Compound synthesis In order to provide a more complete understanding of the present disclosure, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any manner.

[0170] All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of this disclosure.

[0171] The compounds of the present disclosure can be made according to standard chemical practices or as disclosed herein. The following abbreviations are used throughout the following synthetic schemes and in the descriptions for preparing the compounds of Formula I, compounds 1 through 35, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing: Abbreviation Å = angstrom Ac = acetyl Ac2O = acetic anhydride Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMA = dimethylacetamide DME = dimethoxyethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOAc / EA = ethyl acetate EtOH = ethanol HOAc = acetic acid KOAc = potassium acetate LiHMDS = lithium bis(trimethylsilyl)amide MeMgBr = methylmagnesium bromide MeOH = methanol NaOAc = sodium acetate NBS = N-bromosuccinimide Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PTSA = p-toluenesulfonic acid monohydrate rt = room temperature (ambient temperature) T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TsCl = p-toluenesulfonyl chloride UV=ultraviolet light X-Phos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0172] General Synthetic Procedure I:

[0173] [ka]

[0174] Step 1. Preparation of G1-3: To a solution of primary amine substrate G1-1 (46.96 mmol) in MeOH (200 mL), aldehyde G1-2 (46.96 mmol), AcOH (0.5 mL), and NaCNBH3 (8.85 g, 140.88 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was purified by CombiFlash column [DCM / MeOH (10% NH3) = 0-10%] to give the product.

[0175] Step 2. Preparation of G1-4: To a solution of G1-3 (42.19 mmol) in DCM (200 mL) was added TEA (8.5 g, 84.37 mmol) and triphosgene (6.25 g, 21.09 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, HO (500 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL × 3). The combined organic layer was washed with brine (300 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product.

[0176] Step 3. Preparation of G1-5: A solution of G1-4 (0.53 mmol) in DCM / TFA (1:1, 4 mL) was stirred for 1 h at 25° C. The resulting mixture was concentrated to give the product, which was used directly in the next step.

[0177] Step 4. Preparation of G1-6: To a solution of G1-5 (0.5 mmol) in DMSO (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (131 mg, 0.5 mmol) and DIEA (184 mg, 1.42 mmol). The reaction mixture was stirred at 120 °C under N for 2 h. After the reaction was completed, HO (30 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layer was washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum. The residue was purified by prep-HPLC [Gemini-C18 150 × 21.2 mm, 5 μm; ACN-HO (0.1% TFA), 50-70] to give the desired product.

[0178] Synthesis of intermediates: Intermediate A1: 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine

[0179] [ka]

[0180] Step 1. Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one: To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 0.25 mol) in DCM (550 mL) was added AlCl (101.27 g, 0.76 mol) and acetyl chloride (21.92 g, 0.28 mol) at 0 °C under N. The reaction mixture was stirred at room temperature for 7 h under N. MeOH (300 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The reaction solution was adjusted to pH 6-7 with 3N aqueous NaOH and extracted with EA (500 mL × 3). The combined organic layer was washed with brine (300 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the crude product was purified by Combiflash (PE / EtOAc=2:1) ​​to give the product 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one as a yellow solid (43.24 g, 71%). Mass (m / z): 241.0 [M+H] + .

[0181] Step 2. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: To a solution of AlCl3 (27.8 g, 0.20 mol) in DME (200 mL) was added LiAlH4 (4.39 g, 0.1 mol) and 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (10 g, 0.04 mol) at 0 °C. The reaction mixture was stirred at room temperature under N2 for 3 h. After the reaction was completed, H2O (500 mL) was added to the reaction mixture, which was then extracted with EA (200 mL x 3). The combined organic layer was washed with brine (100 mL x 2) and then dried over anhydrous Na2SO4. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the compound product 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (11.5 g, 74%). Mass (m / z): 225.0 [M+H] + .

[0182] Step 3. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide: To a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (25 g, 0.11 mol) in EA (100 mL) was added 3-chloroperoxybenzoic acid (26.84 g, 0.155 mol). The reaction mixture was stirred at room temperature for 3 hours. The solution was washed with saturated Na2CO3 (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give the desired product as a white solid (17.4 g, yield: 64.6%). Mass (m / z): 240.7 [M+H] + .

[0183] Step 4. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: To a solution of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (17.3 g, 71.8 mmol) in NMP (15 mL) was added phosphoryl trichloride (55.05 g, 35.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (50 mL), extracted with EA (30 mL × 3), washed with saturated brine, filtered, concentrated, and the residue was purified by flash column (PE / EA = 5:1) to give the desired product as a white solid (4.1 g, yield: 22%). Mass (m / z): 258.7 [M+H] + .

[0184] Intermediate A2: 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine

[0185] [ka]

[0186] Step 1. Preparation of 5-bromo-4-chloropyridin-2-amine: To a solution of compound 4-chloropyridin-2-amine (300 g, 2.34 mol, 1.0 equivalent) in acetonitrile (3000 mL), NBS (458 g, 2.57 mol, 1.1 equivalent) was added in portions. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then poured into water and filtered. The filter cake was washed with PE and dried to obtain compound 5-bromo-4-chloropyridin-2-amine (407 g, 83.9% yield) as a yellow solid. Mass (m / z): 207 [M+H] + . 1 HNMR (400 MHz, DMSO-d6)δ8.10 (s, 1H), 6.67 (s, 1H), 6.45 (s, 2H).

[0187] Step 2. Preparation of 5-bromo-4-chloro-3-iodopyridin-2-amine: To a solution of compound 5-bromo-4-chloropyridin-2-amine (407 g, 1.97 mol, 1.0 equivalent) in AcOH (2000 mL) was added NIS (666 g, 2.96 mol, 1.5 equivalent) in portions. The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, poured into ice water (5000 mL), adjusted to pH > 7 with KCO, extracted with EA (5000 mL × 3), and washed with a solution of NaSO (5000 mL) and brine (5000 mL). The organic phase was concentrated in vacuo to give compound 5-bromo-4-chloro-3-iodopyridin-2-amine (500 g, 76.3% yield) as a yellow solid. Mass (m / z): 332.7 [M+H] + . 1 HNMR (400 MHz, DMSO-d6)δ8.10 (s, 1H), 6.62 (s, 2H).

[0188] Step 3. Preparation of 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine: To a solution of 5-bromo-4-chloro-3-iodopyridin-2-amine (100 g, 0.300 mol, 1.0 equiv.) and DABCO (101 g, 0.900 mol, 3.0 equiv.) in DMF (2000 mL) was added Pd(PPh3)2Cl2 (21.1 g, 0.03 mol, 0.1 equiv.) under N2. Then (cyclopropylethynyl)trimethylsilane (166 g, 1.20 mol, 4.0 equiv.) was added. The reaction mixture was degassed three times under N2. The reaction mixture was stirred at 120 °C for 10 h. The reaction mixture was filtered, quenched with water (2000 mL), extracted with EA (2000 mL × 3), washed with brine (2000 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel with THF / PE (1:15) to give the compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, 26.2% yield) as a yellow solid.

[0189] Mass (m / z): 344.9[M+H] + .

[0190] Step 4. Preparation of 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine: To a mixture of the compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, 79.0 mmol, 1.0 equiv.) in THF (237 mL), TBAF in THF (1.0 M, 237 mL, 3.0 equiv.) and HO (4.27 g, 237 mmol, 3.0 equiv.) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (1000 mL), extracted with EA (1000 mL x 3), washed with brine (1000 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel using THF / PE (1:4) to give the product compound 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (15 g, 70.4% yield) as a slightly yellow solid. Mass (m / z): 272.9 [M+H] + .1 HNMR (400 MHz, DMSO-d6)δ11.92 (s, 1H), 8.36 (s, 1H), 7.33 - 7.34 (d, J = 4.0 Hz, 1H), 2.11 - 2.16 (m, 1H), 0.84 - 0.86 (m, 2H), 0.62 - 0.64 (m, 2H).

[0191] Intermediate A3: 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine

[0192] [ka]

[0193] Step 1. Preparation of 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone: To a solution of 3-bromo-4-chloro-7H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mol) in DCM (10 mL) was added AlCl (863.78 mg, 6.48 mmol) and 2,2-difluoroacetyl 2,2-difluoroacetate (751.9 mg, 4.32 mol) at 0 °C. The reaction mixture was stirred at 25 °C under N for 7 h. MeOH (30 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was adjusted to pH 6-7 with 3N aqueous NaOH and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and then dried over NaSO. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by Combiflash (eluted with PE / HCO₂ = 2:1) to give the product as a yellow solid (200 mg, 11.67%). Mass (m / z): 308.7[M+H]+.

[0194] Step 2. Preparation of 3-bromo-4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridine: To a solution of AlCl (200 mg, 0.65 mmol) in DME (10 mL) was added LiAlH (64.62 mg, 1.62 mmol) and 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone (430.69 g, 3.23 mmol) at 0 °C. The reaction mixture was stirred at 25 °C under N for 3 h. After the reaction was completed, HO (100 mL) was added, followed by extraction with EA (20 mL × 3). The combined organic layer was washed with brine (10 mL × 2) and then dried over NaSO. The reaction mixture was filtered, and the filtrate was concentrated under vacuum and purified by Combiflash eluting with PE / EA (1:1) to give the compound product 3-bromo-4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridine (50 mg, 13.09%) as a brown solid compound. Mass (m / z): 295.0 [M+H]+.

[0195] Intermediate A4: tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate

[0196] [ka]

[0197] Step 1. N 1Preparation of -(3-bromophenyl)propane-1,3-diamine: To a solution of 1,3-dibromobenzene (18 g, 63.63 mmol), propane-1,3-diamine (14.1 g, 190.87 mmol), KOH (7.14 g, 127.25 mmol), and CuCl (630 mg, 6.36 mmol) was added, and the resulting mixture was stirred at 0 °C under N for 16 h. After the reaction was complete, HO (500 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (300 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash [DCM / MeOH (10% NH) = 0-10%] to give the product as a brown oil (10.7 g, 73%). Mass (m / z): 231.1 [M+H] + .

[0198] Step 2. Preparation of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: Follow steps 1 and 2 of General Synthetic Procedure I to prepare N 1 -(3-Bromophenyl)propane-1,3-diamine and tert-butyl 4-formylpiperidine-1-carboxylate gave the compound tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow oil (11.1 g, 58%). Mass (m / z): 473.9 [M+H] + .

[0199] Intermediate A5: tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate

[0200] [ka]

[0201] Step 1. Preparation of tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: Follow Steps 1 and 2 of General Synthetic Procedure I to prepare N 1 -(3-Bromophenyl)propane-1,3-diamine and tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate gave the compound tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate as a yellow oil (880 mg, 39%). Mass (m / z): 462.2 [M+H] + .

[0202] Intermediates A6 and A7: 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione and 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0203] [ka]

[0204] Step 1. Preparation of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (1.3 g, 2.8 mmol) in DCM (40 mL) was added TFA (2 mL) and HO (2 mL). The reaction mixture was stirred at 25 °C for 16 h. Water (30 mL) was added, and the mixture was extracted with DCM (40 mL × 2). The combined DCM layers were washed with saturated NaHCO (30 mL × 2) and brine (40 mL), dried over NaSO, and concentrated to give the crude product. A solution of this crude product, 1-(3-bromophenyl)-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (1 g, 2.8 mmol) and DIEA (1.09 g, 8.4 mmol) in DMSO (20 mL) was stirred under nitrogen at 120° C. for 2 hours. Water (50 mL) was added, and the mixture was extracted with EA (30 mL×3). The combined organic layers were washed with brine (50 mL×3) and dried over Na2SO4. It was then filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (PE / EA=1:1) to give the product as a brown solid (1.1 g, 57%). Mass (m / z): 607.7 [M+H] + .

[0205] Step 2. Preparation of 3-[5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione and 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione: To a solution of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1.4 g, 2.3 mmol) in AcOH (20 mL) was added Zn powder (1.5 g, 2.3 mmol), and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with brine (20 mL×2) and dried over Na2SO4. Then, it was filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC [Gemini-C18, 150×21.2 mm, 5 μm; ACN—H2O (0.1% TFA), 55-60] to give the product: 3-[5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (430 mg, 27%). Mass (m / z): 680.3 [M+H] + .

[0206] 3-(5-(4-((3-(3-Bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 11%). Mass (m / z): 680.3 [M+H] + .

[0207] Step 3. Preparation of 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione and 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-[6-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (430 mg, 0.72 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (275 mg, 1.08 mmol), and KOAc (213 mg, 2.17 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl (53 mg, 0.072 mmol). The mixture was stirred under nitrogen at 110 °C for 2 hours. Water (15 mL) was added, and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. Then, it was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (DCM / MeOH = 20:1) to give the product as a brown solid (300 mg, 58%). Mass (m / z): 642.4 [M+H] + .

[0208] Following the same procedure, 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione gave the product 3-(1-oxo-5-(4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione as a brown solid (140 mg, 64%). Mass (m / z): 642.3 [M+H] + .

[0209] Synthesis of illustrative compounds: Compound 1: 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}isoindole-1,3-dione

[0210] [ka]

[0211] Step 1. Preparation of N-(3-aminopropyl)aniline: To a solution of iodobenzene (3 g, 0.015 mol), propane-1,3-diamine (3.27 g, 0.04 mol), CuCl (0.15 g, 1.4 mmol), and KOH (1.65 g, 0.03 mol) were added. The reaction mixture was stirred at 0 °C under N for 2 h. After the reaction was completed, HO (50 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum. The residue was purified by Combiflash (DCM / MeOH = 0-5%) to give the desired product (1.97 g, 80%) as a yellow oil. Mass (m / z): 151.2 [M+H] + .

[0212] Step 2. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}isoindole-1,3-dione: According to General Synthetic Procedure I, the compound 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}isoindole-1,3-dione (60 mg, 24%) was obtained from N-(3-aminopropyl)aniline and tert-butyl 4-formylpiperidine-1-carboxylate as a yellow solid. Mass (m / z): 530.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.26-7.22 (m, 6H), 7.10 (t, J = 7.0 Hz, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.07 (d, J = 13.0 Hz, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.38 (t, J = 5.8 Hz, 2H), 3.19 (d, J = 7.2 Hz, 2H), 3.00-2.88 (m, 3H), 2.56 (dd, J = 17.6, 10.8 Hz, 2H), 2.07 - 1.94 (m, 4H), 1.71 (d, J = 11.2 Hz, 2H), 1.20 (d, J = 10.2 Hz, 2H).

[0213] Compound 2: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenylimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0214] [ka]

[0215] Step 1. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenylimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1 -phenylethane-1,2-diamine and tert-butyl 4-formylpiperidine-1-carboxylate gave the compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenylimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione as a yellow solid (130 mg, 21%). Mass (m / z): 516.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.36 - 7.20 (m, 4H), 6.98 (t, J = 7.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.06 (s, 2H), 3.85 - 3.77 (m, 2H), 3.54 - 3.45 (m, 2H), 3.09 (d, J = 7.2 Hz, 2H), 2.98 (t, J = 11.8 Hz, 2H), 2.87 (d, J = 11.8 Hz, 1H), 2.56 (dd, J = 18.8, 12.4 Hz, 2H), 1.99 (dd, J = 20.0, 14.8 Hz, 2H), 1.74 (d, J = 13.6 Hz, 2H), 1.22 (d, J = 11.8 Hz, 2H).

[0216] Compound 3: 5-(4-((3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0217] [ka]

[0218] Step 1. Preparation of tert-butyl 4-((3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (200 mg, 0.44 mmol) in dioxane / HO (10:1, 10 mL) was added 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (124 mg, 0.52 mmol), KCO (130 mg, 0.94 mmol), and Pd(dppf)Cl (34 mg, 0.05 mmol). The reaction mixture was stirred at 90° C. under N2 for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-50%) to give the product tert-butyl 4-((3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow oil (90 mg, 39%). Mass (m / z): 485.1 [M+H] + .

[0219] Step 2. Preparation of 5-(4-((3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following Steps 3 and 4 of General Synthetic Procedure I, compound 5-(4-((3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained as a yellow solid (14 mg, 15%). Mass (m / z): 641.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.58 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7.66 (dd, J = 13.4, 6.8 Hz, 2H), 7.46 - 7.36 (m, 3H), 7.31 (s, 1H), 7.28 - 7.19 (m, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.07 (d, J = 13.2 Hz, 2H), 3.77 - 3.69 (m, 2H), 3.41 (s, 2H), 3.20 (d, J = 7.2 Hz, 2H), 3.06 - 2.79 (m, 4H), 2.69 - 2.53 (m, 3H), 2.06 - 1.93 (m, 4H), 1.71 (d, J = 11.4 Hz, 2H).

[0220] Compound 4: 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[2-oxo-3-(pyridin-2-yl)-1,3-diazinan-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione

[0221] [ka]

[0222] Step 1. Preparation of N-(3-aminopropyl)pyridin-2-amine: To a solution of 2-bromopyridine (5 g, 31.6 mmol) in pyridine (30 mL) was added propane-1,3-diamine (37.6 mL, 450 mmol). The reaction mixture was stirred at 130 °C under N for 16 h. After the reaction was completed, H O (100 mL) was added to the reaction mixture, which was then extracted with EA (100 mL × 3). The combined organic layers were washed with brine (150 mL × 2) and then dried over anhydrous Na SO . After filtration, the solution was concentrated under vacuum. The residue was purified by Combiflash (DCM / MeOH = 0-5%) to give the desired product (3.5 g, 66%) as a yellow oil. Mass (m / z): 152.2 [M+H] + .

[0223] Step 2. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[2-oxo-3-(pyridin-2-yl)-1,3-diazinan-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione: According to General Synthetic Procedure I, compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[2-oxo-3-(pyridin-2-yl)-1,3-diazinan-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione (20 mg, 1.8%) was obtained from N-(3-aminopropyl)pyridin-2-amine and tert-butyl 4-formylpiperidine-1-carboxylate as a yellow solid. Mass (m / z): 531.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.31 (d, J = 4.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.63 (d, J = 4.4 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.05 - 6.98 (m, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.07 (d, J = 12.8 Hz, 2H), 3.94 - 3.82 (m, 2H), 3.42 - 3.36 (m, 2H), 3.24 (d, J = 7.2 Hz, 2H), 3.11 - 2.80 (m, 4H), 2.33 (s, 1H), 2.07 - 1.91 (m, 4H), 1.71 (d, J = 12.2 Hz, 2H), 1.22 (d, J = 9.2 Hz, 2H).

[0224] Compound 5: 5-(4-((3-cyclohexyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0225] [ka]

[0226] Step 1. Preparation of 5-(4-((3-cyclohexyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: According to general synthetic procedure I, compound 5-(4-((3-cyclohexyl-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (13 mg, yield: 3.3%) was obtained from N-(3-aminopropyl)cyclohexanamine and tert-butyl 4-formylpiperidine-1-carboxylate as a yellow solid. Mass (m / z): 536 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 8.7, 2.0 Hz, 1H), 5.02 (dd, J = 128, 5.4 Hz, 1H), 4.02 (t, J = 11.2 Hz, 3H), 3.15 (t, J = 5.8 Hz, 2H), 3.11 - 3.00 (m, 4H), 2.91-2.81 (m, 3H), 2.64 - 2.50 (m, 2H), 2.01 - 1.93 (m, 1H), 1.86 (d, J = 3.4 Hz, 1H), 1.82 - 1.74 (m, 2H), 1.69 (d, J = 12.2 Hz, 2H), 1.63 - 1.49 (m, 3H), 1.44 (d, J = 10.0 Hz, 2H), 1.32 (dt, J = 12.2, 9.6 Hz, 2H), 1.26 - 1.07 (m, 4H), 1.00 (d, J = 12.8 Hz, 1H).

[0227] Compound 6: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenyl-1,3-diazepan-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0228] [ka]

[0229] Step 1. Preparation of 4-(phenylamino)butanenitrile: To a solution of 4-bromobutanenitrile (2 g, 13.51 mmol) and aniline (2.51 g, 27.02 mmol) in DME (14 mL) and DMF (3.5 mL) was added K2CO3 (1.86 g, 13.51 mmol) and KI (4.48 g, 27.02 mmol). The reaction mixture was stirred at 100 °C under N2 for 16 h. Water (30 mL) was added, and the mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. The filtrate was then concentrated to dryness by filtration to give the product as a brown oil (3 g, purity: 70%). Mass (m / z): 161.1 [M+H] + .

[0230] Step 2. N 1 Preparation of -phenylbutane-1,4-diamine: A mixture of 4-(phenylamino)butanenitrile (3000 mg, 18.72 mmol) in BH3-THF (1 M in THF) (37.4 mL, 37.44 mmol) was stirred at 65 °C under N2 for 2 h. The reaction mixture was quenched with MeOH (100 mL) and evaporated. The residue was purified by silica gel column chromatography (DCM / MeOH / NH3 . Purification with HCl (10:1:0.1) gave the product as a colorless oil (900 mg, 42%). Mass (m / z): 165.2 [M+H] + .

[0231] Step 3. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenyl-1,3-diazepan-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1 -phenylbutane-1,4-diamine and tert-butyl 4-formylpiperidine-1-carboxylate gave the compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenyl-1,3-diazepan-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione as a yellow solid (180 mg, 47%). Mass (m / z): 544.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.37 - 7.21 (m, 4H), 7.19 - 7.09 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.08 (d, J = 13.2 Hz, 2H), 3.68 - 3.53 (m, 2H), 3.40 - 3.34 (m, 2H), 3.16 (d, J = 7.2 Hz, 2H), 3.05 - 2.94 (m, 2H), 2.93 - 2.82 (m, 1H), 2.63 - 2.51 (m, 2H), 2.05 - 1.90 (m, 2H), 1.82 - 1.60 (m, 6H), 1.24 - 1.15 (m, 2H).

[0232] Compound 7: 5-(4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0233] [ka]

[0234] Step 1. N 1 Preparation of -(tert-butyl)propane-1,3-diamine: To a solution of 3-(tert-butylamino)propanenitrile (1000 mg, 7.924 mmol) in ethyl ether (15 mL) was added LiAlH (301 mg, 7.924 mmol). The reaction mixture was stirred at 30° C. under N for 16 hours. The reaction mixture was quenched with 15% aqueous NaOH (2 mL) and filtered. The filtrate was collected and evaporated to give the product as a colorless oil (900 mg, 70%). Mass (m / z): 131.2 [M+H] + .

[0235] Step 2. Preparation of benzyl 4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: Following Steps 1 and 2 of General Synthetic Procedure I, N 1 -(tert-butyl)propane-1,3-diamine and tert-butyl 4-formylpiperidine-1-carboxylate gave the compound benzyl 4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a colorless oil (800 mg, 39%). Mass (m / z): 388.2 [M+H] + .

[0236] Step 3. Preparation of 1-(tert-butyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: To a solution of benzyl 4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (400 mg, 1.03 mmol) in MeOH (5 mL) was added 10% Pd / C (40 mg, wt / wt 10%). The reaction mixture was stirred at 50° C. under H2 (1 atm) for 16 h. The reaction mixture was filtered and the filtrate was evaporated to give the product as a colorless oil (220 mg, 67%). Mass (m / z): 254.2 [M+H] + .

[0237] Step 4. Preparation of 5-(4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: According to Step 4 of General Synthetic Procedure I, 1-(tert-butyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidine-2(1H)- From 5-(4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione, the compound 5-(4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained as a yellow solid (190 mg, 45%). Mass (m / z): 510.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.6, 2.2 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H), 3.17 - 3.07 (m, 4H), 3.00 - 2.92 (m, 2H), 2.92 - 2.81 (m, 1H), 2.66 - 2.51 (m, 2H), 2.04 - 1.98 (m, 1H), 1.92 - 1.77 (m, 3H), 1.68 - 1.61 (m, 2H), 1.33 (s, 9H), 1.22 - 1.12 (m, 2H).

[0238] Compound 8: 5-(3-(2-(3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0239] [ka]

[0240] Step 1. Preparation of 5-(3-(2-(3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: To a solution of 5-(3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (80 mg, 0.13 mmol) in dioxane / HO (10:1, 10 mL) was added 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (39 mg, 0.16 mmol), KPO (57 mg, 0.26 mmol), and Pd(dppf)Cl (10 mg, 0.01 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-50%) to give the product as a yellow solid (24 mg, 28%). Mass (m / z): 627.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.58 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.26 - 7.21 (m, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.62 (dd, J = 8.4, 2.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.14 (t, J = 8.2 Hz, 2H), 3.75 - 3.67 (m, 4H), 2.95 - 2.66 (m, 3H), 2.63 - 2.51 (m, 4H), 2.10 - 1.94 (m, 4H), 1.93 - 1.84 (m, 2H).

[0241] Compound 9: 5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0242] [ka]

[0243] Step 1. Preparation of 5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: According to Steps 3 and 4 of General Synthetic Procedure I, the compound 5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained from tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow solid (10 mg, 9%). Mass (m / z): 610.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.29 - 7.21 (m, 4H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.07 (d, J = 12.8 Hz, 2H), 3.69 - 3.64 (m, 2H), 3.37 (d, J = 6.0 Hz, 3H), 3.19 (d, J = 7.2 Hz, 2H), 3.03 - 2.82 (m, 4H), 2.62 - 2.53 (m, 2H), 2.06 - 1.96 (m, 4H), 1.70 (d, J = 10.4 Hz, 2H).

[0244] Compound 10: 5-(3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0245] [ka]

[0246] Step 1. Preparation of 5-(3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: According to Steps 3 and 4 of General Synthetic Procedure I, the compound 5-(3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained from tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate as a yellow solid (25 mg, 13%). Mass (m / z): 596.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.31 - 7.22 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.2 Hz, 1H), 4.14 (t, J = 8.2 Hz, 2H), 3.73 - 3.63 (m, 4H), 3.30 (d, J = 7.0 Hz, 3H), 2.92 - 2.75 (m, 2H), 2.56 (dd, J = 15.2, 9.2 Hz, 2H), 2.09 - 1.94 (m, 4H), 1.88 (dd, J = 14.2, 7.2 Hz, 2H).

[0247] Compound 11: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-(quinolin-6-yl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0248] [ka]

[0249] Step 1. N 1 Preparation of -(quinolin-6-yl)propane-1,3-diamine: To a solution of 6-bromoquinoline (2 g, 9.62 mmol), propane-1,3-diamine (2.14 g, 28.86 mmol), BINAP (270 mg, 0.028 mmol), and t-BuONa (1.4 g, 14.43 mmol) in 1,4-dioxane (10 mL) was added Pd(dba) (220 mg, 0.38 mmol). The resulting mixture was stirred at 100 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash [DCM / MeOH (with 10% NH) = 0-10%] to give product N. 1 -(Quinolin-6-yl)propane-1,3-diamine was obtained as a brown oil (1.69 g, 87%). Mass (m / z): 202.0 [M+H] + .

[0250] Step 2. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-(quinolin-6-yl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1 -(Quinolin-6-yl)propane-1,3-diamine and tert-butyl 4-formylpiperidine-1-carboxylate gave the compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-(quinolin-6-yl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione as a yellow solid (35 mg, 19%). Mass (m / z): 581.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.86 (dd, J = 4.4, 1.6 Hz, 1H), 8.20 (s, 2H), 8.01 (s, 1H), 7.83 (dd, J = 9.0, 2.2 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 7.04 (dd, J = 8.6, 2.4 Hz, 1H), 4.93 (dd, J = 12.4, 5.4 Hz, 1H), 3.97 (d, J = 13.2 Hz, 2H), 3.91 - 3.83 (m, 2H), 3.50 (t, J = 5.8 Hz, 2H), 3.34 (d, J = 7.2 Hz, 2H), 3.00 (t, J = 11.4 Hz, 2H), 2.92 - 2.72 (m, 3H), 2.27 - 2.19 (m, 2H), 2.17 - 2.07 (m, 2H), 1.86 (d, J = 11.2 Hz, 2H), 1.39 (dd, J = 9.4, 6.0 Hz, 2H).

[0251] Compound 12: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-oxo-3-phenylimidazolidin-1-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione

[0252] [ka]

[0253] Step 1. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-oxo-3-phenylimidazolidin-1-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1-phenylethane-1,2-diamine and tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate gave the compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-oxo-3-phenylimidazolidin-1-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione as a yellow solid (54 mg, 13%). Mass (m / z): 502.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 8.4, 2.0 Hz, 1H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 4.18 (t, J = 8.0 Hz, 2H), 3.91 - 3.81 (m, 2H), 3.72 (dd, J = 7.8, 5.6 Hz, 2H), 3.55 - 3.46 (m, 2H), 3.36 (t, J = 6.8 Hz, 2H), 2.92 - 2.70 (m, 4H), 2.12 (dd, J = 7.8, 5.4 Hz, 1H), 2.03 - 1.91 (m, 2H).

[0254] Compound 13: 3-(4-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}phenyl)piperidine-2,6-dione

[0255] [ka]

[0256] Step 1. Preparation of 1-phenyl-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one: To a solution of tert-butyl 4-((2-oxo-3-phenyltetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (230 mg, 0.61 mmol) in DCM (5 mL) was added TFA (2.5 mL). The reaction mixture was stirred at 25° C. under N2 for 2 hours. The solution was concentrated in vacuo to give the desired product (1.97 g, 80%) as a yellow oil. Mass (m / z): 274.3 [M+H] + .

[0257] Step 2. Preparation of 1-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-3-phenyl-1,3-diazinan-2-one: To a solution of 1-phenyl-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (170 mg, 0.62 mmol) in DCM (10 mL) was added (4-bromophenyl)boranediol (150 mg, 0.75 mmol), Cu(OAc) (169 mg, 0.93 mmol), TEA (252 mg, 2.49 mmol), and 4A molecular sieves (100 mg). The reaction mixture was stirred at 25 °C under O for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA = 1:1) to give the product (150 mg, 51%) as a pale yellow solid. Mass (m / z): 427.8 [M+H] +。

[0258] Step 3. Preparation of 1-phenyl-3-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-yl}methyl)-1,3-diazinan-2-one: To a solution of 1-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-3-phenyl-1,3-diazinan-2-one (150 mg, 0.35 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (249 mg, 0.98 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl (26 mg, 0.035 mmol) and KOAc (103 mg, 1.05 mmol) at 25 °C. The reaction mixture was stirred at 90° C. under N for 4 hours. After the reaction was completed, H O (10 mL) was added to the reaction mixture, which was then extracted with EA (20 mL×3). The combined organic layers were washed with brine (50 mL×2) and then dried over anhydrous Na SO . After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (PE / EA=1:1) to give the product (130 mg, 62%) as a yellow oil. Mass (m / z): 476.0 [M+H] + .

[0259] Step 4. Preparation of 1-[(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]-3-phenyl-1,3-diazinan-2-one: To a solution of 1-phenyl-3-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-yl}methyl)-1,3-diazinan-2-one (150 mg, 0.31 mmol) in 1,4-dioxane / HO (10 / 1, 11 mL) was added 2,6-bis(benzyloxy)-3-bromopyridine (116 mg, 0.31 mmol), NaCO (100 mg, 0.95 mmol), and Pd(dppf)Cl (23 mg, 0.031 mmol). The reaction mixture was stirred at 90° C. under N for 4 hours. The resulting mixture was concentrated and purified by flash chromatography (PE / EA=1:1) to give the product (120 mg, 49%) as a yellow oil. Mass (m / z): 638.9 [M+H] + .

[0260] Step 5. Preparation of 3-(4-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}phenyl)piperidine-2,6-dione: To a solution of 1-[(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]-3-phenyl-1,3-diazinan-2-one (120 mg, 0.19 mmol) in MeOH (5 mL) and THF (5 mL) was added 10% Pd / C (60 mg, 50% wt / wt). The reaction mixture was stirred at 40 °C under a 0.4 MPa H atmosphere for 16 h. After filtration, the solution was concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH = 0-5%) to give the desired product (45 mg, 48%) as a yellow solid. Mass (m / z): 461.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.33 - 7.23 (m, 4H), 7.13 - 6.99 (m, 3H), 6.88 (d, J = 8.2 Hz, 2H), 3.68 (dt, J = 11.0, 5.2 Hz, 5H), 3.38 (s, 2H), 3.20 (d, J = 7.2 Hz, 2H), 2.63 (t, J = 11.8 Hz, 3H), 2.16 - 1.96 (m, 4H), 1.69 (d, J = 11.8 Hz, 3H), 1.25 (d, J = 12.2Hz, 3H).

[0261] Compound 14: 5-(4-((3-(3-chlorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0262] [ka]

[0263] Step 1. N 1 Preparation of -(3-chlorophenyl)propane-1,3-diamine: A mixture of 1-chloro-3-iodobenzene (2 g, 8.4 mmol), propane-1,3-diamine (1.86 g, 25.21 mmol), KOH (941 mg, 16.8 mmol), and CuCl (83 mg, 0.84 mmol) was stirred at 0 °C under N for 16 h. After the reaction was complete, HO (200 mL) was added to the reaction mixture, which was then extracted with DCM (200 mL × 3). The combined organic layers were washed with brine (300 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash [DCM / MeOH (10% NH . HO) = 0~10% to obtain product N 1 -(3-Chlorophenyl)propane-1,3-diamine was obtained as a yellow oil (1.34 g, 85%). Mass (m / z): 185.2 [M+H]+ .

[0264] Step 2. Preparation of 5-(4-((3-(3-chlorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1 -(3-Chlorophenyl)propane-1,3-diamine gave the compound 5-(4-((3-(3-chlorophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (55 mg, 10%). Mass (m / z): 563.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.28 (dd, J = 3.8, 2.0 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 7.19 - 7.14 (m, 2H), 4.95 (dd, J = 12.4, 5.2 Hz, 1H), 3.94 (d, J = 13.2 Hz, 2H), 3.75 - 3.67 (m, 2H), 3.47 (t, J = 5.8 Hz, 2H), 3.31 (d, J = 7.2 Hz, 2H), 3.04 (t, J = 12.0 Hz, 2H), 2.92-2.72 (m, 4H), 2.19 - 2.11 (m, 3H), 1.88 (d, J = 12.4 Hz, 2H), 1.48 (d, J = 10.8 Hz, 2H).

[0265] Compound 15: 5-(4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0266] [ka]

[0267] Step 1. Preparation of tert-butyl 4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (500 mg, 1.11 mmol) in toluene / HO (20 / 1, 20 mL) was added cyclopropylboronic acid (124 mg, 1.44 mmol), KPO (705 mg, 3.33 mmol), PCy (31 mg, 0.11 mmol), and Pd(OAc) (12 mg, 0.06 mmol). The reaction mixture was stirred at 100 °C under N for 3 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-30%) to give the product tert-butyl 4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow oil (260 mg, 56%). Mass (m / z): 436.3 [M+Na] + .

[0268] Step 2. Preparation of 5-(4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: According to Steps 3 and 4 of General Synthetic Procedure I, the compound 5-(4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained from tert-butyl 4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow solid (90 mg, 20%). Mass (m / z): 569.8 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.23 - 7.13 (m, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 7.6 Hz, 1H), 4.98 - 4.90 (m, 1H), 3.93 (d, J = 13.0 Hz, 2H), 3.73 - 3.66 (m, 2H), 3.44 (t, J = 5.8 Hz, 2H), 3.30 (d, J = 7.2 Hz, 2H), 3.00 (d, J = 10.8 Hz, 2H), 2.92 - 2.70 (m, 3H), 2.12 (dd, J = 12.2, 5.8 Hz, 4H), 1.92 - 1.83 (m, 3H), 1.44 (d, J = 9.6 Hz, 2H), 0.97 - 0.89 (m, 2H), 0.68 (dd, J = 5.0, 1.6 Hz, 2H).

[0269] Compound 16: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0270] [ka]

[0271] Step 1. Preparation of tert-butyl (3-((4-fluorobenzyl)amino)propyl)carbamate: To a solution of 4-fluorobenzaldehyde (1 g, 8.06 mmol) in MeOH (30 mL) was added tert-butyl (3-aminopropyl)carbamate (1.4 g, 8.06 mmol), AcOH (0.05 mL), and NaBH3CN (1.52 g, 25.19 mmol) at 0 °C. The solvent was removed under reduced pressure, and the residue was purified by Combiflash [DCM / MeOH (10% NH3 .HO) = 0-10%] to give the product tert-butyl (3-((4-fluorobenzyl)amino)propyl)carbamate as a colorless oil (2 g, 88%). Mass (m / z): 283.3 [M+H] + .

[0272] Step 2. N 1 Preparation of -(4-fluorobenzyl)propane-1,3-diamine: A solution of tert-butyl (3-((4-fluorobenzyl)amino)propyl)carbamate (2 g, 7.09 mmol) in HCl / dioxane (4.0 M, 40 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give product N 1 -(4-Fluorobenzyl)propane-1,3-diamine was obtained as a white solid (1.5 g, 81%). Mass (m / z): 183.0 [M+H] + .

[0273] Step 3. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1 -(4-Fluorobenzyl)propane-1,3-diamine gave the compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione as a yellow solid (45 mg, 12%). Mass (m / z): 562.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 3.0 Hz, 2H), 7.07 - 6.97 (m, 3H), 4.94 (dd, J = 12.4, 5.2 Hz, 1H), 4.52 (s, 2H), 3.96 (d, J = 13.2 Hz, 2H), 3.34 - 3.25 (m, 4H), 3.19 (t, J = 5.8 Hz, 2H), 3.04 - 2.95 (m, 2H), 2.87-2.72 (m, 3H), 2.15 - 2.09 (m, 1H), 2.05 - 1.98 (m, 1H), 1.94 (dt, J = 11.6, 5.8 Hz, 2H), 1.81 (d, J = 10.8 Hz, 2H), 1.42 - 1.32 (m, 2H).

[0274] Compound 17: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0275] [ka]

[0276] Step 1. Preparation of tert-butyl (2-((4-fluorobenzyl)amino)ethyl)carbamate: To a solution of 4-fluorobenzaldehyde (1 g, 8.06 mmol) in MeOH (30 mL) was added tert-butyl (2-aminoethyl)carbamate (1.29 g, 8.06 mmol), AcOH (0.05 mL), and NaBH3CN (1.52 g, 25.19 mmol) at 0 °C. The solvent was removed under reduced pressure, and the residue was purified by Combiflash [DCM / MeOH (10% NH3 .HO) = 0-10%] to give the product tert-butyl (3-((4-fluorobenzyl)amino)propyl)carbamate as a colorless oil (1.46 g, 67%). Mass (m / z): 269.2 [M+H] + .

[0277] Step 2. N 1 Preparation of -(4-fluorobenzyl)ethane-1,2-diamine: A solution of tert-butyl (3-((4-fluorobenzyl)amino)propyl)carbamate (1.46 g, 5.45 mmol) in HCl / dioxane (4.0 M, 40 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give product N 1 -(4-Fluorobenzyl)ethane-1,2-diamine was obtained as a white solid (1.3 g, 64%). Mass (m / z): 169.0 [M+H] + .

[0278] Step 3. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: Following General Synthetic Procedure I, 1 -(4-Fluorobenzyl)ethane-1,2-diamine gave the product 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione as a yellow solid (60 mg, 16%). Mass (m / z): 548.0 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.25 - 7.22 (m, 1H), 7.12 - 6.97 (m, 3H), 4.94 (dd, J = 12.0, 5.2 Hz, 1H), 4.34 (s, 2H), 3.95 (d, J = 12.8 Hz, 2H), 3.34 (t, J = 7.6 Hz, 2H), 3.24 - 3.11 (m, 4H), 2.99 (t, J = 11.8 Hz, 2H), 2.92 - 2.72 (m, 3H), 2.19 - 2.08 (m, 1H), 1.92 - 1.80 (m, 3H), 1.41 (dd, J = 22.4, 9.4 Hz, 2H).

[0279] Compound 18: 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[3-(4-methyl-1,3-thiazol-2-yl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione

[0280] [ka]

[0281] Step 1. Preparation of benzyl 4-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)piperidine-1-carboxylate: Following Step 1 of General Synthetic Procedure I, the product was obtained as a yellow oil (5 g, 66%). Mass (m / z): 406.3 [M+H] + .

[0282] Step 2. Preparation of benzyl 4-(((3-aminopropyl)amino)methyl)piperidine-1-carboxylate: To a solution of benzyl 4-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)piperidine-1-carboxylate (5 g, 12 mmol) in DCM (25 mL) and HCl / dioxane (4.0 M, 25 mL). The reaction mixture was stirred at 25 °C under N for 3 h. The solution was concentrated in vacuo to give the desired product (1.97 g, 80%) as a white solid. Mass (m / z): 306.2 [M+H] + .

[0283] Step 3. Preparation of benzyl 4-((2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: Following Step 2 of General Synthetic Procedure I, the product was obtained as a yellow solid (1.16 g, 46%). Mass (m / z): 332.2 [M+H] + .

[0284] Step 4. Preparation of benzyl 4-((3-(4-methylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of benzyl 4-((2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (500 mg, 1.51 mmol) in 1,4-dioxane (30 mL) was added 2-bromo-4-methyl-1,3-thiazole (268 mg, 1.51 mmol), Xantphos (349 mg, 0.60 mmol), Pd(dba) (165 mg, 0.18 mmol), and CsCO (1.77 g, 5.43 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under N for 4 h. After the reaction was completed, H2O (50 mL) was added to the reaction mixture, which was then extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 20:1) to give the product as a brown solid (280 mg, 26%). Mass (m / z): 429.2 [M+H]+ .

[0285] Step 5. Preparation of 1-(4-methyl-1,3-thiazol-2-yl)-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one: To a solution of benzyl 4-((3-(4-methylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (220 mg, 0.51 mmol) in DCM (5 mL) was added BCl (1.0 M in DCM, 4 mL, 3.95 mmol) at −78° C. under N. The reaction mixture was stirred at 25° C. under N for 16 h. After the reaction was complete, HO (20 mL) was added to the reaction mixture at 0° C., followed by extraction with DCM (20 mL × 3). The combined organic layer was washed with brine (20 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo and the residue was purified by prep-TLC (PE / EA=1:1) to give the product as a yellow solid (122 mg, 63%). Mass (m / z): 295.0 [M+H] + .

[0286] Step 6. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[3-(4-methyl-1,3-thiazol-2-yl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione: Follow Step 4 of General Synthetic Procedure I to obtain the desired product (43 mg, 18%) as a yellow solid. Mass (m / z): 551.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.04 (dd, J = 17.6, 11.6 Hz, 4H), 3.40 (d, J = 4.8 Hz, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.94 (dd, J = 29.6, 17.4 Hz, 4H), 2.67 (s, 1H), 2.22 (s, 3H), 2.03 (s, 4H), 1.70 (d, J = 11.8 Hz, 2H), 1.22 (d, J = 11.6 Hz, 2H).

[0287] Compound 19: 3-(1-oxo-5-(4-((2-oxo-3-phenyltetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0288] [ka]

[0289] Step 1. Preparation of 1-phenyl-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: Following steps 1, 2, and 3 of General Synthetic Procedure I, the desired product 1-phenyl-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one was obtained as a yellow oil (1800 mg, purity: 50%). Mass (m / z): 296.1 [M+H] + .

[0290] Step 2. Preparation of 3-(1-oxo-5-(4-((2-oxo-3-phenyltetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione: To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (94 mg, 0.29 mmol) in dioxane (20 mL) was added 1-phenyl-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (200 mg, 0.73 mmol), CsCO (284 mg, 0.87 mmol), Ruphos (27 mg, 0.06 mmol), RuPhos Pd G2 (45 mg, 0.06 mmol) and 4A molecular sieves (4 mg, 0.008 mmol) were added. The reaction mixture was stirred at 100 °C under N for 16 h. After the reaction was completed, HO (20 mL) was added to the reaction mixture, which was then extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product as a white solid (10 mg, 6%). Mass (m / z): 516.3 [M+H] + . 1 H (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.38 - 7.27 (m, 4H), 7.21 (dd, J = 16.6, 9.2 Hz, 2H), 5.20 (dd, J = 13.4, 5.0 Hz, 1H), 4.46 (d, J = 15.8 Hz, 1H), 4.34 (s, 1H), 3.81 (d, J = 11.8 Hz, 2H), 3.74 - 3.70 (m, 2H), 3.48 (s, 2H), 3.36 (d, J = 6.6 Hz, 2H), 3.10 (s, 2H), 2.95 - 2.78 (m, 3H), 2.17 (d, J = 5.6 Hz, 4H), 2.00 (d, J = 12.0 Hz, 2H), 1.72 (s, 2H).

[0291] Compound 20: 3-(4-(4-(2-(2-oxo-3-phenyltetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione

[0292] [ka]

[0293] Step 1. Preparation of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (2 g, 5.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.06 g, 8.1 mmol), and KOAc (1.06 g, 10.8 mmol) in dioxane (30 mL) was added Pd(dppf)Cl (0.4 g, 0.54 mmol). The reaction mixture was stirred at 90 °C under N for 16 h. The mixture was concentrated, and the residue was purified by flash column chromatography (PE / EA = 10:1) to give the product as a brown solid (1.5 g, 70%). Mass (m / z): 418.1 [M+H] + .

[0294] Step 2. Preparation of 1-phenyl-3-[2-(piperidin-4-yl)ethyl]-1,3-diazinan-2-one: Following steps 1, 2, and 3 of General Synthetic Procedure I, the desired product was obtained as a brown solid (650 mg, purity: approximately 50%). Mass (m / z): 288.0 [M+H] + .

[0295] Step 3. Preparation of 1-{2-[1-(4-bromophenyl)piperidin-4-yl]ethyl}-3-phenyl-1,3-diazinan-2-one: A solution of 1-phenyl-3-[2-(piperidin-4-yl)ethyl]-1,3-diazinan-2-one (500 mg, 1.739 mmol), (4-bromophenyl)boranediol (1.04 g, 5.21 mmol), Cu(OAc) (474 ​​mg, 2.609 mmol), TEA (702 mg, 6.958 mmol), and 4A MS (250 mg) in DCM (20 mL) was stirred at room temperature under O for 16 hours. The mixture was concentrated, and the residue was purified by flash column chromatography (DCM:MeOH = 20:1) to give the product as a brown solid (280 mg, 36%). Mass (m / z): 442.9 [M+H] + .

[0296] Step 4. Preparation of 1-(2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethyl)-3-phenyltetrahydropyrimidin-2(1H)-one: To a solution of 1-{2-[1-(4-bromophenyl)piperidin-4-yl]ethyl}-3-phenyl-1,3-diazinan-2-one (260 mg, 0.587 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (294 mg, 0.705 mmol), and KCO (162 mg, 1.175 mmol) in dioxane / HO (10 / 1, 10 mL) was added Pd(dppf)Cl (43 mg, 0.026 mmol). The reaction mixture was stirred at 100° C. under N for 16 hours. The mixture was concentrated, and the residue was purified by flash column (DCM / MeOH=20:1) to give the product as a yellow solid (110 mg, 28%). Mass (m / z): 652.8 [M+H] + .

[0297] Step 5. 3-(4-(4-(2-(2-oxo-3-phenyltetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione: To a solution of 1-(2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethyl)-3-phenyltetrahydropyrimidin-2(1H)-one (80 mg, 0.122 mmol) in MeOH (4 mL) and THF (4 mL) was added 10% Pd / C (40 mg, 50% wt / wt). The reaction mixture was stirred at 40° C. under H at 0.4 MPa for 16 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 30–50] to give the product as a white solid (17 mg, 29%). Mass (m / z): 476.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.27 - 7.19 (m, 4H), 7.11 - 6.93 (m, 3H), 6.84 (d, J = 8.6 Hz, 2H), 3.69 - 3.57 (m, 6H), 2.61 - 2.53 (m, 6H), 2.15 - 1.92 (m, 4H), 1.75 (d, J = 12.2 Hz, 2H), 1.40 (dd, J = 22.8, 16.0 Hz, 2H), 1.33 - 1.09 (m, 4H).

[0298] Compound 21: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(3-(3-(imidazo[1,2-a]pyridin-7-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione

[0299] [ka]

[0300] Step 1. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(3-(3-(imidazo[1,2-a]pyridin-7-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione: To a solution of 5-(3-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (150 mg, 0.25 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (74 mg, 0.30 mmol) in dioxane (5 mL) and water (0.5 mL) was added KPO (107 mg, 0.50 mmol) and Pd(dppf)Cl (18 mg, 0.025 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Pre-HPLC [chromatography column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-HO (0.1% FA), gradient: 20-50] to give the product as a yellow solid (50 mg, 30%). Mass (m / z): 632.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.66 (t, J = 1.8 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.29 - 7.16 (m, 2H), 6.72 (d, J = 2.0 Hz, 1H), 6.59 (dd, J = 8.4, 2.0 Hz, 1H), 5.01 (dd, J = 12.8, 5.4 Hz, 1H), 4.10 (t, J = 8.2 Hz, 2H), 3.74 - 3.64 (m, 4H), 3.36 (t, J = 5.9 Hz, 4H), 2.89 - 2.70 (m, 2H), 2.58 - 2.47 (m, 2H), 2.06 - 2.00 (m, 2H), 1.98 - 1.92 (m, 1H), 1.89 - 1.81 (m, 2H).

[0301] Compound 22: 5-(3-(2-(3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0302] [ka]

[0303] Step 1. Preparation of 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyridine: To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (1 g, 5.05 mmol) and cyclopropylboranediol (867 mg, 10.1 mmol) in DCE (30 mL) was added Na2CO3 (1.07 g, 10.1 mmol), Cu(OAc)2 (917 mg, 5.05 mmol), and 2,2'-bipyridine (789 mg, 5.05 mmol). The reaction mixture was stirred at 70 °C under O2 for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was washed with saturated aqueous copper sulfate (20 mL) and extracted with EA (20 mL). The organic phase was evaporated to give the product as a yellow solid (800 mg, 53%). Mass (m / z): 238.0240.0 [M+H] + .

[0304] Step 2. Preparation of 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine: To a solution of 5-bromo-1-cyclopropylpyrazolo[3,4-b]pyridine (700 mg, 2.94 mmol) and B2(Pin)2 (896 mg, 3.53 mmol) in dioxane (10 mL) was added KOAc (866 mg, 8.82 mmol) and Pd(dppf)Cl2 (215 mg, 0.29 mmol). The reaction mixture was stirred at 90 °C under N2 for 16 h. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA = 2:1) to give the product as a yellow solid (450 mg, 43%). Mass (m / z): 286.1 [M+H] + .

[0305] Step 3. Preparation of 5-(3-(2-(3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: To a solution of 5-(3-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (100 mg, 0.17 mmol) and 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (72 mg, 0.25 mmol) in dioxane (3 mL) and water (0.3 mL) was added KPO (71 mg, 0.34 mmol) and Pd(dppf)Cl (12 mg, 0.017 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Pre-HPLC [chromatography column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-HO (0.1% FA), gradient: 40-70] to give the product as a yellow solid (60 mg, 52%). Mass (m / z): 673.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 7.67 - 7.58 (m, 2H), 7.51 - 7.40 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.14 (t, J = 8.2 Hz, 2H), 4.00 - 3.93 (m, 1H), 3.82 - 3.63 (m, 4H), 3.41 (t, J = 5.8 Hz, 2H), 3.32 - 3.30 (m, 1H), 2.94 - 2.75 (m, 2H), 2.63 - 2.51 (m, 3H), 2.12 - 2.04 (m, 2H), 2.03 - 1.97 (m, 1H), 1.90 (dd, J = 14.0, 7.0 Hz, 2H), 1.24 - 1.20 (m, 2H), 1.16 - 1.11 (m, 2H).

[0306] Compound 23: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-oxo-3-(3-(quinolin-3-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione

[0307] [ka]

[0308] Step 1. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-oxo-3-(3-(quinolin-3-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione: To a solution of 5-(3-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (100 mg, 0.17 mmol) and quinolin-3-ylboranediol (44 mg, 0.25 mmol) in dioxane (3 mL) and water (0.3 mL) was added KPO (71 mg, 0.34 mmol) and Pd(dppf)Cl (12 mg, 0.017 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Pre-HPLC [chromatography column: Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: ACN-HO (0.1% FA), gradient: 40-70] to give the product as a yellow solid (17 mg, 14%). Mass (m / z): 643.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.11 (t, J = 7.8 Hz, 2H), 7.87 - 7.79 (m, 2H), 7.73 - 7.60 (m, 3H), 7.50 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.2 Hz, 1H), 4.15 (t, J = 8.2 Hz, 2H), 3.79 - 3.77 (m, 2H), 3.71 (dd, J = 8.2, 5.8 Hz, 2H), 3.38 (dt, J = 13.6, 6.2 Hz, 4H), 2.90 - 2.75 (m, 2H), 2.64 - 2.52 (m, 2H), 2.14 - 2.05 (m, 2H), 2.02 - 1.97 (m, 1H), 1.90 (dd, J = 14.0, 6.8 Hz, 2H).

[0309] Compound 24: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(3-(3-(2-methyloxazolo[4,5-b]pyridin-6-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione

[0310] [ka]

[0311] Step 1. Preparation of (2-methyloxazolo[4,5-b]pyridin-6-yl)boronic acid: To a solution of 6-bromo-2-methyl-[1,3]oxazolo[4,5-b]pyridine (1 g, 4.69 mmol) and B2(Pin)2 (1.43 g, 5.63 mmol) in dioxane (20 mL) was added KOAc (1.38 g, 14.08 mmol) and Pd(dppf)Cl2 (343 mg, 0.469 mmol). The reaction mixture was stirred at 90 °C under N2 for 16 h. The reaction mixture was evaporated and washed with n-hexane (20 mL). The mixture was filtered and evaporated to dryness. The residue was purified by flash chromatography (ACN / H2O (0.1% FA) = 20% to 40%) to give the product as a yellow solid (500 mg, 47%). Mass (m / z): 179.1 [M+H] + .

[0312] Step 2. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(3-(3-(2-methyloxazolo[4,5-b]pyridin-6-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione: To a solution of 5-(3-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (100 mg, 0.17 mmol) and (2-methyloxazolo[4,5-b]pyridin-6-yl)boronic acid (45 mg, 0.25 mmol) in dioxane (3 mL) and water (0.3 mL) was added KPO (71 mg, 0.34 mmol) and Pd(dppf)Cl (12 mg, 0.017 mmol). The reaction mixture was stirred at 85 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Prep-HPLC [chromatography column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-HO (0.1% FA), gradient: 50-80] to give the product as a yellow solid (40 mg, 34%). Mass (m / z): 648.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.1 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.14 (t, J = 8.2 Hz, 2H), 3.81 - 3.66 (m, 4H), 3.41 (t, J = 5.8 Hz, 2H), 3.31 (s, 2H), 2.94 - 2.76 (m, 2H), 2.70 (s, 3H), 2.62 - 2.51 (m, 2H), 2.11 - 1.97 (m, 3H), 1.89 (dd, J = 14.0, 7.2 Hz, 2H).

[0313] Compound 25: 2-(2,6-dioxopiperidin-3-yl)-5-(3-{2-[2-oxo-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione

[0314] [ka]

[0315] Step 1. Preparation of tert-butyl 3-(2-(3-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: To a mixture of tert-butyl 3-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (80 mg, 0.164 mmol) in dioxane / HO (10:1, 5.5 mL) was added KCO (68 mg, 0.493 mmol), 5-bromo-1H-pyrazolo[3,4-b]pyridine (39 mg, 0.197 mmol), and Pd(dppf)Cl (13 mg, 0.016 mmol). The reaction was degassed with N three times and stirred at 90 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (10 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE:EA = 0-100%) to give the desired product tert-butyl 3-(2-(3-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate as a white solid (80 mg, 92%). Mass (m / z): 477.2 [M+H] + .

[0316] Step 2. Preparation of 1-[2-(azetidin-3-yl)ethyl]-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazinan-2-one: A mixture of tert-butyl 3-(2-(3-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (80.0 mg, 0.167 mmol) in DCM / TFA (3:1, 4.0 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the product 1-[2-(azetidin-3-yl)ethyl]-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazinan-2-one as a yellow solid (40 mg, 57%). Mass (m / z): 377.2 [M+H] + .

[0317] Step 3. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-{2-[2-oxo-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione: To a mixture of 1-[2-(azetidin-3-yl)ethyl]-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazinan-2-one (40 mg, 0.106 mmol) in DMSO (3 mL) was added DIEA (27.5 mg, 0.212 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (29.4 mg, 0.106 mmol). The reaction was stirred at 120° C. for 1 hour. The reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH=10:1) to give the product 2-(2,6-dioxopiperidin-3-yl)-5-(3-{2-[2-oxo-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione as a yellow solid (10 mg, 14%). Mass (m / z): 633.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 14.8, 7.6 Hz, 3H), 6.64 (s, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.90 (dd, J = 12.2, 5.2 Hz, 1H), 4.15 (t, J = 7.8 Hz, 2H), 3.82 (d, J = 5.4 Hz, 2H), 3.72 (d, J = 5.8 Hz, 2H), 3.51 - 3.47 (m, 4H), 2.89 - 2.71 (m, 4H), 2.24 - 2.20 (m, 2H), 2.09 - 2.01 (m, 3H).

[0318] Compound 26: 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0319] [ka]

[0320] Step 1. Preparation of tert-butyl 3-(2-(3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: To a solution of 5-bromo-4-chloro-3-ethyl-1H-indole (100 mg, 0.39 mmol) in dioxane / HO (10:1, 10 mL) was added tert-butyl 3-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (282 mg, 0.58 mmol), KCO (107 mg, 0.77 mmol), and Pd(dppf)Cl (28 mg, 0.04 mmol). The reaction mixture was stirred at 90 °C under N for 16 h. After the reaction was complete, HO (100 mL) was added to the reaction mixture, which was then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (PE / EA = 0-10%) to give the product tert-butyl 3-(2-(3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate as a yellow oil (100 mg, 48%). Mass (m / z): 537.2 [M+H] + .

[0321] Step 2. Preparation of 1-(2-(azetidin-3-yl)ethyl)-3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)tetrahydropyrimidin-2(1H)-one: A solution of tert-butyl 3-(2-(3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (100 mg, 0.19 mmol) in TFA / DCM (3:1, 5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 1-(2-(azetidin-3-yl)ethyl)-3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)tetrahydropyrimidin-2(1H)-one as a yellow oil (80 mg, purity: 60%). Mass (m / z): 437.2 [M+H] + .

[0322] Step 3. Preparation of 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: To a solution of 1-(2-(azetidin-3-yl)ethyl)-3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)tetrahydropyrimidin-2(1H)-one (80 mg, 0.18 mmol) in DMSO (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (50 mg, 0.18 mmol) and DIEA (71 mg, 0.55 mmol). The reaction mixture was stirred at 120° C. under N for 2 h. After the reaction was complete, HO (30 mL) was added to the reaction mixture, which was then extracted with EA (20 mL×3). The combined organic layers were washed with brine (30 mL×2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-indol-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (15 mg, 6%). Mass (m / z): 693.1 [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.56 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 7.09 - 7.04 (m, 2H), 6.76 (s, 1H), 6.59 (s, 1H), 5.04 (dd, J = 12.4, 5.4 Hz, 1H), 4.17 (t, J = 7.8 Hz, 2H), 3.80 - 3.71 (m, 4H), 3.47 (dt, J = 13.8, 6.4 Hz, 4H), 3.00 (d, J = 7.4 Hz, 2H), 2.87 - 2.80 (m, 2H), 2.76 - 2.68 (m, 2H), 2.20 - 2.13 (m, 2H), 2.02 - 1.93 (m, 3H), 1.30 (t, J = 7.4 Hz, 3H).

[0323] Compound 27: 2-(2,6-dioxopiperidin-3-yl)-5-(3-{2-[3-(3-{3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione

[0324] [ka]

[0325] Step 1. Preparation of 5-chloro-3-ethyl-1H-pyrrolo[3,2-b]pyridine: To a solution of 2-chloro-5-hydrazinylpyridine (500 mg, 3.48 mmol) in 5% H2SO4 solution (20 mL) was added butanal (276 mg, 3.83 mmol). The reaction mixture was stirred at 110 °C under N2 for 16 h. The reaction solution was adjusted to pH 8-9 using 40% aqueous KOH solution and then extracted with EA (100 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (PE / EA = 0-50%) to give the product, 5-chloro-3-ethyl-1H-pyrrolo[3,2-b]pyridine, as a yellow solid (236 mg, 52%). Mass (m / z): 181.0 [M+H] + .

[0326] Step 2. Preparation of tert-butyl 3-(2-(3-(3-(3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: To a solution of 5-chloro-3-ethyl-1H-pyrrolo[3,2-b]pyridine (55 mg, 0.30 mmol) in dioxane / HO (10 / 1, 5 mL) was added tert-butyl 3-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (163 mg, 0.33 mmol), KCO (84 mg, 0.61 mmol), and Pd(dppf)Cl (22 mg, 0.03 mmol). The reaction mixture was stirred at 90 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-50%) to give the product tert-butyl 3-(2-(3-(3-(3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate as a yellow oil (80 mg, 52%). Mass (m / z): 504.2 [M+H]+ .

[0327] Step 3. Preparation of 1-(2-(azetidin-3-yl)ethyl)-3-(3-(3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl)phenyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl 3-(2-(3-(3-(3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (80 mg, 0.16 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 1-(2-(azetidin-3-yl)ethyl)-3-(3-(3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl)phenyl)tetrahydropyrimidin-2(1H)-one as a brown oil (80 mg, purity: 60%). Mass (m / z): 404.2 [M+H] + .

[0328] Step 4. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(3-{2-[3-(3-{3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione: To a solution of 1-[2-(azetidin-3-yl)ethyl]-3-(3-{3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)-1,3-diazinan-2-one (80 mg, 0.20 mmol) in DMSO (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (55 mg, 0.20 mmol) and DIEA (77 mg, 0.59 mmol). The reaction mixture was stirred at 120 °C under N for 2 h. After the reaction was complete, HO (50 mL) was added to the reaction mixture, which was then extracted with EA (30 mL × 3). The combined organic layer was washed with brine (30 mL × 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product 2-(2,6-dioxopiperidin-3-yl)-5-(3-{2-[3-(3-{3-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione as a yellow solid (5 mg, 3%). Mass (m / z): 660.2 [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.59 (dd, J = 8.4, 5.6 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.61 (dd, J = 8.4, 2.2 Hz, 1H), 5.04 (dd, J = 12.4, 5.4 Hz, 1H), 4.61 (s, 1H), 4.20 (t, J = 8.2Hz, 2H), 3.86 - 3.72 (m, 4H), 3.50 (dt, J = 13.8, 6.4 Hz, 4H), 2.95 - 2.80 (m, 4H), 2.73 (d, J = 16.0 Hz, 2H), 2.20 (d, J = 5.7 Hz, 2H), 2.02 - 1.98 (m, 2H), 1.36 (t, J = 7.6 Hz, 3H).

[0329] Compound 28: 5-[4-({3-[3-(6-amino-2-chloropyridin-3-yl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0330] [ka]

[0331] Step 1. Preparation of tert-butyl 4-((3-(3-(6-amino-2-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of 5-bromo-6-chloropyridin-2-amine (200 mg, 0.96 mmol) in dioxane / HO (10:1, 10 mL) was added tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (482 mg, 0.96 mmol), KCO (267 mg, 1.93 mmol), and Pd(dppf)Cl (70 mg, 0.1 mmol). The reaction mixture was stirred at 90° C. under N for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH=0-3%) to give the product tert-butyl 4-((3-(3-(6-amino-2-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow oil (322 mg, 66%). Mass (m / z): 522.3 [M+Na] + .

[0332] Step 2. Preparation of 1-(3-(6-amino-2-chloropyridin-3-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl 4-((3-(3-(6-amino-2-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (322 mg, 0.81 mmol) in DCM (3 mL), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 1-(3-(6-amino-2-chloropyridin-3-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one as a brown oil (370 mg, purity: 60%). Mass (m / z): 422.3 [M+Na] + .

[0333] Step 3. Preparation of 5-[4-({3-[3-(6-amino-2-chloropyridin-3-yl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: To a solution of 1-(3-(6-amino-2-chloropyridin-3-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one (200 mg, 0.5 mmol) in DMSO (10 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (138 mg, 0.5 mmol) and DIEA (323 mg, 2.5 mmol). The reaction mixture was stirred at 120 °C under N for 2 hours. After the reaction was complete, HO (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product 5-[4-({3-[3-(6-amino-2-chloropyridin-3-yl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as a yellow solid (80 mg, 24%). Mass (m / z): 656.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 14.6, 6.8 Hz, 2H), 7.30 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.03 (dd, J = 8.6, 2.2 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 4.93 (dd, J = 12.2, 5.4 Hz, 1H), 4.61 (s, 2H), 3.96 (d, J = 13.0 Hz, 2H), 3.81 - 3.74 (m, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.30 (d, J = 7.2 Hz, 2H), 2.99 (t, J = 11.6 Hz, 2H), 2.86 (dd, J = 26.8, 14.6 Hz, 2H), 2.74 (d, J = 15.2 Hz, 1H), 2.18 - 2.13 (m, 2H), 1.83 (d, J = 10.6 Hz, 2H), 1.37 (dd, J = 24.4, 12.2 Hz, 4H).

[0334] Compound 29: 5-(4-((3-(4'-amino-2'-chloro-3'-ethyl-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0335] [ka]

[0336] Step 1. Preparation of 3-chloro-2-ethylaniline: To a mixture of 2-bromo-3-chloroaniline (1000 mg, 4.84 mmol), ethylboronic acid (1.78 g, 24.217 mmol), and KPO (3.08 g, 14.530 mmol) in dioxane / HO (10:1, 20 mL) was added Pd(dppf)Cl.. CHCl (359 mg, 0.484 mmol) was added. The reaction mixture was stirred at 110° C. under N for 18 h. The reaction mixture was concentrated, and the residue was purified by column chromatography (EA / PE=1:6) to give the desired product (300 mg, yield: 37%) as a yellow solid. Mass (m / z): 156 [M+H] + .

[0337] Step 2. Preparation of 4-bromo-3-chloro-2-ethylaniline: To a solution of 3-chloro-2-ethylaniline (200 mg, 1.927 mmol) in ACN (6 mL) was added NBS (377 mg, 2.12 mmol). The reaction mixture was stirred at room temperature under N for 18 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (EA / PE=1:1) to give the desired product (200 mg, yield: 42%) as a yellow solid. Mass (m / z): 234 [M+H] + .

[0338] Step 3. Preparation of tert-butyl 4-((3-(4'-amino-2'-chloro-3'-ethyl-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a mixture of 4-bromo-3-chloro-2-ethylaniline (220 mg, 0.938 mmol), tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (704 mg, 1.407 mmol), and potassium carbonate (259 mg, 1.876 mmol) in 1,4-dioxane / HO (10:1, 5 mL) was added Pd(dppf)Cl . CHCl (76 mg, 0.093 mmol) was added. The reaction mixture was stirred at 90° C. under N for 18 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by Combiflash with MeOH / DCM (1:10) to give the target compound (100 mg, yield: 19%) as a white solid. Mass (m / z): 527 [M+H]+ .

[0339] Step 4. Preparation of 1-(4'-amino-2'-chloro-3'-ethyl-[1,1'-biphenyl]-3-yl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl 4-((3-(4'-amino-2'-chloro-3'-ethyl-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (150 mg, 0.284 mmol) in DCM (2 mL) was added TFA (0.4 mL). The reaction mixture was stirred at room temperature under N for 18 hours. The solution was concentrated under reduced pressure to give the product (125 mg, 97%) as a brown solid. Mass (m / z): 426.9 [M+H] + .

[0340] Step 5. Preparation of 5-(4-((3-(4'-amino-2'-chloro-3'-ethyl-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: A solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (75 mg, 0.271 mmol), 1-[3-(4-amino-2-chloro-3-ethylphenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (127 mg, 0.298 mmol), and DIEA (350 mg, 2.715 mmol) in DMSO (5 mL) was stirred at 120 °C under N for 18 h. After the reaction was complete, HO (10 mL) was added to the reaction mixture, which was then extracted with EA (10 mL × 3). The combined organic layer was washed with brine (20 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum and the residue was purified by prep-HPLC [(Gemini-C18 150 × 21.2 mm, 5 μm; ACN-HO (0.1% FA), 50-70] to give the desired product (10 mg, yield: 5%) as a white solid. Mass (m / z): 683 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.30 - 7.26 (m, 2H), 7.20 - 7.15 (m, 1H), 7.02 (dd, J = 12.0, 5.2 Hz, 2H), 6.63 (d, J = 8.2 Hz, 1H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 3.95 (d, J = 13.0 Hz, 2H), 3.81 - 3.72 (m, 2H), 3.44 (t, J = 5.9 Hz, 2H), 3.30 (d, J = 7.2 Hz, 2H), 2.99 (t, J = 11.4 Hz, 2H), 2.92 - 2.66 (m, 5H), 2.19 - 2.03 (m, 4H), 1.83 (d, J = 10.8 Hz, 2H), 1.43 - 1.30 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H).

[0341] Compound 30: 5-{4-[(3-{3-[2-chloro-4-(ethylamino)phenyl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0342] [ka]

[0343] Step 1. Preparation of 4-bromo-3-chloro-N-ethylaniline: To a solution of 4-bromo-3-chloroaniline (1200 mg, 5.81 mmol) in MeOH (30 mL), acetaldehyde (256 mg, 75.8 mmol), NaBHCN (1096 mg, 17.44 mmol), and AcOH (0.02 mL) were added. The reaction mixture was stirred at 25 °C under N for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA = 0-2%) to give the product 4-bromo-3-chloro-N-ethylaniline as a yellow oil (300 mg, 22%). Mass (m / z): 235.9 [M+H] + .

[0344] Step 2. Preparation of tert-butyl 4-((3-(2'-chloro-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of 4-bromo-3-chloro-N-ethylaniline (300 mg, 1.28 mmol) in dioxane / HO (10 / 1, 10 mL) was added tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (960 mg, 1.92 mmol), KCO (354 mg, 2.56 mmol), and Pd(dppf)Cl (94 mg, 0.13 mmol). The reaction mixture was stirred at 90 °C under N for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash (PE / EA=0-50%) to give the product tert-butyl 4-((3-(2'-chloro-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a brown oil (370 mg, 54%). Mass (m / z): 549.2 [M+Na] + .

[0345] Step 3. Preparation of 1-(2'-chloro-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl 4-((3-(2'-chloro-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (270 mg, 0.51 mmol) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 1-(2'-chloro-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one as a yellow oil (300 mg, purity: 60%). Mass (m / z): 427.2 [M+H] + .

[0346] Step 4. Preparation of 5-{4-[(3-{3-[2-chloro-4-(ethylamino)phenyl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: To a solution of 1-(2'-chloro-4'-(ethylamino)-[1,1'-biphenyl]-3-yl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one (300 mg, 0.70 mmol) in DMSO (10 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (157 mg, 0.70 mmol) and DIEA (366 mg, 3.5 mmol). The reaction mixture was stirred at 120 °C under N for 2 h. After the reaction was complete, HO (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product 5-{4-[(3-{3-[2-chloro-4-(ethylamino)phenyl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as a yellow solid (58 mg, 14%). Mass (m / z): 683.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 14.8, 7.0 Hz, 3H), 7.21 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.69 (s, 1H), 6.56 (s, 1H), 4.93 (dd, J = 12.2, 5.4 Hz, 1H), 3.95 (d, J = 12.6 Hz, 2H), 3.78 (d, J = 5.4 Hz, 2H), 3.45 (d, J = 5.4 Hz, 2H), 3.30 (d, J = 6.8 Hz, 2H), 3.22 - 3.13 (m, 2H), 3.00 (d, J = 12.4 Hz, 2H), 2.87 (s, 3H), 2.13 (d, J = 12.4 Hz, 4H), 1.84 (d, J = 12.6 Hz, 2H), 1.43 - 1.35 (m, 2H), 1.28 (t, J = 7.0 Hz, 3H).

[0347] Compound 31: 3-chloro-4-{3-[3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}methyl)-2-oxo-1,3-diazinan-1-yl]phenyl}-N-methylbenzamide

[0348] [ka]

[0349] Step 1. Preparation of 4-bromo-3-chloro-N-methylbenzamide: To a solution of 4-bromo-3-chlorobenzoic acid (500 mg, 2.12 mmol) in DCM (20 mL) was added methanamine hydrochloride (143 mg, 2.12 mmol), DIEA (1372 mg, 10.62 mmol), and HATU (2423 mg, 6.37 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA = 0-50%) to give the product 4-bromo-3-chloro-N-methylbenzamide as a colorless oil (610 mg, 92%). Mass (m / z): 249.9 [M+H] + .

[0350] Step 2. Preparation of tert-butyl 4-((3-(2'-chloro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of 4-bromo-3-chloro-N-methylbenzamide (200 mg, 0.8 mmol) in dioxane / HO (10 / 1, 10 mL) was added tert-butyl 4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidine-1-carboxylate (402 mg, 0.80 mmol), KCO (222 mg, 1.61 mmol), and Pd(dppf)Cl (59 mg 0.08 mmol) was added. The reaction mixture was stirred at 90° C. under N2 for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-100%) to give the product tert-butyl 4-((3-(2'-chloro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow solid (276 mg, 63%). Mass (m / z): 563.1 [M+Na] + .

[0351] Step 3. Preparation of 3-chloro-N-methyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazinan-1-yl]phenyl}benzamide: A solution of tert-butyl 4-((3-(2'-chloro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (270 mg, 0.5 mmol) in HCl / dioxane (4.0 M, 10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 3-chloro-N-methyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazinan-1-yl]phenyl}benzamide as a yellow solid (210 mg, 95%). Mass (m / z): 441.0 [M+H] + .

[0352] Step 4. Preparation of 3-chloro-4-{3-[3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}methyl)-2-oxo-1,3-diazinan-1-yl]phenyl}-N-methylbenzamide: To a solution of 3-chloro-N-methyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazinan-1-yl]phenyl}benzamide (210 mg, 0.48 mmol) in DMSO (10 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (132 mg, 0.48 mmol) and DIEA (307 mg, 2.38 mmol). The reaction mixture was stirred at 120° C. under N for 2 h. After the reaction was completed, H2O (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-6%) to give the product as a yellow solid (40 mg, 12%). Mass (m / z): 697.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.26 (s, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.04 (dd, J = 8.6, 1.8 Hz, 1H), 6.28 (d, J = 4.6 Hz, 1H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 3.95 (d, J = 12.6Hz, 2H), 3.81 - 3.76 (m, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.30 (d, J = 7.2 Hz, 2H), 3.02 (d, J = 4.8 Hz, 3H), 2.97 (d, J = 11.6 Hz, 2H), 2.91 - 2.71 (m, 3H), 2.20 - 2.08 (m, 4H), 1.84 (d, J = 11.6 Hz, 2H), 1.38 (dd, J = 21.2, 11.8 Hz, 2H).

[0353] Compound 32: 3-chloro-4-{3-[3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}methyl)-2-oxo-1,3-diazinan-1-yl]phenyl}-N,N-dimethylbenzamide

[0354] [ka]

[0355] Step 1. Preparation of 4-bromo-3-chloro-N,N-dimethylbenzamide: To a solution of 4-bromo-3-chlorobenzoic acid (500 mg, 2.12 mmol) in DCM (20 mL) was added dimethylamine hydrochloride (173 mg, 2.12 mmol), DIEA (1372 mg, 10.62 mmol), and HATU (2423 mg, 6.37 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA = 0-50%) to give the product 4-bromo-3-chloro-N,N-dimethylbenzamide as a colorless oil (690 mg, 74%). Mass (m / z): 263.9 [M+H] + .

[0356] Step 2. Preparation of tert-butyl 4-((3-(2'-chloro-4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of 4-bromo-3-chloro-N,N-dimethylbenzamide (158 mg, 0.6 mmol) in dioxane / HO (10 / 1, 15 mL) was added tert-butyl 4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidine-1-carboxylate (300 mg, 0.6 mmol), KCO (166 mg, 1.2 mmol), and Pd(dppf)Cl (44 mg 0.06 mmol) was added. The reaction mixture was stirred at 90° C. under N2 for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-100%) to give the product tert-butyl 4-((3-(2'-chloro-4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow oil (240 mg, 71%). Mass (m / z): 577.0 [M+Na] + .

[0357] Step 3. Preparation of 3-chloro-N,N-dimethyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazinan-1-yl]phenyl}benzamide: A solution of tert-butyl 4-((3-(2'-chloro-4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (240 mg, 0.43 mmol) in HCl / dioxane (4.0 M, 10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 3-chloro-N,N-dimethyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazinan-1-yl]phenyl}benzamide as a yellow solid (260 mg, 92%). Mass (m / z): 455.0 [M+H] + .

[0358] Step 4. Preparation of 3-chloro-4-{3-[3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}methyl)-2-oxo-1,3-diazinan-1-yl]phenyl}-N,N-dimethylbenzamide: To a solution of 3-chloro-N,N-dimethyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazinan-1-yl]phenyl}benzamide (260 mg, 0.57 mmol) in DMSO (10 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (158 mg, 0.57 mmol) and DIEA (369 mg, 2.86 mmol). The reaction mixture was stirred at 120 °C under N for 2 h. After the reaction was complete, HO (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product 3-chloro-4-{3-[3-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl}methyl)-2-oxo-1,3-diazinan-1-yl]phenyl}-N,N-dimethylbenzamide as a yellow solid (120 mg, 29%). Mass (m / z): 711.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 1.4 Hz, 1H), 7.40 (dd, J = 7.6, 5.0 Hz, 2H), 7.37 - 7.32 (m, 3H), 7.27 (d, J = 2.2 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.06 (d, J = 2.2 Hz, 1H), 4.96 - 4.90 (m, 1H), 3.95 (d, J = 13.2 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.30 (d, J = 7.2 Hz, 2H), 3.13 (s, 3H), 3.04 (s, 3H), 2.99 (s, 2H), 2.87 (s, 3H), 2.21 - 2.07 (m, 4H), 1.84 (d, J = 11.2 Hz, 2H), 1.39 (d, J = 9.2 Hz, 2H).

[0359] Compound 33: 5-[4-({3-[3-(2-chloro-4-methanesulfonylphenyl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0360] [ka]

[0361] Step 1. Preparation of 4-bromo-2-iodo-1-(methylsulfanyl)benzene: To a solution of 4-bromo-1-fluoro-2-iodobenzene (1000 mg, 3.32 mmol) in DMF (20 mL) was added MeSNa (1396 mg, 19.94 mmol) and K2CO3 (919 mg, 6.65 mmol). The reaction mixture was stirred at 80 °C under N2 for 16 h. After the reaction was completed, HO (200 mL) was added to the reaction mixture, which was then extracted with EA (100 mL × 3). The combined organic layer was washed with brine (50 mL × 3) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the product, 4-bromo-2-iodo-1-(methylsulfanyl)benzene, as a colorless oil (1300 mg, 71%). Mass (m / z): 352.0 [M+Na] + .

[0362] Step 2. Preparation of 1-bromo-2-chloro-4-methanesulfonylbenzene: To a solution of 1-bromo-2-chloro-4-(methylsulfanyl)benzene (700 mg, 2.95 mmol) in DCM (20 mL) was added 3-chloroperoxybenzoic acid (1526 mg, 8.84 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. After the reaction was complete, HO (100 mL) was added to the reaction mixture, which was then extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (PE / EA = 0-100%) to give the product, 1-bromo-2-chloro-4-methanesulfonylbenzene, as a white solid (500 mg, 62%). Mass (m / z): 267.2 [M+H] + .

[0363] Step 3. Preparation of tert-butyl 4-((3-(2'-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of 1-bromo-2-chloro-4-methanesulfonylbenzene (300 mg, 1.11 mmol) in dioxane / HO (15 mL) was added tert-butyl 4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidine-1-carboxylate (1112 mg, 2.23 mmol), KCO (308 mg, 2.23 mmol), and Pd(dppf)Cl (81 mg 0.11 mmol) was added. The reaction mixture was stirred at 80° C. under N2 for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA=0-100%) to give the product tert-butyl 4-((3-(2'-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate as a yellow solid (150 mg, 23%). Mass (m / z): 584.0 [M+Na] + .

[0364] Step 4. Preparation of 1-[3-(2-chloro-4-methanesulfonylphenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one: To a solution of tert-butyl 4-((3-(2'-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (150 mg, 0.27 mmol) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated to give the product 1-[3-(2-chloro-4-methanesulfonylphenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one as a yellow solid (200 mg, purity: 60%). Mass (m / z): 462.0 [M+H] + .

[0365] Step 5. Preparation of 5-[4-({3-[3-(2-chloro-4-methanesulfonylphenyl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: To a solution of 1-[3-(2-chloro-4-methanesulfonylphenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (200 mg, 0.43 mmol) in DMSO (10 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (120 mg, 0.43 mmol) and DIEA (279 mg, 2.16 mmol). The reaction mixture was stirred at 80 °C under N for 2 hours. After the reaction was completed, HO (100 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and then dried over anhydrous NaSO. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product 5-[4-({3-[3-(2-chloro-4-methanesulfonylphenyl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as a yellow solid (15 mg, 4%). Mass (m / z): 718.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.49 (dd, J = 8.4, 2.0 Hz, 1H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 4.18 (t, J = 8.0 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.72 (dd, J = 7.8, 5.6 Hz, 2H), 3.55 - 3.47 (m, 2H), 3.36 (t, J = 6.8 Hz, 2H), 2.93 - 2.69 (m, 4H), 2.12 (dd, J = 7.8, 5.4 Hz, 1H), 2.03 - 1.92 (m, 2H).

[0366] Compound 34: 5-(4-((3-(3-(7-chloro-1-ethyl-1H-indazol-6-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0367] [ka]

[0368] Step 1. Preparation of 4-bromo-3-chloro-2-fluorobenzaldehyde: To a solution of 1-bromo-2-chloro-3-fluorobenzene (2000 mg, 9.549 mmol) in THF (20 mL) was added LDA (2 M in THF, 7.2 mL, 14.32 mmol) dropwise at −78° C. under N2. The reaction mixture was stirred at −78° C. under N2 for 1 hour. DMF (1046 mg, 14.323 mmol) was added dropwise at −78° C. under N2. The reaction mixture was stirred at room temperature under N2 for 3 hours. The solution was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by column chromatography (DCM / PE=1:10) to give the target compound (700 mg, 52%) as a brown oil.

[0369] Step 2. Preparation of 6-bromo-7-chloro-1-ethyl-1H-indazole: To a solution of 4-bromo-3-chloro-2-fluorobenzaldehyde (600 mg, 2.562 mmol) in NMP (12 mL) was added ethylhydrazine dihydrochloride (1219 mg, 12.634 mmol), potassium carbonate (1746 mg, 12.634 mmol), and TEA (1276 mg, 12.634 mmol). The reaction mixture was stirred at 160 °C under N for 18 h. Water (30 mL) was added, and the mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over NaSO. The filtrate was then concentrated by filtration. The residue was purified by column chromatography (EA / PE = 1:2) to give the target product (300 mg, 43.46%) as a white solid. Mass (m / z): 259 [M+H] + .

[0370] Step 3. Preparation of tert-butyl 4-((3-(3-(7-chloro-1-ethyl-1H-indazol-6-yl)phenyl)-2oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a mixture of 6-bromo-7-chloro-1-ethylindazole (300 mg, 1.155 mmol), tert-butyl [4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]formate (867 mg, 1.733 mmol), and potassium carbonate (319 mg, 2.311 mmol) in 1,4-dioxane / HO (10:1, 6 mL) under N was added Pd(dppf)Cl (94 mg, 0.115 mmol). The reaction mixture was stirred at 90 °C for 18 h. The mixture was concentrated, and the residue was purified by Combiflash (MeOH / DCM=1:10) to give the target compound (300 mg, yield: 44.58%) as a white solid. Mass (m / z): 474 [M+Na] + .

[0371] Step 4. Preparation of 1-(3-(7-chloro-1-ethyl-1H-indazol-6-yl)phenyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl [4-({3-[3-(7-chloro-1-ethylindazol-6-yl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]formate (300 mg, 0.542 mmol) in DCM (3 mL) was added TFA (0.6 mL). The reaction mixture was stirred at room temperature under N for 18 hours. The solution was concentrated under reduced pressure to give the target compound (200 mg, 73%) as a brown oil. Mass (m / z): 452 [M+H] + .

[0372] Step 5. Preparation of 5-(4-((3-(3-(7-chloro-1-ethyl-1H-indazol-6-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: A solution of 1-[3-(7-chloro-1-ethylindazol-6-yl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (100 mg, 0.221 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (73 mg, 0.265 mmol), and DIEA (285 mg, 2.212 mmol) in DMSO (5 mL) was stirred at 120 °C under N for 1 h. Water (20 mL) was added, and the mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3) and dried over Na SO . The filtrate was then concentrated by filtration. The residue was purified by prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN—HO (0.1% FA), 20–50] to give the desired product (7 mg, 4.39%) as a yellow solid. Mass (m / z): 708 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.21 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.47 - 7.28 (m, 4H), 7.28 - 7.18 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 4.84 - 4.75 (m, 2H), 4.06 (d, J = 12.6 Hz, 2H), 3.73 (d, J = 5.9 Hz, 2H), 3.38 (d, J = 5.9 Hz, 2H), 3.20 (d, J = 7.0 Hz, 2H), 2.97 (t, J = 11.7 Hz, 2H), 2.86 (d, J = 13.5 Hz, 1H), 2.60 (s, 2H), 2.05 (s, 4H), 1.71 (d, J = 11.7 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.21 (d, J = 19.9 Hz, 2H).

[0373] Compound 35: 5-(4-((3-(2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0374] [ka]

[0375] Step a. Preparation of 1-(5-bromo-4-chloro-1H-indol-3-yl)ethan-1-one: To a solution of AlCl (28.91 g, 216.93 mmol) in DCM (100 mL) was added dropwise acetyl chloride (8.51 g, 108.46 mmol) at 0 °C. Then, 5-bromo-4-chloro-1H-indole (5 g, 21.69 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature under N for 18 hours. The mixture was poured into ice water, whereupon a brown solid precipitated. The mixture was filtered, and the cake was dried to obtain the target compound (5.5 g, 88.38%) as a brown solid. Mass (m / z): 272 [M+H] + .

[0376] Step b. Preparation of 5-bromo-4-chloro-3-ethyl-1H-indole: To a solution of AlCl (26.9 g, 201.81 mmol) in DME (500 mL) was added LiAlH (3.83 g, 100.91 mmol) at 0 °C. Then, 1-(5-bromo-4-chloro-1H-indol-3-yl)ethenone (5.5 g, 20.181 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature under N for 3 hours. The mixture was poured into ice water, and the mixture was extracted with EA (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over Na SO , and concentrated to give the target compound (2.5 g, 45.52%) as a gray solid. Mass (m / z): 258 [M+H] + .

[0377] Step c. Preparation of 4-chloro-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole: To a mixture of 5-bromo-4-chloro-3-ethyl-1H-indole (500 mg, 1.933 mmol), B2Pin2 (736 mg, 2.9 mmol), and potassium acetate (379 mg, 3.867 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl (157 mg, 0.193 mmol) under N. The reaction mixture was stirred at 90 °C under N for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 1:6) to give the target compound (250 mg, 38.07%) as a white solid. Mass (m / z): 306 [M+H] + .

[0378] Step 1. N 1 Preparation of -(2-bromopyridin-4-yl)propane-1,3-diamine: To a mixture of CuCl (17 mg, 0.176 mmol) in propane-1,3-diamine (2 mL) was added 2-bromo-4-iodopyridine (500 mg, 1.761 mmol) at 0° C. The reaction mixture was stirred at 0° C. under N2 for 2 hours. Water (20 mL) was added and extracted with DCM (20 mL × 2). The DCM layer was washed with brine (20 mL × 2), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (MeOH / DCM = 1:1) to give the target compound (200 mg, 44.42%) as a brown solid. Mass (m / z): 230 [M+H] + .

[0379] Step 2. Preparation of tert-butyl 4-(((3-((2-bromopyridin-4-yl)amino)propyl)amino)methyl)piperidine-1-carboxylate: To a solution of N-(3-aminopropyl)-2-bromopyridin-4-amine (200 mg, 0.869 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (185 mg, 0.869 mmol) in MeOH (2 mL) was added NaBHCN (163 mg, 2.607 mmol) at 0° C. The reaction mixture was stirred at room temperature under N for 18 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=10:1) to give the target compound (260 mg, yield: 66.49%) as a brown oil. Mass (m / z): 427 [M+H] + .

[0380] Step 3. Preparation of tert-butyl 4-((3-(2-bromopyridin-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-[({3-[(2-bromopyridin-4-yl)amino]propyl}amino)methyl]piperidine-1-carboxylate (260 mg, 0.608 mmol) and DIEA (156 mg, 1.2168 mmol) in DCM (10 mL) was added a solution of triphosgene (90 mg, 0.304 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at 40 °C under N for 18 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE=1:1) to give the target compound (150 mg, yield: 51.66%) as a brown solid. Mass (m / z): 453 [M+H]+.

[0381] Step 4. Preparation of tert-butyl 4-((3-(2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a mixture of tert-butyl 4-{[3-(2-bromopyridin-4-yl)-2-oxo-1,3-diazinan-1-yl]methyl}piperidine-1-carboxylate (200 mg, 0.441 mmol), 4-chloro-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (202 mg, 0.661 mmol), and potassium carbonate (121 mg, 0.852 mmol) in 1,4-dioxane / HO (10:1, 2 mL) was added Pd(dppf)Cl (35 mg, 0.044 mmol) under N. The reaction mixture was stirred at 90 °C under N for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by Combiflash (MeOH / DCM=1:10) to give the target compound (200 mg, yield: 73.91%) as a white solid. Mass (m / z): 552 [M+H] + .

[0382] Step 5. Preparation of 1-(2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: To a solution of tert-butyl 4-({3-[2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidine-1-carboxylate (300 mg, 0.542 mmol) in DCM (3 mL) was added TFA (0.6 mL). The reaction mixture was stirred at room temperature under N for 18 hours. The solution was concentrated under reduced pressure to give the target compound (150 mg, 48.86%) as a brown oil. Mass (m / z): 452 [M+H] + .

[0383] Step 6. Preparation of 5-(4-((3-(2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Solution of 1-[2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl]-3-(piperidin-4-ylmethyl)-1,3-diazinan-2-one (100 mg, 0.221 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (73 mg, 0.265 mmol) and DIEA (285 mg, 2.212 mmol) in DMSO (5 mL). The reaction mixture was stirred at 120°C under N2 for 1 hour. Water (20 mL) was added, and the mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by prep-HPLC [Gemini-C18, 150 x 21.2 mm, 5 um; ACN-H2O (0.1% FA), 20-50] to give the desired product (7.5 mg, 4.66%) as a yellow solid. Mass (m / z): 708 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 11.08 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 43.1 Hz, 4H), 7.17 (d, J = 8.3 Hz, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.07 (d, J = 12.6 Hz, 2H), 3.83 - 3.74 (m, 2H), 3.39 (s, 4H), 3.23 (d, J = 7.2 Hz, 2H), 2.97 (d, J = 7.0 Hz, 3H), 2.54 (s, 3H), 2.06-1.98 (m, 4H), 1.71 (d, J = 10.9 Hz, 2H), 1.29-1.21 (m, 5H).

[0384] Compound A: 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0385] [ka]

[0386] Step 1. Preparation of tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (11.1 g, 24.48 mmol) in dioxane (200 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (9.3 g, 36.72 mmol), KOAc (7.2 g, 73.45 mmol), and Pd(dppf)Cl (1.79 g, 2.45 mmol). The reaction mixture was stirred at 90 °C under N for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH=0-10%) to give the product as a brown oil (12.3 g, 80%). Mass (m / z): 522.0 [M+H] + .

[0387] Step 2. Preparation of tert-butyl 4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (12.3 g, 24.58 mmol) in dioxane / HO (10:1, 200 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (6.37 g, 24.58 mmol), KCO (10.19 g, 73.73 mmol), and Pd(dppf)Cl (1.79 g, 2.46 mmol). The reaction mixture was stirred at 90 °C under N for 4 h. After the reaction was completed, HO (300 mL) was added to the reaction mixture, which was then extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (300 mL x 2) and then dried over anhydrous NaSO. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product as a brown solid (5.83 g, 39%). Mass (m / z): 552.0 [M+H] + .

[0388] Step 3. Preparation of 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Preparation of tert-butyl 4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione according to Steps 3 and 4 of General Synthetic Procedure I. From 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate, the compound 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained as a yellow solid (1.45 g, 21%). Mass (m / z): 707.7 [M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.08 (s, 1H), 8.11 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.37 (ddd, J = 25.2, 13.8, 8.2 Hz, 5H), 7.22 (t, J = 9.8 Hz, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.07 (d, J = 12.8 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.39 (t, J = 5.8 Hz, 2H), 3.20 (d, J = 7.2 Hz, 2H), 3.02 - 2.82 (m, 5H), 2.62 - 2.53 (m, 2H), 2.03 (dd, J = 12.8, 7.2 Hz, 4H), 1.71 (d, J = 11.8 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H).

[0389] Compound B: 5-(4-((3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0390] [ka]

[0391] Step 1. Preparation of tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: Following Steps 1 and 2 of General Synthetic Procedure I, the product tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 56%) was obtained from tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate as a yellow oil. Mass (m / z): 488.2 [M+H] + .

[0392] Step 2. Preparation of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 1.41 mmol) in dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (538 mg, 2.12 mmol), KOAc (416 mg, 4.24 mmol), and Pd(dppf)Cl (103 mg, 0.14 mmol). The reaction mixture was stirred at 90 °C under N for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product (650 mg, 89%) as a brown oil. Mass (m / z): 536.0 [M+H] + .

[0393] Step 3. Preparation of tert-butyl 4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (650 mg, 1.26 mmol) in dioxane / HO (10:1, 15 mL) was added 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (343 mg, 1.26 mmol), KCO (523 mg, 3.79 mmol), and Pd(dppf)Cl (92 mg, 0.13 mmol). The reaction mixture was stirred at 90 °C under N for 4 h. After the reaction was complete, HO (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL x 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combiflash (DCM / MeOH = 0-10%) to give the product (250 mg, 34%) as a yellow oil. Mass (m / z): 578.3 [M+H] + .

[0394] Step 4. Preparation of 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione: Preparation of tert-butyl 4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione according to Steps 3 and 4 of General Synthetic Procedure I. From 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate, the compound 5-(4-(2-(3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione was obtained as a yellow solid (85 mg, 23%). Mass (m / z): 751.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (d, J = 2.4 Hz, 1H), 11.11 (s, 1H), 8.11 (s, 1H), 7.69 (d, J = 11.6 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.34 - 7.28 (m, 2H), 7.23 - 7.19 (m, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.75 - 3.69 (m, 2H), 3.59 (d, J = 12.4 Hz, 2H), 3.36 (d, J = 10.2 Hz, 4H), 2.90 - 2.82 (m, 3H), 2.56 (dd, J = 19.8, 10.6 Hz, 2H), 2.23 - 2.15 (m, 1H), 2.04 (dd, J = 14.6, 9.2 Hz, 3H), 1.84 (d, J = 11.8 Hz, 2H), 1.50 (d, J = 6.8 Hz, 3H), 1.37 - 1.28 (m, 2H), 0.83 (ddd, J = 8.2, 6.0, 4.0 Hz, 2H), 0.66 - 0.60 (m, 2H).

[0395] Compound C: 3-(5-{4-[(3-{3-[4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

[0396] [ka]

[0397] Step 1. Preparation of 3-(5-{4-[(3-{3-[4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione: To a solution of 3-{1-oxo-5-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (70 mg, 0.11 mmol), 5-bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine (39 mg, 0.11 mmol), and KPO (69 mg, 0.33 mmol) in 1,4-dioxane / HO (10:1, 3 mL) was added Pd(dppf)Cl (8 mg, 0.011 mmol). The solution was stirred under nitrogen at 85 °C for 16 hours. The reaction was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over Na2SO4. The filtrate was then concentrated by filtration. The residue was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 μm; ACN—H2O (0.1% FA), 35–50] to give the product as a yellow solid (2 mg, 2.5%). Mass (m / z): 730.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 10.93 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.43 - 7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 5.03 (d, J = 12.6 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.18 (d, J = 17.2 Hz, 1H), 3.89 (d, J = 11.4 Hz, 2H), 3.74 (s, 2H), 3.54 (d, J = 16.6 Hz, 2H), 3.40 (s, 2H), 3.20 (s, 2H), 2.85 (dd, J = 25.6, 13.0 Hz, 2H), 2.63 (d, J = 28.0 Hz, 2H), 2.33 (s, 1H), 2.06 (s, 2H), 1.93 (s, 2H), 1.70 (d, J = 11.0 Hz, 2H), 1.24 (s, 2H).

[0398] Compound D: 3-(6-{4-[(3-{3-[4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

[0399] [ka]

[0400] Step 1. Preparation of 3-(6-{4-[(3-{3-[4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}-2-oxo-1,3-diazinan-1-yl)methyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione: 3-{1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (100 mg, 0.15 mmol), 3 To a solution of -bromo-4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridine (55 mg, 0.18 mmol) and KPO (99 mg, 0.46 mmol) in 1,4-dioxane / HO (5 mL) was added Pd(dppf)Cl (11 mg, 0.015 mmol). The solution was stirred at 85 °C under nitrogen for 16 h. The reaction was cooled to room temperature. Water (15 mL) was added and the mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and dried over NaSO. It was then filtered, and the filtrate was concentrated. The crude product was purified by Prep-HPLC [Gemini-C18, 150 × 21.2 mm, 5 um; Purification with ACN-H2O (0.1% FA), 30-50] gave the product as a yellow solid (6 mg, 5.1%). Mass (m / z): 730.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.10 (d, J = 1.8 Hz, 1H), 10.97 (s, 1H), 8.15 (d, J = 12.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.38 (td, J = 15.2, 7.8 Hz, 4H), 7.23 (dd, J = 16.4, 8.0 Hz, 2H), 7.15 (s, 1H), 6.48 - 6.12 (m, 1H), 5.09 (dd, J = 13.2, 5.0 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.86 - 3.66 (m, 4H), 3.52 (td, J = 17.2, 4.2 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.22 (d, J = 7.2 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.71 (t, J = 11.5 Hz, 2H), 2.58 (d, J = 17.0 Hz, 1H), 2.42 - 2.29 (m, 1H), 2.10 - 2.00 (m, 2H), 1.98-1.85 (m, 2H), 1.71 (d, J = 11.2 Hz, 2H), 1.32-1.23 (m, 2H).

[0401] Compound E: 5-({2-[3-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0402] [ka]

[0403] Step 1. Preparation of tert-butyl N-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}carbamate: According to Steps 1 and 2 of General Synthetic Procedure I, the compound tert-butyl N-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}carbamate was obtained from N-(3-aminopropyl)-3-bromoaniline as a yellow solid (0.93 g, 85%). Mass (m / z): 420.0 [M+Na] + .

[0404] Step 2. Preparation of tert-butyl-N-(2-{2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}ethyl)carbamate: To a mixture of tert-butyl-N-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}carbamate (930 mg, 2.33 mmol) in dioxane (20 mL) was added KOAc (687 mg, 7.01 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.18 g, 4.67 mmol), and Pd(dppf)Cl (171 mg, 0.233 mmol). The reaction was degassed with N and stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL), then extracted with EA (50 mL × 3), washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 0-50%) to give the product tert-butyl-N-(2-{2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}ethyl)carbamate as a yellow solid (0.53 g, 46%). Mass (m / z): 445.3 [M+H] + .

[0405] Step 3. Preparation of tert-butyl-N-{2-[3-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}carbamate: To a mixture of tert-butyl-N-(2-{2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazinan-1-yl}ethyl)carbamate (500 mg, 1.12 mmol) in dioxane / HO (10:1, 10.0 mL) was added KCO (465 mg, 3.37 mmol), 3-bromo-4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridine (320 mg, 1.23 mmol), and Pd(dppf)Cl (82 mg, 0.112 mmol). The reaction was degassed with N and stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL), then extracted with EA (50 mL × 3), washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EA = 0-60%) to give the product tert-butyl-N-{2-[3-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}carbamate as a brown solid (430 mg, 69%). Mass (m / z): 498.2 [M+H] + .

[0406] Step 4. Preparation of 5-({2-[3-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: According to Steps 3 and 4 of General Synthetic Procedure I, tert-butyl-N-{2-[3-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione was prepared. 3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}carbamate to give the compound 5-({2-[3-(3-{4-chloro-5-ethyl-7H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2-oxo-1,3-diazinan-1-yl]ethyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as a yellow solid (15 mg, 5%). Mass (m / z): 654.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 13.23 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.40 - 7.33 (m, 3H), 6.95 (s, 1H), 6.75 (d, J = 7.8 Hz, 1H), 4.91 (dd, J = 11.8, 5.0 Hz, 1H), 3.75 (s, 4H), 3.47 (d, J = 28.4 Hz, 4H), 3.04 (dd, J = 14.6, 7.2 Hz, 2H), 2.90 - 2.69 (m, 3H), 2.18-2.09 (m, 3H), 1.36 (t, J = 7.2 Hz, 3H).

[0407] Compound F: 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0408] [ka]

[0409] Step 1. Preparation of tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: Follow Steps 1 and 2 of General Synthetic Procedure I to prepare N 1 From -(3-bromophenyl)propane-1,3-diamine, the compound tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate was obtained as a yellow oil (880 mg, 39%). Mass (m / z): 462.2 [M+H] + .

[0410] Step 2. Preparation of tert-butyl 3-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: To a solution of tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (740 mg, 1.68 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (642 mg, 2.53 mmol), KOAc (825 mg, 8.42 mmol), and Pd(dppf)Cl (62 mg, 0.08 mmol). The reaction mixture was stirred at 90° C. under N for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by Combiflash (PE / EA = 0-100%) to give the product tert-butyl 3-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (450 mg, 54%). Mass (m / z): 486.2 [M+H] + .

[0411] Step 3. Preparation of tert-butyl 3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: To a solution of tert-butyl 3-(2-(2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate (450 mg, 0.9 mmol) in dioxane / HO (10:1, 15 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (240 mg, 0.93 mmol), KCO (383 mg, 2.78 mmol), and Pd(dppf)Cl (68 mg, 0.09 mmol). The reaction mixture was stirred at 90 °C under N for 4 h. After the reaction was complete, HO (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated under vacuum, and the residue was purified by Combiflash (DCM / MeOH = 0-2%) to give the product tert-butyl 3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate as a yellow oil (370 mg, 74%). Mass (m / z): 538.1 [M+H] + .

[0412] Step 4. Preparation of 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: According to Steps 3 and 4 of General Synthetic Procedure I, tert-butyl 3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was prepared. 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-dione was obtained as a yellow solid (136 mg, 21%) from 5-(3-(2-(3-(3-(4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Mass (m / z): 694.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (d, J = 2.4 Hz, 1H), 11.07 (s, 1H), 8.11 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.43 - 7.30 (m, 4H), 7.21 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 8.4, 2.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.14 (t, J = 8.2 Hz, 2H), 3.78 - 3.65 (m, 4H), 3.39 (t, J = 5.8 Hz, 2H), 3.31 (s, 2H), 2.90 (dd, J = 14.8, 7.4 Hz, 2H), 2.81 (dd, J = 22.9, 6.8 Hz, 2H), 2.60 (s, 1H), 2.54 (s, 2H), 2.09 - 2.03 (m, 2H), 1.89 (d, J = 6.8 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H).

[0413] General assay procedure: GSPT1 degradation assay HL-60 cells (4×10^ 6 Cells (cells / well) were seeded into 6-well culture plates (Costar, 3516) and treated with various concentrations of test compounds. After 2 hours of incubation, cells were harvested and lysed. Protein concentrations were determined using a BCA protein assay kit (Thermo, 23227). GSPT1 protein levels were determined by Western blot using a GSPT1 polyclonal antibody. Proteins were loaded into each well of a precast gel and subjected to electrophoretic separation by SDS-PAGE. Proteins resolved by SDS-PAGE were transferred to PVDF, blocked with 5% nonfat milk, and probed with anti-GSPT1 antibody (Proteintech, 10763-1-AP) or anti-β-actin antibody (CST, 3700S) using standard Western blotting procedures. Blot intensities were quantified using ImageJ software, and the intensities of the GSPT1 bands were normalized to the respective β-actin bands. GSPT1 degradation results were then calculated. The reported compound C84971 (see WO2021126974A1 and WO2021126973A1) was used as a reference. The results of the degradation assay are shown in Table 2 below.

[0414] [Table 5A]

[0415] [Table 5B]

[0416] The above results show that most of the compounds listed in Table 2 have much better GSPT1 degradation than the previously reported compound C84971 (see WO2021126974A1 and WO2021126973A1).

[0417] Cell viability assay HL-60 cells were seeded at a density of 7000 cells per well in 96-well culture plates (Corning 3903) with IMDM and treated with test compounds according to a six-point serial dilution. RPMI 1640 (0.1% DMSO) was used as a control for each well. After 72 hours of incubation, cell viability was determined using the CellTiter-Glo Assay Kit (Promega, G9242) according to the manufacturer's instructions. Dose-response curves were determined and IC values ​​were calculated according to the nonlinear regression method using GraphPad Prism software. 50 The values ​​were calculated. The results of the cell viability assay are shown in Table 3 below.

[0418] [Table 6]

[0419] Other embodiments The present disclosure provides merely illustrative embodiments. Those skilled in the art will readily recognize from the present disclosure and the claims that various changes, modifications, and variations can be made without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

1. Formula (I): 【Chemical 1】 a compound of the formula: (xvii) each R' is independently selected from hydrogen, halogen, straight-chain, branched, and cyclic alkyl groups; (xviii) m and n are independently selected from 0, 1, and 2; (xix) X and Z are independently selected from: zero or a linear, branched, or cyclic alkylene group; a linear, branched, or cyclic heteroalkylene group; and a linear, branched, or cyclic alkyl group; (xx) Y and W are independently absent, -O-, -C(O)-, or -C(O)R x -, -C(S)-, -C(S)R x -, -[C(R x R y )] p -, -S-, -S(O) 2 -, -S(O) 2 R x -, NR x - and -NR x C(O)-; further wherein p is selected from 1, 2, 3, 4, 5, and 6; R x is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups; (xxi) Ring A is 【Chemistry 2】 (In the formula, R a is selected from hydrogen, straight-chain, branched, and cyclic alkyl groups, and prodrug groups; each R 1 and each R 2 is hydrogen, halogen, OR z and linear, branched, and cyclic alkyl groups; z is selected from hydrogen, linear, branched and cyclic alkyl groups, carbocyclic groups, heterocyclic groups, aryl groups, and heteroaryl groups. Selected from; (xxii) Ring B is absent or selected from optionally substituted cycloalkyl groups and heterocycloalkyl groups; (xxiii) Ring C is absent or selected from optionally substituted aryl and heteroaryl groups; (xxiv) Ring D is selected from absent or optionally substituted cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups; wherein the linear, branched and cyclic alkyl groups, linear, branched and cyclic alkenyl groups, linear, branched and cyclic alkylene groups, carbocyclic groups, linear and branched heteroalkenyl groups, linear, branched and cyclic alkynyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are optionally substituted with at least one group selected from the following groups: halogen groups, Hydroxy, thiols, amino, Cyano, -OC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)OC 1 ~C 6 linear, branched and cyclic alkyl groups; -NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -N(C 1 ~C 6 linear, branched and cyclic alkyl groups) 2 , -NHC(O)C 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)NHC 1 ~C 6 linear, branched and cyclic alkyl groups; -C(O)N(C 1 ~C 6 ) 2 linear, branched and cyclic alkyl groups; -NH aryl group, -N (aryl group) 2 , -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) 2 , -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -S(O) 2 C 1 ~C 6 linear, branched and cyclic alkyl groups; C 1 ~C 6 linear, branched and cyclic alkyl groups; C 2 ~C 6 linear, branched and cyclic alkenyl groups, C 1 ~C 6 linear, branched and cyclic hydroxyalkyl groups; C 1 ~C 6 linear, branched and cyclic aminoalkyl groups; C 1 ~C 6 linear, branched and cyclic alkoxy groups, C 1 ~C 6 linear, branched and cyclic thioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkyl groups; C 1 ~C 6 linear, branched and cyclic haloaminoalkyl groups; C 1 ~C 6 linear, branched and cyclic halothioalkyl groups; C 1 ~C 6 linear, branched and cyclic haloalkoxy groups; benzyloxy, benzylamino, and benzylthio groups, a 3- to 6-membered heterocycloalkenyl group; 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups].

2. Ring A 【Chemistry 3】 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 46, wherein:

3. Ring A 【Chemistry 4】 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 46, wherein:

4. Ring A 【Chemistry 5】 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 46, wherein:

5. Ring A 【Chemistry 6】 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 46, wherein:

6. 【Table 1A】 Table 1B Table 1C Table 1D a compound selected from: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

7. 10. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of claims 1 to 6, and at least one pharmaceutically acceptable carrier.

8. A method for treating or alleviating a disease, disorder, or condition mediated by degradation of GSPT1 protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt of any one of claims 1 to 6, or the pharmaceutical composition of claim 7.

9. 10. A method for reducing GSPT1 protein activity in a disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt of any one of claims 1 to 6, or a pharmaceutical composition of claim 7.

10. 【Table 2】 A method for treating or alleviating a disease, disorder, or condition mediated by degradation of GSPT1 protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from: 【Request 11】 【Table 3】 A method for reducing GSPT1 protein activity in a disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from:

12. 12. The method of any one of claims 8 to 11, wherein the disease, disorder, or condition is cancer.

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