GSPT1 degradation agent, composition containing GSPT1 degradation agent and use method of GSPT1 degradation agent

Abstract

The present application provides a compound of formula (I), a tautomer thereof, a deuterated derivative of the compound or the tautomer, and a pharmaceutically acceptable salt of the above, a composition comprising the compound of formula (I), the tautomer thereof, the deuterated derivative of the compound or the tautomer, and / or the pharmaceutically acceptable salt of the above, and methods of using the compositions in the treatment of diseases, disorders, or conditions mediated, for example, by Gl to S phase conversion protein 1 (GSPT1) degradation. # imgabs0 #

Description

TECHNICAL FIELD

[0001] The present disclosure provides compounds of formula I, their tautomers, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of the foregoing substances; compositions comprising compounds of formula I, their tautomers, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances; and methods of using the compositions to treat diseases, disorders or conditions mediated by, for example, G1 to S phase transition 1 (GSPT1) protein degradation. BACKGROUND ART

[0002] Abnormal protein function and misregulation of protein synthesis can lead to uncontrolled cell growth, proliferation, and migration, resulting in cancer. Translation termination is a GTP-dependent process that is regulated by two key proteins, eukaryotic release factor eRF1 and eRF3. The translation termination factor eRF3, also known as GSPT1 (G1 to S phase transition 1) protein, is a GTPase that interacts with eRF1 to promote termination codon recognition and the release of nascent peptides from ribosomes (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 complexing with eRF1 and ribosomes 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, 4065-4072; Frolova et al., Eukaryotic polypeptide chain release factor eRF3 is an eRF1- and ribosome-dependent guanosine triphosphatase, RNA, 1996, 2, 334-341). In addition to its role in translation termination in response to termination codons (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, 3807–3814; 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), The GSPT1 protein is involved in cell cycle regulation, cytoskeleton organization, and apoptosis. Therefore, reduced GSPT1 levels may impair the control of cell proliferation and promote cell migration and scar formation. In fact, increased expression of the 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, 2046-2049; Wright and Lange, Newer Potential Biomarkers in Prostate Cancer, Rev. Urol, 2007, 9(4), 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):1581-1585; Hashimoto, et al.,Translation termination factor eRF3 is targeted for caspase-mediated proteolytic cleavage and degradation during DNAdamage-inducedapoptosis,Apoptosis,2012,17(12):1287-1299;Tian,The role of miR-144 / GSPT1 axisin gastric cancer,Eur.Rev.Med.Pharmacol.Sci.,2018,22(13):4138-4145;Sun,etal.,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;Zhang,et al.,Downregulation of microRNA-27b-3p via aberrant DNAmethylation contributes to malignant behavior ofgastric cancer cells by targeting GSPT1,Biomed Pharmacother.,2019,119:109417;Powell,etal.,Selective Degradation of GSPT1 by Cereblon Modulators Identifiedvia aFocused Combinatorial Library,ACS Chem.Biol.,2020,15(10):2722-2730;Nishiguchi,et al.,Identification of Potent,Selective,and Orally BioavailableSmall-Molecule GSPT1 / 2Degraders from a Focused Library of CereblonModulators,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). Therefore, the GSPT1 protein was identified as an oncogenic driver and a new cancer target, through which the active translation leading to the malignant phenotype of cancer cells can be disrupted. One mechanism to disrupt disease protein drivers is to reduce the cellular concentration of these proteins through protein degradation. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which can ubiquitinate various other proteins for further degradation.

[0003] Although different GSPT1 degraders have been tested in clinical trials and pre-clinical settings, dose-limiting toxicity and limited efficacy have been observed. A novel GSPT1 degrader has the potential to improve clinical outcomes. Summary of the Invention

[0004] One aspect of the present disclosure provides a compound selected from compounds of formula I, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing substances, which can be used to treat diseases mediated by GSPT1 protein degradation. For example, disclosed herein are compounds having the following structural formula I, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing substances:

[0005]

[0006] Wherein:

[0007] (i) Each R’ is independently selected from: hydrogen, halogen groups, straight-chain alkyl, branched-chain alkyl, and cycloalkyl;

[0008] (ii) m and n are independently selected from: 0, 1, and 2;

[0009] (iii) X and Z are independently absent or selected from: straight-chain alkylene, branched-chain alkylene, cycloalkylene, straight-chain heteroalkylene, branched-chain heteroalkylene, cycloheteroalkylene, and straight-chain alkyl, branched-chain alkyl, cycloalkyl;

[0010] (iv) Y and W are independently absent or selected from: –O–, –C(O)–, –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, where p is selected from: 1, 2, 3, 4, 5 and 6; and R x is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, carbocyclic group, heterocyclic group, aryl and heteroaryl;

[0011] (v) Ring A is selected from:

[0012]

[0013] where R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl and prodrug groups; each R 1 and each R 2 is independently selected from: hydrogen, halogen group, OR z and straight-chain alkyl, branched-chain alkyl and cycloalkyl; further, where R z is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, carbocyclic group, heterocyclic group, aryl and heteroaryl;

[0014] (vi) Ring B is absent or is selected from: optionally substituted cycloalkyl and heterocycloalkyl;

[0015] (vii) Ring C is absent or is selected from: optionally substituted aryl and heteroaryl,

[0016] (viii) Ring D is absent or is selected from: optionally substituted cycloalkyl, heterocycloalkyl and heteroaryl;

[0017] wherein the straight-chain alkyl, branched-chain alkyl and cycloalkyl, straight-chain alkenyl, branched-chain alkenyl and cycloalkenyl, straight-chain alkylene, branched-chain alkylene and cycloalkylene, carbocyclic group, straight-chain and branched-chain heteroalkenyl, straight-chain alkynyl, branched-chain alkynyl and cycloalkynyl, heterocyclic group, aryl and heteroaryl are optionally substituted with at least one group selected from the following groups:

[0018] halogen group,

[0019] hydroxyl,

[0020] thiol,

[0021] amino,

[0022] cyano,

[0023] -OC(O)C1-C6 straight-chain, branched-chain and cycloalkyl,

[0024] -C(O)OC1-C6 straight-chain, branched-chain and cycloalkyl,

[0025] -NHC1-C6 linear, branched, and cycloalkyl,

[0026] -N(C1-C6 linear, branched, and cycloalkyl)2,

[0027] -NHC(O)C1-C6 linear, branched, and cycloalkyl,

[0028] -C(O)NHC1-C6 linear, branched, and cycloalkyl,

[0029] -C(O)N(C1-C6)2 linear, branched, and cycloalkyl,

[0030] -NH aryl,

[0031] -N(aryl)2,

[0032] -NHC(O)aryl,

[0033] -C(O)NH aryl,

[0034] -NH heteroaryl,

[0035] -N(heteroaryl)2,

[0036] -NHC(O)heteroaryl,

[0037] -C(O)NH heteroaryl,

[0038] -S(O)2C1-C6 linear, branched, and cycloalkyl,

[0039] C1-C6 linear, branched, and cycloalkyl,

[0040] C2-C6 linear, branched, and cycloalkenyl,

[0041] C1-C6 linear, branched, and cycloalkylol,

[0042] C1-C6 linear, branched, and cycloaminoalkyl,

[0043] C1-C6 linear, branched, and cycloalkoxy,

[0044] C1-C6 linear, branched, and cycloalkylthio,

[0045] C1-C6 linear, branched, and cycloalkylhalide,

[0046] C1-C6 linear, branched, and cycloalkylhaloaminoalkyl,

[0047] C1-C6 linear, branched, and cycloalkylhalothioalkyl,

[0048] C1-C6 linear, branched, and cycloalkylhaloalkoxy,

[0049] Benzyloxy, benzylamino, and benzylthio,

[0050] 3- to 6-membered heteroalkenyl,

[0051] 3- to 6-membered heterocyclic group, and

[0052] 5- and 6-membered heteroaryl.

[0053] In one aspect of the present disclosure, the compounds of Formula I are selected from: Compounds 1 to 24 shown below, their tautomers, deuterated derivatives of said compounds or tautomers, and pharmaceutically acceptable salts of the foregoing substances.

[0054] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula I, its tautomer, a deuterated derivative of said compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from Compounds 1 to 24 shown below, its tautomer, a deuterated derivative of said compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances. These compositions may further comprise additional active agents.

[0055] Another aspect of the present disclosure provides a method of treating a disease, disorder, or condition mediated by GSPT1 protein degradation in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, its tautomer, a deuterated derivative of said compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to the subject a therapeutically effective amount of a compound selected from Compounds 1 to 24 shown below, its tautomer, a deuterated derivative of said compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to the subject a therapeutically effective amount of a compound selected from Compounds A to F shown below, its tautomer, a deuterated derivative of said compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing substances, or a pharmaceutical composition comprising any of the foregoing.

[0056] In some embodiments disclosed herein, a treatment method includes administering an additional active agent to a subject in need thereof, which can be administered in the same pharmaceutical composition as a compound of Formula I, its tautomer, 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, a treatment method includes administering, in the same composition or a separate composition, a compound selected from Compounds 1 to 24 shown below, its tautomer, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, and an additional active agent. In some embodiments disclosed herein, a treatment method includes administering, in the same composition or a separate composition, a compound selected from Compounds A to F shown below, its tautomer, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, and an additional active agent.

[0057] Also disclosed herein is a method for reducing the activity of GSPT1 protein, including administering to a subject a therapeutically effective amount of a compound of Formula I, its tautomer, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, a method for degrading GSPT1 protein includes administering to a subject a compound selected from Compounds 1 to 24 shown below, its tautomer, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments disclosed herein, a method for degrading GSPT1 protein includes administering to a subject a compound selected from Compounds A to F shown below, its tautomer, a deuterated derivative of the compound or tautomer, and / or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The foregoing summary of the disclosure and the following detailed description will be better understood when read in conjunction with the accompanying drawings. For purposes of illustrating the disclosure, the drawings show some but not all alternative embodiments. However, it should be understood that the disclosure is not limited to the precise arrangements and instrumentalities shown. These drawings are incorporated into the specification and form a part of the specification, and help to explain the principles of the disclosure.

[0059] Figure 1 A Western blot showing the degradation of GSPT1 in HL-60 cells by Compound A of the present disclosure.

[0060] Figure 2 A Western blot showing the degradation of GSPT1 in HL-60 cells by Compound A and 8 of the present disclosure.

[0061] Figure 3 Shows the Western blot of the degradation of GSPT1 by Compound 28 of the present disclosure in HL-60 cells.

[0062] Figure 4 Shows the Western blot of the degradation of GSPT1 in HL-60 cells by Compound F of the present disclosure. Detailed implementation mode

[0063] I. Definitions

[0064] When the terms "a" or "an" as used herein refer to a noun, they encompass the expression "at least one", and thus encompass both the singular and plural units of the noun. For example, "additional agent" refers to a single or two or more additional agents.

[0065] The terms "GSPT1" or "GSPT1 protein" used interchangeably herein are also referred to as the translation termination factor eRF3. The G1 to S phase transition 1 (GSPT1) protein is a GTPase that interacts with eRF1 to promote termination codon recognition and the release of nascent peptides from ribosomes. It is involved in cell cycle regulation, cytoskeletal organization, and apoptosis.

[0066] As used herein, the term "degrader" refers to a molecular reagent that binds to a protein kinase such as hematopoietic progenitor cell kinase 1 and subsequently reduces the steady-state protein level of the kinase. In some embodiments, the degraders disclosed herein reduce the steady-state protein kinase level 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, the degraders disclosed herein reduce the steady-state protein kinase level by at least 65%. In some embodiments, the degraders disclosed herein reduce the steady-state protein kinase level by at least 85%.

[0067] When referring to the compounds of the present disclosure, the term "compound" refers to a collection of molecules having the same chemical structure, unless otherwise specified 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), with the difference that there may be isotopic variations among the constituent atoms of the molecules. Thus, it will be clear to those skilled in the art that a compound represented by a particular chemical structure containing a designated deuterium atom will also contain a lesser amount of isotopologues having a hydrogen atom at one or more of the designated deuterium positions in that structure. The relative amounts of such isotopologues in the compounds of the present disclosure will depend on many factors, including, for example, the isotopic purity of the reagents used to prepare the compound and the efficiency of incorporation of the isotope in the various synthetic steps used to prepare the compound. However, as described above, the total relative amount of such isotopologues will be less than 49.9% of the compound. In other embodiments, the total relative amount of such isotopologues will be less than 47.5% of the compound, less than 40% of the compound, less than 32.5% of the compound, less than 25% of the compound, less than 17.5% of the compound, less than 10% of the compound, less than 5% of the compound, less than 3% of the compound, less than 1% of the compound, or less than 0.5% of the compound.

[0068] As used herein, "optionally substituted" may be interchangeable with the phrase "substituted or unsubstituted". Generally, the term "substituted" means that a hydrogen group in a given structure is replaced by a group of a particular substituent. Unless otherwise specified, 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 can be substituted by more than one substituent selected from the designated groups, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present disclosure are those that result in the formation of stable or chemically viable compounds.

[0069] The term "isotopologue" refers to species whose chemical structures differ only in their isotopic composition. Additionally, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present application are within the scope of the present disclosure in addition to replacing hydrogen with deuterium or tritium or 13 C or 14 C replacing carbon.

[0070] Unless otherwise specified, the structures described herein are also intended to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present application 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.

[0071] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the migration of atoms (such as hydrogen atoms) or groups within the molecule.

[0072] As used herein, "stereoisomers" refer to enantiomers and diastereomers.

[0073] As used herein, a "deuterated derivative" is a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D" or " 2 H"). It should be recognized that some variation in natural isotope abundances will occur in the synthesized compounds depending on the source of the chemical materials used in the synthesis. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotope substitution in the deuterated derivatives disclosed herein. Thus, unless otherwise specified, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced by deuterium at a level far above its natural isotope abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporated at each designated deuterium), at least 4500 (67.5% deuterium incorporated at each designated deuterium), at least 5000 (75% deuterium incorporated at each designated deuterium), at least 5500 (82.5% deuterium incorporated at each designated deuterium), at least 6000 (90% deuterium incorporated at each designated deuterium), at least 6333.3 (95% deuterium incorporated at each designated deuterium), at least 6466.7 (97% deuterium incorporated at each designated deuterium), or at least 6600 (99% deuterium incorporated at each designated deuterium) for each deuterium atom.

[0074] As used herein, the term "isotope enrichment factor" refers to the ratio of the isotope abundance of a particular isotope to its natural abundance.

[0075] As used herein, the term "alkyl" refers to a fully saturated, straight-chain or branched-chain, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, alkyl contains 1 to 30 alkyl carbon atoms. In some embodiments, alkyl contains 1 to 20 alkyl carbon atoms. In some embodiments, alkyl contains 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl contains 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl contains 1 to 6 alkyl carbon atoms. In some embodiments, alkyl contains 1 to 4 alkyl carbon atoms. In other embodiments, alkyl contains 1 to 3 alkyl carbon atoms. In still other embodiments, alkyl contains 1 to 2 alkyl carbon atoms. In some embodiments, alkyl is substituted. In some embodiments, alkyl is unsubstituted. In some embodiments, alkyl is straight-chain or unbranched. In some embodiments, alkyl is branched.

[0076] The term "cycloalkyl" refers to a fully saturated monocyclic C 3-8 hydrocarbon or a spiro, fused or bridged bicyclic or tricyclic C 8-14 hydrocarbon, wherein any single ring in the bicyclic system has 3 to 7 members. In some embodiments, cycloalkyl is substituted. In some embodiments, cycloalkyl is unsubstituted. In some embodiments, cycloalkyl is C3 to C 12 cycloalkyl. In some embodiments, cycloalkyl is C3 to C8 cycloalkyl. In some embodiments, cycloalkyl is C3 to C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] The term "carbocyclic group" encompasses the term "cycloalkyl" and refers to a fully saturated or partially saturated monocyclic C 3-8 hydrocarbon or a spiro, fused or bridged bicyclic or tricyclic C 8-14 hydrocarbon, as it contains one or more unsaturated units but is not aromatic, wherein any single ring in the bicyclic system has 3 to 7 members. Bicyclic carbocyclic groups include combinations of a monocyclic carbocyclic ring fused to, for example, a phenyl ring. In some embodiments, carbocyclic group is substituted. In some embodiments, carbocyclic group is unsubstituted. In some embodiments, carbocyclic group is C3 to C 12 carbocyclic group. In some embodiments, carbocyclic group is C3 to C 10 carbocyclic group. In some embodiments, carbocyclic group is C3 to C8 carbocyclic group. Non-limiting examples of monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc.

[0078] As used herein, the term "alkylene" refers to a divalent alkyl radical. C 1-10Representative examples of alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylidene, n-butylene, sec-butylene, isobutylene, 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.

[0079] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl is substituted. In some embodiments, the alkenyl is unsubstituted. In some embodiments, the alkenyl is straight-chain, straight-chain or unbranched. In some embodiments, the alkenyl is branched.

[0080] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon triple bond, such as a straight-chain or branched-chain group of 2 to 8 carbon atoms, herein referred to as C 2-8 alkynyl. 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.

[0081] As used herein, the term "heterocyclic group" refers to a non-aromatic (i.e., fully saturated or partially saturated, as it contains one or more unsaturated units but is not aromatic), monocyclic or spiro, fused or bridged bicyclic or tricyclic ring system, wherein one or more of the ring members are heteroatoms independently selected. Bicyclic heterocyclic groups include, for example, combinations of a monocyclic group with: a monocyclic heteroaryl fused to the monocyclic heterocyclic group; a monocyclic heterocyclic group fused to another monocyclic heterocyclic group; a monocyclic heterocyclic group fused to a phenyl group; a monocyclic heterocyclic group fused to a monocyclic carbocyclic / cycloalkyl group; and a monocyclic heteroaryl fused to a monocyclic carbocyclic / cycloalkyl group. In some embodiments, the "heterocyclic group" moiety contains from 3 to 14 ring members, wherein one or more of the ring members are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in the bicyclic or tricyclic ring system contains from 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has a heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has a heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has a heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocyclic group is a 3- to 12-membered heterocyclic group. In some embodiments, the heterocyclic group is a 4- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 3- to 8-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- to 8-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- or 6-membered heterocyclic group. In some embodiments, the heterocyclic group is a 6-membered heterocyclic group. Non-limiting examples of monocyclic heterocyclic groups include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, tetrahydrothienyl, dihydropyranyl, tetrahydropyridyl, and the like.

[0082] The term "heteroatom" refers to one or more of oxygen, sulfur, and nitrogen, including any oxidized form of nitrogen or sulfur or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen in a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in an N-substituted pyrrolidinyl).

[0083] As used herein, the term "unsaturated" refers to a moiety having one or more unsaturated units or degrees. Unsaturation is a state in a compound where not all available valence bonds are satisfied by substituents, and thus the compound contains double or triple bonds.

[0084] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one carbon of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is connected between two carbon atoms.

[0085] The term "halogen" includes F, Cl, Br, and I, namely fluorine, chlorine, bromine, and iodine, respectively.

[0086] As used herein, the "cyano" or "nitrile" group refers to -C≡N.

[0087] As used herein, an "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system having a delocalized π electron 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 for an aromatic ring as defined above and may be fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined below.

[0088] The term "aryl", used alone or as part of a larger moiety such as "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to a monocyclic or spiro, fused, or bridged bicyclic or tricyclic ring system having a total of five to fourteen ring members, wherein each ring in the ring system is an aromatic ring containing only carbon atoms, and wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl include phenyl (C6) and naphthyl (C 10 ) rings. In some embodiments, the aryl is substituted. In some embodiments, the aryl is unsubstituted.

[0089] The term "heteroaryl" refers to a monocyclic or spiro, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic, at least one ring in the ring 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, combinations of a monocyclic ring with: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, the heteroaryl is substituted. In some embodiments, the heteroaryl has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl has one heteroatom. In some embodiments, the heteroaryl has two heteroatoms. In some embodiments, the heteroaryl is a monocyclic ring system having five ring members. In some embodiments, the heteroaryl is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl 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- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridyl, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, and the like.

[0090] "Spiro ring system" refers to a ring system having two or more rings, wherein each pair of rings shares only one common atom.

[0091] The term "prodrug moiety" refers to a group that is covalently linked to a compound and causes the compound to have improved oral bioavailability and / or tumor targeting and / or be more active in vivo. Certain compounds of Formula I may contain a prodrug moiety, 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). A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes a chemical change under physiological conditions to provide the active compound. Prodrugs are often useful because in some cases they may be more readily administered than the parent drug. For example, they may be bioavailable by oral administration while the parent drug is not. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. Examples (but not limited to) of prodrug moieties are part of a compound, such as an ester, but are subsequently metabolically hydrolyzed to a carboxylic acid to release the active entity. Other examples of prodrug moieties include peptidyl derivatives of the compound.

[0092] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene dichloride" (CH2Cl2), 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-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0093] 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 (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0094] The present disclosure provides pharmaceutically acceptable salts of the disclosed compounds. The salts of the compounds are formed between an acid and a basic group of the compound (e.g., an amino functional group) or between a base and an acidic group of the compound (e.g., a carboxyl functional group).

[0095] As used herein, the term "pharmaceutically acceptable" refers to a component that is suitable for use in contact with the tissues of humans and other mammals within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" refer to any non-toxic salts that can directly or indirectly provide the compounds of the present disclosure when administered to a recipient. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S.M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, pages 1-19.

[0096] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen sulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfates, bisulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, octanedioates, decanedioates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, mandelates, and the like. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0097] Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4(alkyl)4 salts. The present disclosure also contemplates quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonate and glucosamine salts.

[0098] The term "subject" refers to an animal, including but not limited to a human.

[0099] The term "therapeutically effective amount" refers to the amount of a compound that, upon administration, produces the desired effect (e.g., improving the symptoms of a disease, disorder, or condition mediated by the degradation of GSPT1, reducing the severity of a disease, disorder, or condition mediated by the degradation of GSPT1 or its symptoms, and / or reducing the progression of a disease, disorder, or condition mediated by the degradation of GSPT1 or its symptoms). The exact amount of the therapeutically effective amount will depend on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0100] As used herein, the term "treat" and its cognates refer to slowing or halting the progression of a disease. "Treat" and its cognates as used herein include, but are not limited to, the following: completely or partially relieving a disease, disorder, or condition mediated by the degradation of GSPT1 and disease-related complications, reducing the risk of a disease, disorder, or condition mediated by the degradation of GSPT1 and disease-related complications. Improvement of any of these symptoms or reduction of their severity can be readily evaluated according to methods and techniques known in the art or developed subsequently.

[0101] The term "cancer" includes, but is not limited to, the following cancers: oral (e.g., buccal cavity, lip, tongue, mouth, pharynx) epidermoid carcinoma; cardia cancer, such as sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, such as bronchial carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis, hamartoma, mesothelioma; gastrointestinal cancers, such as esophageal (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel / small intestines (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel / large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma), colon, colorectal, colorectum, rectum; urogenital cancers, including renal (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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer, such as hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, cholangiocarcinoma; bone cancer, such as osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system cancers, including skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers, including cancers of the uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (cancer), breast cancer; blood cancers, such as blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), hairy cell; lymphatic system diseases; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers, such as papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, anaplastic thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal cancers, such as neuroblastoma.

[0102] The compounds and compositions of the present application can be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (drug combinations) or treatment modalities, such as conventional chemotherapeutic agents or any other anti-proliferative, anti-cancer, and / or non-drug therapies, etc. For example, the anti-proliferative or anti-cancer substances can have additive or synergistic effects. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compounds will of course vary depending on the type of co-drug employed, the specific drug used, the condition being treated, etc. The combination therapy includes co-administering the compounds of the present application further with one or more other bioactive ingredients (such as but not limited to conventional chemotherapeutic agents, kinase inhibitors, a second different anti-tumor drug), as well as non-drug therapies (such as but not limited to surgery or radiotherapy). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds (preferably compounds capable of enhancing the effect of the compounds of the present application). The compounds of the present application can be administered simultaneously (as a single formulation or separate formulations) or sequentially with other drug therapies or treatment modalities. Generally, combination therapy contemplates the use of two or more drugs within a single treatment cycle or course of treatment.

[0103] The terms "about" and "approximately", when used in connection with the dosage, amount or weight percentage of a component of a composition or dosage form, include the value or range of the specified dosage, amount or weight percentage, which a person of ordinary skill in the art would recognize as providing a pharmacological effect equivalent to that obtained from the specified dosage, amount or weight percentage.

[0104] II. Compounds and Compositions

[0105] In a first embodiment, the compounds of the present disclosure are compounds of the following structural formula I, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing substances:

[0106]

[0107] Wherein:

[0108] (i) Each R' is independently selected from: hydrogen, a halogen group, a straight-chain alkyl group, a branched-chain alkyl group, and a cycloalkyl group;

[0109] (ii) m and n are independently selected from: 0, 1, and 2;

[0110] (iii) X and Z are independently absent or selected from: a straight-chain alkylene group, a branched-chain alkylene group, a cycloalkylene group, a straight-chain heteroalkylene group, a branched-chain heteroalkylene group, a cycloheteroalkylene group, and a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group;

[0111] (iv) Y and W are independently absent or selected from: –O–, –C(O)–, –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; and R x is selected from: hydrogen, a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0112] (v) Ring A is selected from:

[0113]

[0114] Wherein R a is selected from: hydrogen, a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, and a prodrug group; each R 1 and each R 2Independently selected from: hydrogen, a halogen group, OR z and a straight-chain alkyl group, a branched-chain alkyl group, and a cycloalkyl group; further, wherein R z is selected from: hydrogen, a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0115] (vi) Ring B is absent or selected from: an optionally substituted cycloalkyl group and a heterocycloalkyl group;

[0116] (vii) Ring C is absent or selected from: an optionally substituted aryl group and a heteroaryl group;

[0117] (viii) Ring D is absent or selected from: an optionally substituted cycloalkyl group, a heterocycloalkyl group, and a heteroaryl group;

[0118] wherein the straight-chain alkyl group, the branched-chain alkyl group, the cycloalkyl group, the straight-chain alkenyl group, the branched-chain alkenyl group, the cycloalkenyl group, the straight-chain alkylene group, the branched-chain alkylene group, the cycloalkylene group, the carbocyclic group, the straight-chain and branched-chain heteroalkenyl groups, the straight-chain alkynyl group, the branched-chain alkynyl group, the cycloalkynyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally substituted with at least one group selected from the following groups:

[0119] a halogen group,

[0120] a hydroxyl group,

[0121] a thiol group,

[0122] an amino group,

[0123] a cyano group,

[0124] -OC(O)C1-C6 straight-chain, branched-chain, and cycloalkyl groups,

[0125] -C(O)OC1-C6 straight-chain, branched-chain, and cycloalkyl groups,

[0126] -NHC1-C6 straight-chain, branched-chain, and cycloalkyl groups,

[0127] -N(C1-C6 straight-chain, branched-chain, and cycloalkyl groups)2,

[0128] -NHC(O)C1-C6 straight-chain, branched-chain, and cycloalkyl groups,

[0129] -C(O)NHC1-C6 straight-chain, branched-chain, and cycloalkyl groups,

[0130] -C(O)N(C1-C6)2 straight-chain, branched-chain, and cycloalkyl groups,

[0131] -NH aryl group,

[0132] -N(aryl group)2,

[0133] -NHC(O) aryl group,

[0134] -C(O)NH aryl,

[0135] -NH heteroaryl,

[0136] -N(heteroaryl)2,

[0137] -NHC(O)heteroaryl,

[0138] -C(O)NH heteroaryl,

[0139] -S(O)2C1-C6 linear, branched, and cycloalkyl,

[0140] C1-C6 linear, branched, and cycloalkyl,

[0141] C2-C6 linear, branched, and cycloalkenyl,

[0142] C1-C6 linear, branched, and cycloalkylol,

[0143] C1-C6 linear, branched, and cycloaminoalkyl,

[0144] C1-C6 linear, branched, and cycloalkoxy,

[0145] C1-C6 linear, branched, and cycloalkylthio,

[0146] C1-C6 linear, branched, and cycloalkylhalide,

[0147] C1-C6 linear, branched, and cycloalkylhaloaminoalkyl,

[0148] C1-C6 linear, branched, and cycloalkylhalothio,

[0149] C1-C6 linear, branched, and cycloalkylhaloalkoxy,

[0150] Benzyloxy, benzylamino, and benzylthio,

[0151] 3- to 6-membered heteroalkenyl,

[0152] 3- to 6-membered heterocyclic group, and

[0153] 5- and 6-membered heteroaryl.

[0154] In a second embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, X is absent; and all other variables not specifically defined herein are as defined in the first embodiment.

[0155] In a third embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, X is a linear alkylene; and all other variables not specifically defined herein are as defined in the first embodiment.

[0156] In a fourth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, X is a methylene group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0157] In a fifth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, X is an ethylene group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0158] In a sixth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Z does not exist; and all other variables not specifically defined herein are as defined in the first embodiment.

[0159] In a seventh embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Z is a straight-chain alkylene group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0160] In an eighth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Z is a methylene group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0161] In a ninth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Z is an ethylene group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0162] In a tenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring B is selected from heterocycloalkyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0163] In an eleventh embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring B is selected from: And all other variables not specifically defined herein are as defined in the first embodiment.

[0164] In a twelfth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is an optionally substituted aryl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0165] In the thirteenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0166] In the fourteenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with a halogen group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0167] In the fifteenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with fluorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0168] In the sixteenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with chlorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0169] In the seventeenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with bromine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0170] In the eighteenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with an alkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0171] In the nineteenth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with a cycloalkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0172] In the twentieth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is a phenyl group substituted with a cyclopropyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0173] In the twenty - first embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is an optionally substituted heteroaryl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0174] In the twenty-second embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is pyridyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0175] In the twenty-third embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is pyridyl substituted with a halogen group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0176] In the twenty-fourth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is pyridyl substituted with fluorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0177] In the twenty-fifth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is pyridyl substituted with chlorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0178] In the twenty-sixth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is pyridyl substituted with bromine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0179] In the twenty-seventh embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring C is quinolinyl.

[0180] In the twenty-eighth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is an optionally substituted heteroaryl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0181] In the twenty-ninth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is pyridyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0182] In the thirtieth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is pyridyl substituted with a halogen group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0183] In the thirty - first embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is a pyridyl group substituted by fluorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0184] In the thirty - second embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is a pyridyl group substituted by chlorine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0185] In the thirty - third embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present application, ring D is a pyridyl group substituted by bromine; and all other variables not specifically defined herein are as defined in the first embodiment.

[0186] In the thirty - fourth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is a thiazolyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0187] In the thirty - fifth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is a thiazolyl group substituted by an alkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0188] In the thirty - sixth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring D is a thiazolyl group substituted by methyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0189] In the thirty - seventh embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, if rings C and D do not exist, then X is a straight - chain alkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0190] In the thirty - eighth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, X is methyl; and all other variables not specifically defined herein are as defined in the first embodiment.

[0191] In the thirty - ninth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, if rings C and D do not exist, then X is a branched - chain alkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0192] In the fortieth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, X is a tert-butyl group.

[0193] In the forty-first embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, if ring C and ring D are absent, X is a cycloalkyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0194] In the forty-second embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, X is a cyclohexyl group; and all other variables not specifically defined herein are as defined in the first embodiment.

[0195] In the forty-third embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, m is 1 and n is 1; and all other variables not specifically defined herein are as defined in the first embodiment.

[0196] In the forty-fourth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, each R' is hydrogen; and all other variables not specifically defined herein are as defined in the first embodiment.

[0197] In the forty-fifth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, m is 2 and n is 1; and all other variables not specifically defined herein are as defined in the first embodiment.

[0198] In the forty-sixth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, each R' is hydrogen; and all other variables not specifically defined herein are as defined in the first embodiment.

[0199] In the forty-seventh embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring A is and all other variables not specifically defined herein are as defined in the first embodiment.

[0200] In the forty-eighth embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups; and all other variables not specifically defined herein are as defined in the first embodiment.

[0201] In the forty-ninth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring A is And all other variables not specifically defined herein are as defined in the first embodiment.

[0202] In the fiftieth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups; and all other variables not specifically defined herein are as defined in the first embodiment.

[0203] In the fifty-first embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring A is And all other variables not specifically defined herein are as defined in the first embodiment.

[0204] In the fifty-second embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups; and all other variables not specifically defined herein are as defined in the first embodiment.

[0205] In the fifty-third embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, ring A is And all other variables not specifically defined herein are as defined in the first embodiment.

[0206] In the fifty-fourth embodiment, among the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups; and all other variables not specifically defined herein are as defined in the first embodiment.

[0207] In certain embodiments, at least one compound of the present disclosure is selected from Compounds 1 to 35 shown in Table 1 below, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing substances.

[0208] Table 1

[0209]

[0210]

[0211]

[0212]

[0213] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the group consisting of compounds of Formula I, Compounds 1 to 35, their tautomers, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of the foregoing substances, or a pharmaceutical composition comprising any one of the foregoing and at least one pharmaceutically acceptable carrier.

[0214] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable carrier is selected from: pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0215] It should also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapies; that is, the pharmaceutical compositions disclosed herein can also comprise additional active agents. Alternatively, a pharmaceutical composition comprising a compound selected from the group consisting of compounds of Formula I, Compounds 1 to 35, their tautomers, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of the foregoing substances, or a pharmaceutical composition comprising any one of the foregoing can be administered simultaneously, before, or after a composition comprising an additional active agent as a separate composition.

[0216] As discussed above, the pharmaceutical compositions disclosed herein contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be selected from excipients 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, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants suitable for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 to 1999, Marcel Dekker, New York disclose various carriers for formulating pharmaceutical compositions and their known preparation techniques. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as producing any adverse biological effects or interacting with any other component of the pharmaceutical composition in a harmful manner, its use is considered to be 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), buffering substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene-block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), 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, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0217] III. Methods of Treatment and Uses

[0218] In another aspect of the present disclosure, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, including the compounds of Formula I, Compounds 1 to 35, their tautomers, deuterated derivatives of the compounds or tautomers, Compounds A to F, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions thereof, are used for treating diseases, disorders, or conditions mediated by GSPT1 protein degradation. In another aspect, the compounds, their tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein are provided, including the compounds of Formula I, Compounds 1 to 24, their tautomers, deuterated derivatives of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, Compounds A to F, or pharmaceutical compositions thereof, for use in the preparation of a medicament for treating diseases, disorders, or conditions mediated by GSPT1 protein degradation. In another aspect, a method of treating a disease, disorder, or condition mediated by GSPT1 protein degradation in a subject is provided, comprising administering a therapeutically effective amount of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including 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 substances, Compounds A to F, or pharmaceutical compositions thereof.

[0219] 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, kidney cancer, prostate cancer, testicular cancer, colorectal cancer, lung cancer, bladder cancer, urothelial cancer, cervical cancer, head and neck cancer, esophageal cancer and gastric 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 lymphocyte leukemia (LGL), acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0220] In some embodiments, the cancer is selected from the following cancers: oral (such as buccal cavity, lip, tongue, mouth, pharynx) epidermoid carcinoma; cardiac cancer, such as sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, such as bronchial carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatosis, hamartoma, mesothelioma; gastrointestinal cancers, such as esophageal (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric (carcinoma, lymphoma, leiomyosarcoma), pancreatic (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, colorectum, rectum; urogenital cancers, including renal (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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer, such as hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, cholangiocarcinoma; bone cancer, such as osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system cancers, including skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecological cancers, including uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, sertoli-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast cancer;Blood cancers, such as blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), hairy cell; lymphatic system diseases; skin cancers, including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid cancers, such as 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, paraganglioma; and adrenal cancers, such as neuroblastoma.;

[0221] In another aspect of the present disclosure, the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of Formula I, Compounds 1 to 24, their tautomers, deuterated derivatives of said compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, Compounds A to F, or their pharmaceutical compositions, are used to reduce GSPT1 activity. In another aspect, there is disclosed herein the use of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of Formula I, Compounds 1 to 24, their tautomers, deuterated derivatives of said compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, Compounds A to F, or their pharmaceutical compositions, for the preparation of a medicament for reducing protein kinase activity. In another aspect, there is disclosed a method for reducing GSPT1 activity, comprising administering to a subject a therapeutically effective amount of the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein, including compounds of Formula I, Compounds 1 to 35, their tautomers, deuterated derivatives of said compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, Compounds A to F, or their pharmaceutical compositions. In another aspect, there is disclosed a method for reducing GSPT1 activity, comprising contacting the protein kinase with the compounds, tautomers, deuterated derivatives, and / or pharmaceutically acceptable salts disclosed herein (including compounds of Formula I, Compounds 1 to 24, their tautomers, deuterated derivatives of said compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing substances, Compounds A to F, or their pharmaceutical compositions).

[0222] The compounds of Formula I, Compounds 1 to 35, their tautomers, deuterated derivatives of said compounds or tautomers, Compounds A to F, and / or pharmaceutically acceptable salts of the foregoing substances, or their pharmaceutical compositions may be administered once daily, twice daily, or three times daily, for example, for the treatment of diseases, disorders, or conditions mediated by GSPT1 degradation.

[0223] In some embodiments, 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 in an amount of 2 mg to 1500 mg or 5 mg to 1000 mg.

[0224] The 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 can be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, buccally, vaginally, transdermally, by patch, by pump, or via an implanted reservoir, and the pharmaceutical composition will be formulated accordingly. Parenteral administration includes, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intralung, intrathecal, rectal, and topical modes of administration. Parenteral administration can be effected, for example, by continuous infusion over a selected period of time. Other modes of administration contemplated in the present disclosure are 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.

[0225] A useful dose or therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein can be determined by comparing its in vitro activity and in vivo activity in an animal model. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0226] One of ordinary skill in the art will recognize that when the amount of a disclosed compound is given, the relevant amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free radical form of the compound. The amounts of the compounds, tautomers, pharmaceutically acceptable salts, and deuterated derivatives disclosed herein are based on the free radical form of the reference compound. For example, "1000 mg of at least one compound selected from the group consisting of a compound of formula I and a pharmaceutically acceptable salt thereof" includes 1000 mg of the compound of formula I and a pharmaceutically acceptable salt of the compound of formula I having a concentration equivalent to 1000 mg of the compound of formula I.

[0227] In another aspect of the present disclosure, the compounds and compositions disclosed herein can be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (drug combinations) or modalities of treatment (such as anti-proliferative agents, anti-cancer agents, immunomodulators or anti-inflammatory agents and / or non-drug therapies, etc.). For example, anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory substances can produce synergistic effects. When the compounds disclosed herein are administered in combination with other therapies, the dosage of the co-administered compounds will of course vary depending on the type of co-drug employed, the specific drug used, the condition being treated, etc. Combination therapy includes further combining the compounds of the present application with one or more other bioactive ingredients (such as a second kinase inhibitor, a second different anti-tumor agent) and non-drug therapies (such as surgery or radiotherapy). For example, the compounds disclosed herein can be used in combination with other pharmaceutically active compounds (preferably compounds capable of enhancing the effects of the compounds disclosed herein). The compounds disclosed herein can be administered simultaneously (as a single formulation or separate formulations) or sequentially with other pharmaceutical therapies or modalities of treatment. Generally, combination therapy contemplates the administration of two or more drugs within a single treatment cycle or course of treatment. In another aspect of the present disclosure, the compounds can be administered in combination with one or more individual agents (such as chemotherapeutic agents, immunotherapeutic agents or adjuvant therapeutic agents). In one embodiment, the individual agent is selected from: anti-PD1 antibodies (such as pembrolizumab), HDAC inhibitors (such as panobinostat, romidepsin, vorinostat or citarinostat), BCL-2 inhibitors (such as venetoclax), BTK inhibitors (such as ibrutinib or acalabrutinib), mTOR inhibitors (such as everolimus), PI3K inhibitors (such as idelalisib), PKCβ inhibitors (such as enzastaurin), SYK inhibitors (such as fostamatinib), JAK2 inhibitors (such as fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib or momelotinib), aurora kinase inhibitors (such as alisertib), EZF12 inhibitors (such as tazemetostat, GSK126, CPI-1205, 3-deazaneplanocinA), EPZ005687, Ell, UNC1999 or sinefungin), BET inhibitors (such as birabresib), hypomethylating agents (such as 5-azacytidine or decitabine), DOTlL inhibitors (such as pinometostat), FIAT inhibitors (such as C646), WDR5 inhibitors (such as OICR-9429), DNMTl inhibitors (such as GSK3484862), LSD-1 inhibitors (such as compound C or seclidemstat), G9A inhibitors (such as UNC0631), PRMT5 inhibitors (such as GSK3326595), BRD inhibitors (such as LP99), SUV420FU / F12 inhibitors (such as A-196), CARMl inhibitors (such as EZM2302), PLKl inhibitors (such as BI2536), NEK2 inhibitors (such as JF1295), MEK inhibitors (such as trametinib, binimetinib, cobimetinib, selumetinib), PF1F19 inhibitors, PIM inhibitors (such as LGF1-447), IGF-IR inhibitors (such as linsitinib), XPOl inhibitors (such as selinexor), BIRC5 inhibitors (such as YMl 55), PARP inhibitors (such as Olaparib), EGFR inhibitors (such as Osimertinib), HER2 / NEU inhibitors (such as tucatinib), SRC inhibitors (such as dasatinib), AKT inhibitors (such as Ipatasertib), platinum or chemotherapeutic agents (such as bendamustine, bleomycin, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, cisplatin, taxanes or dexamethasone).

[0228] Non-limiting exemplary embodiments

[0229] 1. A compound of formula (I), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing substances:

[0230]

[0231] , wherein:

[0232] (ix) Each R’ is independently selected from: hydrogen, a halogen group, a straight-chain alkyl group, a branched-chain alkyl group, and a cycloalkyl group;

[0233] (x) m and n are independently selected from: 0, 1, and 2;

[0234] (xi) X and Z are independently absent or selected from: a straight-chain alkylene group, a branched-chain alkylene group, a cycloalkylene group, a straight-chain heteroalkylene group, a branched-chain heteroalkylene group, a cycloheteroalkylene group, and a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group;

[0235] (xii) Y and W are independently absent or selected from: –O–, –C(O)–, –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; and R x is selected from: hydrogen, a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0236] (xiii) Ring A is selected from:

[0237]

[0238] wherein R a is selected from: hydrogen, a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, and a prodrug group; each R 1 and each R 2 is independently selected from: hydrogen, a halogen group, OR z and a straight-chain alkyl group, a branched-chain alkyl group, and a cycloalkyl group; further, wherein R z is selected from: hydrogen, a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0239] (xiv) Ring B is absent or selected from: an optionally substituted cycloalkyl group and a heterocycloalkyl group;

[0240] (xv) Ring C is absent or selected from: optionally substituted aryl and heteroaryl;

[0241] (xvi) Ring D is absent or selected from: optionally substituted cycloalkyl, heterocycloalkyl, and heteroaryl;

[0242] Wherein the straight-chain alkyl, branched-chain alkyl, and cycloalkyl, straight-chain alkenyl, branched-chain alkenyl, and cycloalkenyl, straight-chain alkylene, branched-chain alkylene, and cycloalkylene, carbocyclic group, straight-chain and branched-chain heteroalkenyl, straight-chain alkynyl, branched-chain alkynyl, and cycloalkynyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with at least one group selected from the following groups:

[0243] Halogen group,

[0244] Hydroxyl,

[0245] Mercaptan,

[0246] Amino,

[0247] Cyano,

[0248] -OC(O)C1-C6 straight-chain, branched-chain, and cycloalkyl,

[0249] -C(O)OC1-C6 straight-chain, branched-chain, and cycloalkyl,

[0250] -NHC1-C6 straight-chain, branched-chain, and cycloalkyl,

[0251] -N(C1-C6 straight-chain, branched-chain, and cycloalkyl)2,

[0252] -NHC(O)C1-C6 straight-chain, branched-chain, and cycloalkyl,

[0253] -C(O)NHC1-C6 straight-chain, branched-chain, and cycloalkyl,

[0254] -C(O)N(C1-C6)2 straight-chain, branched-chain, and cycloalkyl,

[0255] -NH aryl,

[0256] -N(aryl)2,

[0257] -NHC(O) aryl,

[0258] -C(O)NH aryl,

[0259] -NH heteroaryl,

[0260] -N(heteroaryl)2,

[0261] -NHC(O) heteroaryl,

[0262] -C(O)NH heteroaryl,

[0263] -S(O)2C1-C6 linear, branched and cycloalkyl,

[0264] C1-C6 linear, branched and cycloalkyl,

[0265] C2-C6 linear, branched and cycloalkenyl,

[0266] C1-C6 linear, branched and cycloalkylhydroxy,

[0267] C1-C6 linear, branched and cycloalkylaminoalkyl,

[0268] C1-C6 linear, branched and cycloalkoxy,

[0269] C1-C6 linear, branched and cycloalkylthio,

[0270] C1-C6 linear, branched and cycloalkylhaloalkyl,

[0271] C1-C6 linear, branched and cycloalkylhaloaminoalkyl,

[0272] C1-C6 linear, branched and cycloalkylhalothioalkyl,

[0273] C1-C6 linear, branched and cycloalkylhaloalkoxy,

[0274] Benzyloxy, benzylamino and benzylthio,

[0275] 3- to 6-membered heteroalkenyl,

[0276] 3- to 6-membered heterocyclic group, and

[0277] 5- and 6-membered heteroaryl.

[0278] 2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein X is absent.

[0279] 3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein X is a linear alkylene group.

[0280] 4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 3, wherein X is methylene.

[0281] 5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 3, wherein X is ethylene.

[0282] 6. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein Z is absent.

[0283] 7. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 5, wherein Z is a straight-chain alkylene group.

[0284] 8. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 7, wherein Z is a methylene group.

[0285] 9. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 7, wherein Z is an ethylene group.

[0286] 10. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 9, wherein ring B is selected from heterocycloalkyl.

[0287] 11. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 10, wherein ring B is selected from:

[0288] 12. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 11, wherein ring C is an optionally substituted aryl group.

[0289] 13. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 12, wherein ring C is a phenyl group.

[0290] 14. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 12, wherein ring C is a phenyl group substituted with a halogen group.

[0291] 15. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 14, wherein ring C is a phenyl group substituted with fluorine.

[0292] 16. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 14, wherein ring C is a phenyl group substituted with chlorine.

[0293] 17. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 14, wherein ring C is a phenyl group substituted with bromine.

[0294] 18. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 12, wherein ring C is a phenyl group substituted with an alkyl group.

[0295] 19. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 12, wherein ring C is a phenyl group substituted with a cycloalkyl group.

[0296] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 19, wherein ring C is a phenyl group substituted with a cyclopropyl group.

[0297] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-11, wherein ring C is an optionally substituted heteroaryl group.

[0298] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 21, wherein ring C is a pyridyl group.

[0299] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 21, wherein ring C is a pyridyl group substituted with a halogen group.

[0300] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 23, wherein ring C is a pyridyl group substituted with fluorine.

[0301] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 23, wherein ring C is a pyridyl group substituted with chlorine.

[0302] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 23, wherein ring C is a pyridyl group substituted with bromine.

[0303] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 21, wherein ring C is a quinolinyl group.

[0304] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-27, wherein ring D is an optionally substituted heteroaryl group.

[0305] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 28, wherein ring D is a pyridyl group.

[0306] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 28, wherein ring D is a pyridyl group substituted with a halogen group.

[0307] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 30, wherein ring D is a pyridyl group substituted with fluorine.

[0308] The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 30, wherein ring D is a pyridyl group substituted with chlorine.

[0309] 33. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 30, wherein ring D is a pyridyl group substituted with bromine.

[0310] 34. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 28, wherein ring D is a thiazolyl group.

[0311] 35. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 28, wherein ring D is a thiazolyl group substituted with an alkyl group.

[0312] 36. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 30, wherein ring D is a thiazolyl group substituted with a methyl group.

[0313] 37. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein if rings C and D do not exist, X is a straight-chain alkyl group.

[0314] 38. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 37, wherein X is a methyl group.

[0315] 39. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein if rings C and D do not exist, X is a branched-chain alkyl group.

[0316] 40. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 39, wherein X is a tert-butyl group.

[0317] 41. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 1, wherein if rings C and D do not exist, X is a cycloalkyl group.

[0318] 42. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 41, wherein X is a cyclohexyl group.

[0319] 43. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-42, wherein m is 1 and n is 1.

[0320] 44. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 43, wherein each R' is hydrogen.

[0321] 45. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1-42, wherein m is 2 and n is 1.

[0322] 46. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 45, wherein each R' is hydrogen.

[0323] 47. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 46, wherein ring A is

[0324] 48. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 47, wherein R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups.

[0325] 49. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 46, wherein ring A is

[0326] 50. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 49, wherein R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups.

[0327] 51. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 46, wherein ring A is

[0328] 52. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 51, wherein R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups.

[0329] 53. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 - 46, wherein ring A is

[0330] 54. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of embodiment 53, wherein R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl and cycloalkyl, and prodrug groups.

[0331] 55. A compound selected from the following:

[0332]

[0333]

[0334]

[0335]

[0336] Its tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing substances.

[0337] 56. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, and / or pharmaceutically acceptable salt according to any one of embodiments 1-53 and at least one pharmaceutically acceptable carrier.

[0338] 57. A method of treating or alleviating a disease, disorder, or condition mediated by GSPT1 protein degradation, 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 1-53 or the pharmaceutical composition of embodiment 54.

[0339] 58. A method of 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 1-53 or the pharmaceutical composition of embodiment 54.

[0340] 59. A method of treating or alleviating a disease, disorder, or condition mediated by GSPT1 protein degradation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, its tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing substances, wherein the compound is selected from:

[0341]

[0342] 60. A method of 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, its tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing substances, wherein the compound is selected from:

[0343]

[0344]

[0345] 61. The method according to any one of embodiments 57-60, wherein the disease, disorder, or condition is cancer.

[0346] 62. The method of embodiment 61, wherein the cancer is a solid tumor.

[0347] 63. The method of embodiment 62, wherein the solid tumor is selected from: brain cancer, breast cancer, gastric cancer, kidney cancer, prostate cancer, testicular cancer, colorectal cancer, lung cancer, bladder cancer, urothelial cancer, cervical cancer, head and neck cancer, esophageal cancer and gastric cancer, osteosarcoma, cervical cancer, endometrial cancer, ovarian cancer, squamous cell carcinoma, peritoneal cancer, neuroendocrine cancer, hepatocellular carcinoma, pancreatic cancer, urogenital cancer, laryngeal cancer, skin cancer, nervous system cancer, thyroid cancer, and rhabdomyosarcoma.

[0348] 64. The method of embodiment 61, wherein the cancer is a blood cancer.

[0349] 65. The method of embodiment 64, wherein the blood 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 lymphocyte leukemia (LGL), acute lymphoblastic leukemia, acute lymphocytic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0350] 66. The method of any one of embodiments 57-65, further comprising administering to the subject an existing standard treatment or an FDA-approved therapy.

[0351] 67. The method of any one of embodiments 57-65, further comprising administering to the subject at least one additional agent.

[0352] 68. The method of embodiment 67, wherein the at least one additional agent is selected from: chemotherapeutic agents, immunotherapeutic agents, and adjuvant therapeutic agents.

[0353] Examples

[0354] Compound Synthesis

[0355] To fully understand the present disclosure, the following examples are disclosed. It should be understood that these examples are for illustrative purposes only and should not be considered as limiting the present disclosure in any way.

[0356] All specific and general compounds and the disclosed intermediates used to make these compounds are considered to be part of the present disclosure.

[0357] The compounds of the present disclosure can be prepared according to standard chemical practices or as disclosed herein. In the following synthetic schemes, and in the description of preparing compounds of Formula I, Compounds 1 to 35, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing substances, and deuterated derivatives of any of the foregoing substances, the following abbreviations are used:

[0358] Abbreviation

[0359] = Angstrom

[0360] Ac = Acetyl

[0361] Ac2O = Acetic anhydride

[0362] Boc2O = Di-tert-butyl dicarbonate

[0363] DCM = Dichloromethane

[0364] DIEA = N,N-Diisopropylethylamine or N-Ethyl-N-isopropyl-propan-2-amine

[0365] DMAP = 4-(Dimethylamino)pyridine

[0366] DMA = Dimethylacetamide

[0367] DME = 1,2-Dimethoxyethane

[0368] DMF = N,N-Dimethylformamide

[0369] DMSO = Dimethyl sulfoxide

[0370] EtOAc / EA = Ethyl acetate

[0371] EtOH = Ethanol

[0372] HOAc = Acetic acid

[0373] KOAc = Potassium acetate

[0374] LiHMDS = Lithium bis(trimethylsilyl)amide

[0375] MeMgBr = Methylmagnesium bromide

[0376] MeOH = Methanol

[0377] NaOAc = Sodium acetate

[0378] NBS = N-Bromosuccinimide

[0379] Pd(dppf)2Cl2 = Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[0380] PTSA = p-Toluenesulfonic acid monohydrate

[0381] rt = room temperature

[0382] T3P = 2,4,6 - Tripropyl - 1,3,5,2,4,6 - trioxatriphosphinane - 2,4,6 - trioxide

[0383] TEA = Triethylamine

[0384] TFA = Trifluoroacetic acid

[0385] THF = Tetrahydrofuran

[0386] TsCl = p - Toluenesulfonyl chloride

[0387] UV = Ultraviolet

[0388] X - Phos = 2 - Dicyclohexylphosphino - 2′,4′,6′ - triisopropylbiphenyl

[0389] General synthetic procedure I:

[0390]

[0391] Step 1. Preparation of G1 - 3: At 0 °C, to a solution of primary amine substrate G1 - 1 (46.96 mmol) in MeOH (200 mL), add aldehyde G1 - 2 (46.96 mmol), AcOH (0.5 mL), and NaCNBH3 (8.85 g, 140.88 mmol). Stir the reaction mixture at room temperature for 2 h. Remove the solvent under reduced pressure, and purify the residue by Combi - flash column [DCM / MeOH (10% NH3) = 0 - 10%] to obtain the product.

[0392] Step 2. Preparation of G1 - 4: At 0 °C, to a solution of G1 - 3 (42.19 mmol) in DCM (200 mL), add TEA (8.5 g, 84.37 mmol) and triphosgene (6.25 g, 21.09 mmol). Stir the reaction mixture at room temperature for 2 h. After the reaction is complete, add H2O (500 mL) to the reaction mixture, and then extract with DCM (500 mL × 3). Wash the combined organic layers with brine (300 mL x 2), and then dry over anhydrous Na2SO4. Filter and concentrate the solution in vacuo, and purify the residue by Combi - flash (DCM / MeOH = 0 - 10%) to obtain the product.

[0393] Step 3. Preparation of G1 - 5: Stir a solution of G1 - 4 (0.53 mmol) in DCM / TFA (1:1, 4 mL) at 25 °C for 1 h. Concentrate the resulting mixture to obtain the product, which is directly used in the next step.

[0394] 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-fluoroisoindoline-1,3-dione (131 mg, 0.5 mmol) and DIEA (184 mg, 1.42 mmol). The reaction mixture was stirred at 120 °C under N2 for 2 h. After completion of the reaction, H2O (30 mL) was added to the reaction mixture, and then it was 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. The residue was purified by preparative HPLC [Gemini-C18 150x 21.2 mm, 5 um; ACN--H2O (0.1% TFA), 50-70] to give the desired product.

[0395] Synthesis of intermediates:

[0396] Intermediate A1: 5-Bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine

[0397]

[0398] Step 1. Preparation of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one: At 0 °C under N2, to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 0.25 mol) in DCM (550 mL) was added AlCl3 (101.27 g, 0.76 mol) and acetyl chloride (21.92 g, 0.28 mol). The reaction mixture was stirred at room temperature under N2 for 7 h. 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 x3). The combined organic layers were washed with brine (300 mL x 3), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the crude product was purified by Combi-flash (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] + 。

[0399] Step 2. Preparation of 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine: At 0 °C, 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) were added to a solution of AlCl3 (27.8 g, 0.20 mol) in DME (200 mL). The reaction mixture was stirred at room temperature under N2 for 3 hours. After completion of the reaction, H2O (500 mL) was added to the reaction mixture, and then it was extracted with EA (200 mL x 3). The combined organic layers were 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] + 。

[0400] 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), and 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] + 。

[0401] Step 4. Preparation of 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine: At 0 °C, phosphorus oxychloride (55.05 g, 35.9 mmol) was added 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). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (50 mL), extracted with EA (30 mL x 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] + 。

[0402] Intermediate A2: 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine

[0403]

[0404] Step 1. Preparation of 5-bromo-4-chloropyridin-2-amine: NBS (458 g, 2.57 mol, 1.1 eq) was added portionwise to a solution of 4-chloropyridin-2-amine (300 g, 2.34 mol, 1.0 eq) in acetonitrile (3000 mL). The reaction mixture was stirred at room temperature for 6 hours. Then the reactants were poured into water and filtered. The filter cake was washed with PE and dried to obtain the compound 5-bromo-4-chloropyridin-2-amine (407 g, 83.9% yield), as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.67 (s, 1H), 6.45 (s, 2H).

[0405] Step 2. Preparation of 5-bromo-4-chloro-3-iodopyridin-2-amine: NIS (666 g, 2.96 mol, 1.5 eq) was added portionwise to a solution of 5-bromo-4-chloropyridin-2-amine (407 g, 1.97 mol, 1.0 eq) in AcOH (2000 mL). The reaction mixture was stirred at 80 °C for 4 hours. The reactants were cooled to room temperature, poured into ice water (5000 mL), the pH was adjusted to >7 with K2CO3, and extracted with EA (5000 mL x 3), and washed with Na2SO3 solution (5000 mL) and brine (5000 mL). The organic phase was concentrated in vacuo to obtain the 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) δ 8.10 (s, 1H), 6.62 (s, 2H).

[0406] Step 3. Preparation of 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine: Under N2, to a solution of 5-bromo-4-chloro-3-iodopyridin-2-amine (100 g, 0.300 mol, 1.0 eq), DABCO (101 g, 0.900 mol, 3.0 eq) in DMF (2000 mL) was added Pd(PPh3)2Cl2 (21.1 g, 0.03 mol, 0.1 eq). Then compound (cyclopropyl ethynyl)trimethylsilane (166 g, 1.20 mol, 4.0 eq) was added. The reaction was degassed 3 times under N2. The reaction mixture was stirred at 120 °C for 10 h. The reactants were filtered, quenched with water (2000 mL), extracted with EA (2000 mL x 3), washed with brine (2000 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography with THF / PE (1:15) to give compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, yield 26.2%), as a yellow solid.

[0407] Mass(m / z): 344.9 [M+H] + 。

[0408] Step 4. Preparation of 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine: To a mixture of compound 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (27 g, 79.0 mmol, 1.0 eq) in THF (237 mL) was added TBAF (1.0 M in THF, 237 mL, 3.0 eq) and H2O (4.27 g, 237 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (1000 mL), extracted with EA (1000 mL x 3), washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography with THF / PE (1:4) to give the product compound 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (15 g, yield 70.4%), as a pale yellow solid. Mass(m / z): 272.9 [M+H] + . 1 HNMR(400 MHz, DMSO-d6) δ 11.92 (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).

[0409] Intermediate A3: 5-Bromo-4-chloro-3-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine

[0410]

[0411] Step 1. Preparation of 1-{5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-2,2-difluoroethanone: At 0 °C, aluminum chloride (863.78 mg, 6.48 mmol) and difluoroacetic anhydride (2,2-difluoroacetyl 2,2-difluoroacetate) (751.9 mg, 4.32 mmol) were added to a solution of 3-bromo-4-chloro-7H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mmol) in DCM (10 mL). The reaction mixture was stirred at 25 °C for 7 hours under N2. Methanol (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 x 3). The combined organic layers were washed with brine (30 mL x 3), then dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by Combi-flash (eluted with PE / EA = 2:1) to give the product as a yellow solid (200 mg, 11.67%). Mass (m / z): 308.7 [M+H]+.

[0412] Step 2. Preparation of 3-bromo-4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridine: At 0 °C, lithium aluminum hydride (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) were added to a solution of aluminum chloride (200 mg, 0.65 mmol) in DME (10 mL). The reaction mixture was stirred at 25 °C for 3 hours under N2. After completion of the reaction, water (100 mL) was added, and then it was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), then dried over Na2SO4. The reaction mixture was filtered, the filtrate was concentrated in vacuo and purified by combi-flash, eluted 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]+.

[0413] Intermediate A4: tert-Butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate

[0414]

[0415] Step 1. N 1 -Preparation of (3-bromophenyl)propane-1,3-diamine: To a solution of 1,3-dibromobenzene (18 g, 63.63 mmol) and propane-1,3-diamine (14.1 g, 190.87 mmol) was added KOH (7.14 g, 127.25 mmol) and CuCl (630 mg, 6.36 mmol), and the resulting mixture was stirred at 0 °C under N2 for 16 h. After completion of the reaction, H2O (500 mL) was added to the reaction mixture, and then the mixture was extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL x 2), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combi-flash [DCM / MeOH (10% NH3) = 0 - 10%] to give the product as a brown oil (10.7 g, 73%). Mass (m / z): 231.1 [M+H] + 。

[0416] Step 2. Preparation of tert-Butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: According to Steps 1 and 2 of General Synthetic Procedure I, from N 1 -(3-bromophenyl)propane-1,3-diamine and tert-butyl 4-formylpiperidine-1-carboxylate, the compound tert-Butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate was obtained as a yellow oil (11.1 g, 58%). Mass (m / z): 473.9 [M+H] + 。

[0417] Intermediate A5: tert-Butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate

[0418]

[0419] Step 1. Preparation of tert-Butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: According to Steps 1 and 2 of General Synthetic Procedure I, from 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, which was a yellow oil (880 mg, 39%). Mass (m / z): 462.2 [M+H] + 。

[0420] 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-diazin-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

[0421]

[0422] Step 1. Preparation of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazin-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) were added TFA (2 mL) and H2O (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 NaHCO3 (30 mL×2) and brine (40 mL), dried over Na2SO4 and concentrated to give the crude product. The crude product 1-(3-bromophenyl)-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one (1 g, 2.8 mmol) and DIEA (1.09 g, 8.4 mmol) in DMSO (20 mL) were stirred under nitrogen at 120 °C for 2 h. Water (50 mL) was added and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4. Then, by filtration, 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] + 。

[0423] Step 2.3 - Preparation of [5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazin-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-oxoisoindol-2-yl)piperidine-2,6-dione: To a solution of 5-(4-{[3-(3-bromophenyl)-2-oxo-1,3-diazin-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). 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 x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4. Then, the filtrate was concentrated by filtration. The residue was purified by preparative HPLC [Gemini-C18, 150 x 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-diazin-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] + 。

[0424] 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] + 。

[0425] Preparation of 1-oxo-6-[4-({2-oxo-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-diazin-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-diazin-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)Cl2 (53 mg, 0.072 mmol). The mixture was stirred at 110 °C under nitrogen for 2 h. 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), dried over Na2SO4. Then, the filtrate was concentrated by filtration. 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] + 。

[0426] Following the same procedure, from 3-(5-(4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 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 was obtained as a brown solid (140 mg, 64%). Mass (m / z): 642.3 [M+H] + 。

[0427] Synthesis of Exemplary Compounds:

[0428] Compound 1: 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}isoindoline-1,3-dione

[0429]

[0430] Step 1. Preparation of N-(3-aminopropyl)aniline: To a solution of iodobenzene (3 g, 0.015 mol) was added 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). The reaction mixture was stirred at 0 °C under N2 for 2 h. After completion of the reaction, H2O (50 mL) was added to the reaction mixture, and then the mixture was extracted with EA (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. The residue was purified by Combi-flash (DCM / MeOH = 0 - 5%) to give the desired product (1.97 g, 80%) as a yellow oil. Mass (m / z): 151.2 [M+H] + 。

[0431] 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}isoindoline-1,3-dione: According to the general synthetic procedure I, from N-(3-aminopropyl)aniline and tert-butyl 4-formylpiperidine-1-carboxylate, 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(2-oxo-3-phenyl-1,3-diazinan-1-yl)methyl]piperidin-1-yl}isoindoline-1,3-dione (60 mg, 24%) was obtained as a yellow solid. Mass (m / z): 530.3 [M+H] + . 11H 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).

[0432] Compound 2: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenylimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0433]

[0434] 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: According to General Synthetic Procedure I, from N 1 -phenylethane-1,2-diamine and tert-butyl 4-formylpiperidine-1-carboxylate, compound 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-oxo-3-phenylimidazolidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione was obtained as a yellow solid (130 mg, 21%). Mass (m / z): 516.2 [M + H] + . 11H 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).

[0435] 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

[0436]

[0437] 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 / H2O (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), K2CO3 (130 mg, 0.94 mmol), and Pd(dppf)Cl2 (34 mg, 0.05 mmol). 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 Combi-flash (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] + .

[0438] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(3-(4-chloropyridin-3-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: According to Steps 3 and 4 of General Synthetic Procedure I, 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] + . 1 H 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).

[0439] Compound 4: 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[2-oxo-3-(pyridin-2-yl)-1,3-diazin-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione

[0440]

[0441] 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 N2 for 16 h. After completion of the reaction, H2O (100 mL) was added to the reaction mixture, and then it was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo. The residue was purified by Combi-flash (DCM / MeOH = 0–5%) to give the desired product (3.5 g, 66%) as a yellow oil. Mass (m / z): 152.2 [M+H]+ .

[0442] Preparation of (2,6-dioxopiperidin-3-yl)-5-(4-{[2-oxo-3-(pyridin-2-yl)-1,3-diazin-1-yl]methyl}piperidin-1-yl)isoindoline-1,3-dione in Step 2.2: According to the general synthesis procedure I, using N-(3-aminopropyl)pyridin-2-amine and tert-butyl 4-formylpiperidine-1-carboxylate, the compound (2,6-dioxopiperidin-3-yl)-5-(4-{[2-oxo-3-(pyridin-2-yl)-1,3-diazin-1-yl]methyl}piperidin-1-yl)isoindoline-1,3-dione (20 mg, 1.8%) was obtained 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).

[0443] 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

[0444]

[0445] 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 the general synthetic procedure I, using N-(3-aminopropyl)cyclohexanamine and tert-butyl 4-formylpiperidine-1-carboxylate, 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 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).

[0446] 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

[0447]

[0448] 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 x 2), dried over Na2SO4. Then filtered, and the filtrate was concentrated to dryness to give the product as a brown oil (3 g, purity: 70%). Mass (m / z): 161.1 [M+H] + .

[0449] Step 2. Preparation of N 1 -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 . H2O = 10:1:0.1) to give the product as a colorless oil (900 mg, 42%). Mass (m / z): 165.2 [M+H] + .

[0450] 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: According to the general synthetic procedure I, from N 1 -phenylbutane-1,4-diamine and tert-butyl 4-formylpiperidine-1-carboxylate, 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 was obtained as a yellow solid (180 mg, 47%). Mass (m / z): 544.1 [M+H] + . 11H 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).

[0451] 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

[0452]

[0453] Step 1. Preparation of N 1 -(tert-Butyl)propane-1,3-diamine: To a solution of 3-(tert-butylamino)propionitrile (1000 mg, 7.924 mmol) in diethyl ether (15 mL) was added LiAlH4 (301 mg, 7.924 mmol). The reaction mixture was stirred at 30 °C for 16 h under N2. The reaction mixture was quenched with 15% aqueous NaOH solution (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] + .

[0454] Step 2. Preparation of benzyl 4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: According to Steps 1 and 2 of General Synthetic Procedure I, from N 1 -(tert-Butyl)propane-1,3-diamine and tert-butyl 4-formylpiperidine-1-carboxylate, benzyl 4-((3-(tert-butyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate was obtained as a colorless oil (800 mg, 39%). Mass (m / z): 388.2 [M + H] + .

[0455] 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] + .

[0456] 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, from 1-(tert-butyl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one 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).

[0457] 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

[0458]

[0459] Preparation of 1.5-(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 / H2O (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), K3PO4 (57 mg, 0.26 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol). The reaction mixture was stirred at 85 °C under N2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combi-flash (PE / EA = 0–50%) to give the product as a yellow solid (24 mg, 28%). Mass (m / z): 627.2 [M+H] + . 1 H 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).

[0460] 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

[0461]

[0462] Step 1.5 - 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, starting from tert-butyl 4-((3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate, 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 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).

[0463] 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

[0464]

[0465] 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, starting from tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate, 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 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).

[0466] 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

[0467]

[0468] Step 1. N 1Preparation of N-(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)2 (220 mg, 0.38 mmol). The resulting mixture was stirred at 100 °C under N2 for 16 h. The solvent was removed under reduced pressure, and the residue was purified by Combi-flash [DCM / MeOH (added 10% NH3) = 0 - 10%] to give the product N 1 -(quinolin-6-yl)propane-1,3-diamine, as a brown oil (1.69 g, 87%). Mass (m / z): 202.0 [M+H] + .

[0469] 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: According to the general synthetic procedure I, from N 1 -(quinolin-6-yl)propane-1,3-diamine and tert-butyl 4-formylpiperidine-1-carboxylate, 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 was obtained as a yellow solid (35 mg, 19%). Mass (m / z): 581.1 [M+H] + . 11H 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).

[0470] 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

[0471]

[0472] 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: According to General Synthetic Procedure I, from N 1 -phenylethane-1,2-diamine and tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate, 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(2-(2-oxo-3-phenylimidazolidin-1-yl)ethyl)azetidin-1-yl)isoindoline-1,3-dione was obtained as a yellow solid (54 mg, 13%). Mass (m / z): 502.2 [M+H] + . 11H 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).

[0473] Compound 13: 3-(4-{4-[(2-oxo-3-phenyl-1,3-diazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidine-2,6-dione

[0474]

[0475] Step 1. Preparation of 1-phenyl-3-(piperidin-4-ylmethyl)-1,3-diazin-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 h. 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] + 。

[0476] Step 2. Preparation of 1-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-3-phenyl-1,3-diazin-2-one: To a solution of 1-phenyl-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one (170 mg, 0.62 mmol) in DCM (10 mL) were added (4-bromophenyl)boronic acid pinacol ester (150 mg, 0.75 mmol), Cu(OAc)2 (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 O2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by Combi-flash (PE / EA = 1:1) to give the product (150 mg, 51%) as a light yellow solid. 427.8 [M+H]+ 。

[0477] Step 3. Preparation of 3-phenyl-3-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-yl}methyl)-1,3-diazin-2-one: At 25 °C, Pd(dppf)Cl2 (26 mg, 0.035 mmol) and KOAc (103 mg, 1.05 mmol) were added to a solution of 1-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-3-phenyl-1,3-diazin-2-one (150 mg, 0.35 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bis(1,3,2-dioxaborolane) (249 mg, 0.98 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 90 °C under N2 for 4 h. After completion of the reaction, H2O (10 mL) was added to the reaction mixture, and then the mixture was extracted with EA (20 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 Combi-flash (PE / EA = 1:1) to give the product (130 mg, 62%) as a yellow oil. Mass (m / z): 476.0 [M+H] + 。

[0478] Step 4. Preparation of 1-[(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]-3-phenyl-1,3-diazin-2-one: 2,6-Bis(benzyloxy)-3-bromopyridine (116 mg, 0.31 mmol), Na2CO3 (100 mg, 0.95 mmol) and Pd(dppf)Cl2 (23 mg, 0.031 mmol) were added to a solution of 3-phenyl-3-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-yl}methyl)-1,3-diazin-2-one (150 mg, 0.31 mmol) in 1,4-dioxane / H2O (10 / 1, 11 mL). The reaction mixture was stirred at 90 °C under N2 for 4 h. 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] + 。

[0479] Step 5.3 - Preparation of (4 - {4 - [(2 - oxo - 3 - phenyl - 1,3 - diazin - 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 - diazin - 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 for 16 h under a H2 atmosphere of 0.4 MPa. 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] + . 1 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 = 12.2 Hz, 3H).

[0480] 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

[0481]

[0482] Step 1. N 1 - (3 - chlorophenyl)propane - 1,3 - diamine preparation: 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 for 16 h under N2. After completion of the reaction, H2O (200 mL) was added to the reaction mixture, and then it was extracted with DCM (200 mL × 3). The combined organic layers were washed with brine (300 mL x 2), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combi - flash [DCM / MeOH (10% NH3 .Purify [H2O) = 0 - 10%] to obtain product N 1 -(3-chlorophenyl)propane-1,3-diamine, which is a yellow oil (1.34 g, 85%). Mass (m / z): 185.2 [M+H] + .

[0483] 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: According to the general synthesis process I, from N 1 -(3-chlorophenyl)propane-1,3-diamine, obtain 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, which is a yellow solid (55 mg, 10%). Mass (m / z): 563.9 [M+H] + . 1 1H 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).

[0484] 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

[0485]

[0486] 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 / H2O (20 / 1, 20 mL) was added cyclopropylboronic acid (124 mg, 1.44 mmol), K3PO4 (705 mg, 3.33 mmol), PCy3 (31 mg, 0.11 mmol) and Pd(OAc)2 (12 mg, 0.06 mmol). The reaction mixture was stirred at 100 °C under N2 for 3 h. The solvent was removed under reduced pressure and the residue was purified by Combi-flash (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] + .

[0487] 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, from tert-butyl 4-((3-(3-cyclopropylphenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate, 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 as a yellow solid (90 mg, 20%). Mass (m / z): 569.8 [M+H] + . 11H 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).

[0488] 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

[0489]

[0490]

[0491] Step 1. Preparation of tert-butyl (3-((4-fluorobenzyl)amino)propyl)carbamate: At 0 °C, 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). The solvent was removed under reduced pressure, and the residue was purified by Combi-flash [DCM / MeOH (10% NH3 . H2O) = 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] + 。

[0492] Step 2. Preparation of N 1 -(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 h. The solvent was removed under reduced pressure to give the product N 1-(4-Fluorobenzyl)propane-1,3-diamine, a white solid (1.5 g, 81%). Mass (m / z): 183.0 [M+H] + .

[0493] 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: According to the general synthesis procedure I, starting from N 1 -(4-Fluorobenzyl)propane-1,3-diamine, 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 was obtained as a yellow solid (45 mg, 12%). Mass (m / z): 562.3 [M+H] + . 1 H 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).

[0494] Compound 17: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxoimidazolin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0495]

[0496] Step 1. Preparation of tert-butyl (2-((4-fluorobenzyl)amino)ethyl)carbamate: At 0 °C, 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). The solvent was removed under reduced pressure, and the residue was purified by Combi-flash [DCM / MeOH (10% NH3 . H2O) = 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] + .

[0497] Step 2. Preparation of N 1 -(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 h. The solvent was removed under reduced pressure to give the product N 1 -(4-fluorobenzyl)ethane-1,2-diamine as a white solid (1.3 g, 64%). Mass (m / z): 169.0 [M+H] + .

[0498] Step 3. Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxoimidazolin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione: According to the general synthetic procedure I, from N 1 -(4-fluorobenzyl)ethane-1,2-diamine, the product 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-fluorobenzyl)-2-oxoimidazolin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione was obtained as a yellow solid (60 mg, 16%). Mass (m / z): 548.0 [M+H] + . 11H 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).

[0499] 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)isoindoline-1,3-dione

[0500]

[0501] Step 1. Preparation of benzyl 4-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)piperidine-1-carboxylate: According to 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] + 。

[0502] 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) was added HCl / dioxane (4.0 M, 25 mL). The reaction mixture was stirred at 25 °C under N2 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] + 。

[0503] Step 3. Preparation of benzyl 4-((2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: According to 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] + 。

[0504] Step 4. Preparation of benzyl 4-(((3-(4-methylthiazol-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate): At 25 °C, 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), Pd2(dba)3 (165 mg, 0.18 mmol) and Cs2CO3 (1.77 g, 5.43 mmol). The reaction mixture was stirred at 100 °C under N2 for 4 h. After completion of the reaction, H2O (50 mL) was added to the reaction mixture, and then it was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combi-flash (DCM / MeOH = 20:1) to give the product as a brown solid (280 mg, 26%). Mass (m / z): 429.2 [M+H] + 。

[0505] Step 5. Preparation of 1-(4-methyl-1,3-thiazol-2-yl)-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one: At -78 °C under N2, 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 BCl3 (1.0 M in DCM, 4 mL, 3.95 mmol). The reaction mixture was stirred at 25 °C under N2 for 16 h. After completion of the reaction, H2O (20 mL) was added to the reaction mixture at 0 °C, and then it was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by preparative TLC (PE / EA = 1:1) to give the product as a yellow solid (122 mg, 63%). Mass (m / z): 295.0 [M+H] + 。

[0506] Preparation of (2,6-dioxopiperidin-3-yl)-5-(4-{[3-(4-methyl-1,3-thiazol-2-yl)-2-oxo-1,3-diazin-1-yl]methyl}piperidin-1-yl)isoindoline-1,3-dione: According to Step 4 of General Synthetic Procedure I, the desired product (43 mg, 18%) was obtained as a yellow solid. Mass (m / z): 551.2 [M+H] + . 1 H 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).

[0507] 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

[0508]

[0509] Preparation of 1-phenyl-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: According to 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] + .

[0510] Preparation of (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) were added 1-phenyl-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one (200 mg, 0.73 mmol), Cs2CO3 (284 mg, 0.87 mmol), Ruphos (27 mg, 0.06 mmol), RuPhos Pd G2 (45 mg, 0.06 mmol) mmol), and 4A molecular sieve (4 mg, 0.008 mmol). The reaction mixture was stirred at 100 °C under N2 for 16 h. After completion of the reaction, H2O (20 mL) was added to the reaction mixture, and then it was extracted with EA (20 mL x 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 Combi-flash (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).

[0511] Compound 20: 3-(4-(4-(2-(2-oxo-3-phenyltetrahydropyrimidin-1(2H)-yl)ethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione

[0512]

[0513] 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’-bis(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)Cl2 (0.4 g, 0.54 mmol). The reaction mixture was stirred at 90 °C under N2 for 16 h. The mixture was concentrated and the residue was purified by flash column (PE / EA = 10:1) to give the product as a brown solid (1.5 g, 70%). Mass (m / z): 418.1 [M+H] + 。

[0514] Step 2. Preparation of 1-phenyl-3-[2-(piperidin-4-yl)ethyl]-1,3-diazin-2-one: According to Steps 1, 2, and 3 of General Synthetic Procedure I, the desired product was obtained as a brown solid (650 mg, purity: ~50%). Mass (m / z): 288.0 [M+H] + 。

[0515] Step 3. Preparation of 1-{2-[1-(4-bromophenyl)piperidin-4-yl]ethyl}-3-phenyl-1,3-diazin-2-one: At room temperature under O2, a solution of 1-phenyl-3-[2-(piperidin-4-yl)ethyl]-1,3-diazin-2-one (500 mg, 1.739 mmol), (4-bromophenyl)boronic acid pinacol ester (1.04 g, 5.21 mmol), Cu(OAc)2 (474 mg, 2.609 mmol), TEA (702 mg, 6.958 mmol), and 4A MS (250 mg) in DCM (20 mL) was stirred for 16 h. The mixture was concentrated and the residue was purified by flash column (DCM:MeOH = 20:1) to give the product as a brown solid (280 mg, 36%). Mass (m / z): 442.9 [M+H] + 。

[0516] Preparation of (4-(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-diazin-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 K2CO3 (162 mg, 1.175 mmol) in dioxane / H2O (10 / 1, 10 mL) was added Pd(dppf)Cl2 (43 mg, 0.026 mmol). The reaction mixture was stirred at 100 °C under N2 for 16 h. 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] + .

[0517] Preparation of 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 H2 at 0.4 MPa for 16 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC [Gemini-C18, 150x 21.2 mm, 5um; ACN-H2O (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).

[0518] 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

[0519]

[0520] 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 K3PO4 (107 mg, 0.50 mmol) and Pd(dppf)Cl2 (18 mg, 0.025 mmol). The reaction mixture was stirred at 85 °C under N2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by Pre-HPLC [column: Gemini-C18 150x 21.2 mm, 5um; mobile phase: ACN-H2O (0.1% FA), gradient: 20-50], giving the product as a yellow solid (50 mg, 30%). Mass (m / z): 632.0 [M+H] + . 11H 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).

[0521] 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

[0522]

[0523] 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 cyclopropylboronic acid pinacol ester (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 solution (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): 238.0 240.0 [M+H] + 。

[0524] Preparation of 2-(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-(cyclopropyl)pyrazolo[3,4-b]pyridine (700 mg, 2.94 mmol) and B2(Pin)2 (896 mg, 3.53 mmol) in dioxane (10 mL) were 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] + .

[0525] 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 2-(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) were added K3PO4 (71 mg, 0.34 mmol) and Pd(dppf)Cl2 (12 mg, 0.017 mmol). The reaction mixture was stirred at 85 °C under N2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by Pre-HPLC [column: Gemini-C18 150x 21.2 mm, 5um; mobile phase: ACN-H2O (0.1% FA), gradient: 40-70] to give the product as a yellow solid (60 mg, 52%). Mass (m / z): 673.0 [M+H] + . 11H 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).

[0526] 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

[0527]

[0528] Preparation of (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-ylboronic acid pinacol ester (44 mg, 0.25 mmol) in dioxane (3 mL) and water (0.3 mL) was added K3PO4 (71 mg, 0.34 mmol) and Pd(dppf)Cl2 (12 mg, 0.017 mmol). The reaction mixture was stirred at 85 °C under N2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by Pre-HPLC [column: -Gemini-C18 150x21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA), gradient: 40 - 70] to give the product as a yellow solid (17 mg, 14%). Mass (m / z): 643.0 [M+H] + . 1 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).

[0529] 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

[0530]

[0531] 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% - 40%) to give the product as a yellow solid (500 mg, 47%). Mass (m / z): 179.1 [M + H] + 。

[0532] 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 - diazin - 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 K3PO4 (71 mg, 0.34 mmol) and Pd(dppf)Cl2 (12 mg, 0.017 mmol). The reaction mixture was stirred at 85 °C under N2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC [column: β - Gemini - C18 150x21.2 mm, 5um; mobile phase: ACN - H2O (0.1% FA), gradient: 50 - 80] to give the product as a yellow solid (40 mg, 34%). Mass (m / z): 648.0 [M + H] + . 11H 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).

[0533] 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-diazin-1-yl]ethyl}azetidin-1-yl)isoindole-1,3-dione

[0534]

[0535] 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 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 / H2O (10:1, 5.5 mL) was added K2CO3 (68 mg, 0.493 mmol), 5-bromo-1H-pyrazolo[3,4-b]pyridine (39 mg, 0.197 mmol) and Pd(dppf)Cl2 (13 mg, 0.016 mmol). The reaction was degassed with N2 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 x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column (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] + 。

[0536] Preparation of 1-[2-(azetidin-3-yl)ethyl]-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazin-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-diazin-2-one as a yellow solid (40 mg, 57%). Mass (m / z): 377.2 [M+H] + 。

[0537] Preparation of (2,6-dioxopiperidin-3-yl)-5-(3-{2-[2-oxo-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazin-1-yl]ethyl}azetidin-1-yl)isoindoline-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-diazin-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-fluoroisoindoline-1,3-dione (29.4 mg, 0.106 mmol). The reaction was stirred at 120 °C for 1 h. The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give the product (2,6-dioxopiperidin-3-yl)-5-(3-{2-[2-oxo-3-(3-{1H-pyrazolo[3,4-b]pyridin-5-yl}phenyl)-1,3-diazin-1-yl]ethyl}azetidin-1-yl)isoindoline-1,3-dione as a yellow solid (10 mg, 14%). Mass (m / z): 633.2 [M+H] + . 1 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).

[0538] 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

[0539]

[0540] Step 1. Preparation of tert-butyl 1-(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 / H2O (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), K2CO3 (107 mg, 0.77 mmol), and Pd(dppf)Cl2 (28 mg, 0.04 mmol). The reaction mixture was stirred at 90 °C under N2 for 16 h. After completion of the reaction, H2O (100 mL) was added to the reaction mixture, and then the mixture was extracted with DCM (50 mL x 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 (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] + 。

[0541] 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 h. 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] + 。

[0542] Preparation of (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-1(2H)-one (80 mg, 0.18 mmol) in DMSO (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.18 mmol) and DIEA (71 mg, 0.55 mmol). The reaction mixture was stirred at 120 °C under N2 for 2 h. After completion of the reaction, H2O (30 mL) was added to the reaction mixture, and then the mixture was extracted with EA (20 mL x 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 (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] + . 1 H 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).

[0543] 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)isoindoline-1,3-dione

[0544]

[0545] Step 1. Preparation of 5-chloro-3-ethyl-1H-pyrrolo[3,2-b]pyridine: Butyraldehyde (276 mg, 3.83 mmol) was added to a solution of 2-chloro-5-hydrazinopyridine (500 mg, 3.48 mmol) in 5% H2SO4 solution (20 mL). The reaction mixture was stirred at 110 °C for 16 h under N2. The pH of the reaction solution was adjusted to 8 - 9 with 40% aqueous KOH solution, and then extracted with EA (100 mL x 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 (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] + 。

[0546] 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: 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), K2CO3 (84 mg, 0.61 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added to a solution of 5-chloro-3-ethyl-1H-pyrrolo[3,2-b]pyridine (55 mg, 0.30 mmol) in dioxane / H2O (10 / 1, 5 mL). The reaction mixture was stirred at 90 °C for 16 h under N2. 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] +。

[0547] 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] + 。

[0548] 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-diazin-1-yl]ethyl}azetidin-1-yl)isoindoline-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-diazin-2-one (80 mg, 0.20 mmol) in DMSO (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (55 mg, 0.20 mmol) and DIEA (77 mg, 0.59 mmol). The reaction mixture was stirred at 120 °C under N2 for 2 hours. After completion of the reaction, H2O (50 mL) was added to the reaction mixture, and then it was extracted with EA (30 mL x 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 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-diazin-1-yl]ethyl}azetidin-1-yl)isoindoline-1,3-dione as a yellow solid (5 mg, 3%). Mass (m / z): 660.2 [M+H] + . 11H 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 = 8.2 Hz, 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).

[0549] 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)isoindoline-1,3-dione

[0550]

[0551] 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 / H2O (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), K2CO3 (267 mg, 1.93 mmol), and Pd(dppf)Cl2 (70 mg, 0.1 mmol). 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 (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] + 。

[0552] Step 2. Preparation of (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) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. 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] + .

[0553] Step 3. Preparation of 5-[4-({3-[3-(6-amino-2-chloropyridin-3-yl)phenyl]-2-oxo-1,3-diazin-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 N2 for 2 h. After completion of the reaction, 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 (100 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 - 10%) to give the product 5-[4-({3-[3-(6-amino-2-chloropyridin-3-yl)phenyl]-2-oxo-1,3-diazin-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] + . 11H 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).

[0554] 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

[0555]

[0556] 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 K3PO4 (3.08 g, 14.530 mmol) in dioxane / H2O (10:1, 20 mL) was added Pd(dppf)Cl2 . CH2Cl2 (359 mg, 0.484 mmol). The reaction mixture was stirred at 110 °C under N2 for 18 h. The reaction mixture was concentrated and the residue was purified by column chromatography (EA / PE = 1:6) to afford the desired product (300 mg, yield: 37%) as a yellow solid. Mass (m / z): 156 [M+H] + .

[0557] 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 N2 for 18 h. 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] + 。

[0558] 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 / H2O (10:1, 5 mL) was added Pd(dppf)Cl2 . CH2Cl2 (76 mg, 0.093 mmol). The reaction mixture was stirred at 90 °C under N2 for 18 h. The reaction was filtered and the filtrate was concentrated. The residue was purified by Combi-flash with MeOH / DCM (1:10) to give the target compound (100 mg, yield: 19%), as a white solid. Mass (m / z): 527 [M+H] + 。

[0559] 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 N2 for 18 h. 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] + 。

[0560] 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-fluoroisoindoline-1,3-dione (75 mg, 0.271 mmol), 1-[3-(4-amino-2-chloro-3-ethylphenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one (127 mg, 0.298 mmol) and DIEA (350 mg, 2.715 mmol) in DMSO (5 mL) was stirred at 120 °C under N2 for 18 h. After completion of the reaction, H2O (10 mL) was added to the reaction mixture, and then the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 3), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by preparative HPLC [(Gemini-C18 150x 21.2 mm, 5 um; ACN-H2O (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).

[0561] Compound 30: 5-{4-[(3-{3-[2-chloro-4-(ethylamino)phenyl]phenyl}-2-oxo-1,3-diazin-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0562]

[0563] 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) was added acetaldehyde (256 mg, 75.8 mmol), NaBH3CN (1096 mg, 17.44 mmol) and AcOH (0.02 mL). The reaction mixture was stirred at 25 °C under N2 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] + 。

[0564] 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 / H2O (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), K2CO3 (354 mg, 2.56 mmol) and Pd(dppf)Cl2 (94 mg, 0.13 mmol). 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 - 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] + 。

[0565] Preparation of (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 h. 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] + .

[0566] Preparation of 5-{4-[(3-{3-[2-chloro-4-(ethylamino)phenyl]phenyl}-2-oxo-1,3-diazin-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindoline-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-fluoroisoindoline-1,3-dione (157 mg, 0.70 mmol) and DIEA (366 mg, 3.5 mmol). The reaction mixture was stirred at 120 °C under N2 for 2 h. After completion of the reaction, 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 - 10%) to give the product 5-{4-[(3-{3-[2-chloro-4-(ethylamino)phenyl]phenyl}-2-oxo-1,3-diazin-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (58 mg, 14%). Mass (m / z): 683.1 [M+H] + . 11H 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).

[0567] 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

[0568]

[0569] 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) were added methylamine 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 N2 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] + 。

[0570] 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 / H2O (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-diazin-1-yl}methyl)piperidine-1-carboxylate (402 mg, 0.80 mmol), K2CO3 (222 mg, 1.61 mmol) and Pd(dppf)Cl2 (59 mg, 0.08 mmol). 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] + 。

[0571] Preparation of 3-chloro-N-methyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazin-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 h. The resulting mixture was concentrated to give the product 3-chloro-N-methyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazin-1-yl]phenyl}benzamide as a yellow solid (210 mg, 95%). Mass (m / z): 441.0 [M+H] + 。

[0572] 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-diazin-1-yl]phenyl}-N-methylbenzamide: To a solution of 3-chloro-N-methyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazin-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 N2 for 2 h. After completion of the reaction, H2O (100 mL) was added to the reaction mixture, and then the mixture was 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] + . 1 H 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 = 12.6 Hz, 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).

[0573] 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-diazin-1-yl]phenyl}-N,N-dimethylbenzamide

[0574]

[0575] 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 for 16 h under N2. 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] + 。

[0576] 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 / H2O (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), K2CO3 (166 mg, 1.2 mmol) and Pd(dppf)Cl2 (44 mg, 0.06 mmol). The reaction mixture was stirred at 90 °C for 16 h under N2. 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] + 。

[0577] Step 3. Preparation of 3-chloro-N,N-dimethyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazin-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 h. The resulting mixture was concentrated to give the product 3-chloro-N,N-dimethyl-4-{3-[2-oxo-3-(piperidin-4-ylmethyl)-1,3-diazin-1-yl]phenyl}benzamide as a yellow solid (260 mg, 92%). Mass (m / z): 455.0 [M+H] + .

[0578] 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-diazin-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-diazin-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 N2 for 2 h. After completion of the reaction, H2O (100 mL) was added to the reaction mixture, and then the mixture was 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 - 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-diazin-1-yl]phenyl}-N,N-dimethylbenzamide as a yellow solid (120 mg, 29%). Mass (m / z): 711.1 [M+H] + . 11H 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).

[0579] Compound 33: 5-[4-({3-[3-(2-Chloro-4-methylsulfonylphenyl)phenyl]-2-oxo-1,3-diazinan-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0580]

[0581] Step 1. Preparation of 4-bromo-2-iodo-1-(methylthio)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 completion of the reaction, H2O (200 mL) was added to the reaction mixture, and then the mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the product 4-bromo-2-iodo-1-(methylthio)benzene as a colorless oil (1300 mg, 71%). Mass (m / z): 352.0 [M+Na] + 。

[0582] Step 2. Preparation of 1-bromo-2-chloro-4-(methylsulfonyl)benzene: To a solution of 1-bromo-2-chloro-4-(methylthio)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 N2 for 16 h. After completion of the reaction, H2O (100 mL) was added to the reaction mixture, and then it was extracted with DCM (100 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 (PE / EA = 0 - 100%) to give the product 1-bromo-2-chloro-4-(methylsulfonyl)benzene as a white solid (500 mg, 62%). Mass (m / z): 267.2 [M+H] + 。

[0583] 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-(methylsulfonyl)benzene (300 mg, 1.11 mmol) in dioxane / H2O (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), K2CO3 (308 mg, 2.23 mmol), and Pd(dppf)Cl2 (81 mg, 0.11 mmol). 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] + 。

[0584] Step 4. Preparation of [3-(2-chloro-4-(methylsulfonyl)phenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazin-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 h. The resulting mixture was concentrated to give the product [3-(2-chloro-4-(methylsulfonyl)phenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one as a yellow solid (200 mg, purity: 60%). Mass (m / z): 462.0 [M+H] + .

[0585] Step 5. Preparation of 5-[4-({3-[3-(2-chloro-4-(methylsulfonyl)phenyl)phenyl]-2-oxo-1,3-diazin-1-yl}methyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione: To a solution of [3-(2-chloro-4-(methylsulfonyl)phenyl)phenyl]-3-(piperidin-4-ylmethyl)-1,3-diazin-2-one (200 mg, 0.43 mmol) in DMSO (10 mL) were 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 N2 for 2 h. After completion of the reaction, H2O (100 mL) was added to the reaction mixture, and then it was 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 - 10%) to give the product 5-[4-({3-[3-(2-chloro-4-(methylsulfonyl)phenyl)phenyl]-2-oxo-1,3-diazin-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] + . 11H 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).

[0586] 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

[0587]

[0588] Step 1. Preparation of 4-bromo-3-chloro-2-fluorobenzaldehyde: At -78 °C under N2, a solution of 1-bromo-2-chloro-3-fluorobenzene (2000 mg, 9.549 mmol) in THF (20 mL) was added dropwise to LDA (2 M in THF, 7.2 mL, 14.32 mmol). The reaction mixture was stirred at -78 °C under N2 for 1 h. 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 h. The solution was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4. Then, the filtrate was 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.

[0589] 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 N2 for 18 h. Water (30 mL) was added and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na2SO4. Then, the filtrate was 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] + 。

[0590] Step 3. Preparation of tert-butyl 4-((3-(3-(7-chloro-1-ethyl-1H-indazol-6-yl)phenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: Under N2, to a solution 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)piperidine-1-carboxylate (867 mg, 1.733 mmol) and potassium carbonate (319 mg, 2.311 mmol) in 1,4-dioxane / H2O (10:1, 6 mL) was added Pd(dppf)Cl2 (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 combi-flash (MeOH / DCM = 1:10) to give the target compound (300 mg, yield: 44.58%), as a white solid. Mass (m / z): 474 [M+Na] + 。

[0591] Step 4. Preparation of (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]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 N2 for 18 h. The solution was concentrated under reduced pressure to give the title compound (200 mg, 73%) as a brown oil. Mass (m / z): 452 [M+H] + .

[0592] 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-fluoroisoindoline-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 N2 for 1 h. 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), dried over Na2SO4. Then the filtrate was concentrated by filtration. The residue was purified by preparative HPLC [Gemini-C18, 150 x 21.2 mm, 5 μm; ACN-H2O (0.1% FA), 20-50] to give the desired product (7 mg, 4.39%) as a yellow solid. Mass (m / z): 708 [M+H] + . 11H 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).

[0593] 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

[0594]

[0595] Step a. Preparation of 1-(5-bromo-4-chloro-1H-indol-3-yl)ethan-1-one: At 0 °C, acetyl chloride (8.51 g, 108.46 mmol) was added dropwise to a solution of AlCl3 (28.91 g, 216.93 mmol) in DCM (100 mL). 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 N2 for 18 h. The mixture was poured into ice water and a brown solid precipitated. The mixture was filtered and the filter cake was dried to give the target compound (5.5 g, 88.38%), as a brown solid. Mass (m / z): 272 [M+H] + 。

[0596] Step b. Preparation of 5-bromo-4-chloro-3-ethyl-1H-indole: At 0 °C, LiAlH4 (3.83 g, 100.91 mmol) was added to a solution of AlCl3 (26.9 g, 201.81 mmol) in DME (500 mL). Then 1-(5-bromo-4-chloro-1H-indol-3-yl)ethanone (ethenone) (5.5 g, 20.181 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature under N2 for 3 hours. The mixture was poured into ice water and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4 and concentrated to give the target compound (2.5 g, 45.52%), as a grey solid. Mass (m / z): 258 [M+H] + 。

[0597] Step c. Preparation of 4-chloro-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole: Under N2, Pd(dppf)Cl2 (157 mg, 0.193 mmol) was added 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). The reaction mixture was stirred at 90 °C under N2 for 18 hours. 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] + 。

[0598] Step 1. N 1 -(2-bromopyridin-4-yl)propane-1,3-diamine preparation: At 0 °C, 2-bromo-4-iodopyridine (500 mg, 1.761 mmol) was added to a mixture of CuCl (17 mg, 0.176 mmol) in propane-1,3-diamine (2 mL). The reaction mixture was stirred at 0 °C under N2 for 2 hours. Water (20 mL) was added and the mixture was extracted with DCM (20 mL x 2). The DCM layer was washed with brine (20 mL x 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] + 。

[0599] Preparation of tert-butyl 4-(((3-((2-bromopyridin-4-yl)amino)propyl)amino)methyl)piperidine-1-carboxylate: At 0 °C, NaBH3CN (163 mg, 2.607 mmol) was added 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). The reaction mixture was stirred at room temperature under N2 for 18 h. 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] + 。

[0600] Preparation of tert-butyl 4-((3-(2-bromopyridin-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate: At 0 °C, a solution of triphosgene (90 mg, 0.304 mmol) in DCM (2 mL) was added 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). The reaction mixture was stirred at 40 °C under N2 for 18 h. 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]+.

[0601] 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: Under N2, Pd(dppf)Cl2 (35 mg, 0.044 mmol) was added 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 / H2O (10:1, 2 mL). The reaction mixture was stirred at 90 °C for 18 h under N2. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by combi-flash (MeOH / DCM = 1:10) to give the title compound (200 mg, yield: 73.91%) as a white solid. Mass (m / z): 552 [M+H] + .

[0602] Preparation of 1-(2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl)-3-(piperidin-4-ylmethyl)tetrahydropyrimidin-2(1H)-one: TFA (0.6 mL) was added 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). The reaction mixture was stirred at room temperature for 18 h under N2. The solution was concentrated under reduced pressure to give the title compound (150 mg, 48.86%) as a brown oil. Mass (m / z): 452 [M+H] + .

[0603] Preparation of 6.5-(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: A solution of 1-[2-(4-chloro-3-ethyl-1H-indol-5-yl)pyridin-4-yl]-3-(piperidin-4-ylmethyl)-1,3-diazin-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 for 1 hour under N2. 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), dried over Na2SO4. Then, the filtrate was concentrated by filtration. The residue was purified by preparative HPLC [Gemini-C18, 150 x 21.2 mm, 5um; 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] + . 1 H 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).

[0604] 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

[0605]

[0606] 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)Cl2 (1.79 g, 2.45 mmol). The reaction mixture was stirred at 90 °C under N2 for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combi-flash (DCM / MeOH = 0 - 10%) to give the product as a brown oil (12.3 g, 80%). Mass (m / z): 522.0 [M+H] + 。

[0607] 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 / H2O (10:1, 200 mL) was added 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (6.37 g, 24.58 mmol), K2CO3 (10.19 g, 73.73 mmol), and Pd(dppf)Cl2 (1.79 g, 2.46 mmol). The reaction mixture was stirred at 90 °C under N2 for 4 h. After completion of the reaction, H2O (300 mL) was added to the reaction mixture, and then it was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (300 mL x 2), and then dried over anhydrous Na2SO4. After filtration, the solution was concentrated in vacuo, and the residue was purified by Combi-flash (DCM / MeOH = 0 - 10%) to give the product as a brown solid (5.83 g, 39%). Mass (m / z): 552.0 [M+H] + 。

[0608] 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: According to Steps 3 and 4 of General Synthetic Procedure I, starting from 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, 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).

[0609] 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

[0610]

[0611] Step 1. Preparation of tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate: According to Steps 1 and 2 of General Synthetic Procedure I, using tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate, the product tert-butyl 4-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)piperidine-1-carboxylate (660 mg, 56%) was obtained as a yellow oil. Mass(m / z): 488.2 [M+H] + 。

[0612] 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’-bis(1,3,2-dioxaborolane) (538 mg, 2.12 mmol), KOAc (416 mg, 4.24 mmol), and Pd(dppf)Cl2 (103 mg, 0.14 mmol). The reaction mixture was stirred at 90 °C under N2 for 2 h. The solvent was removed under reduced pressure, and the residue was purified by Combi-flash (DCM / MeOH = 0 - 10%) to give the product (650 mg, 89%) as a brown oil. Mass(m / z): 536.0 [M+H] + 。

[0613] Preparation of tert-butyl 4-((2-(2-oxo-3-(3-(4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)tetrahydropyrimidin-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 / H2O (10:1, 15 mL), 5-bromo-4-chloro-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (343 mg, 1.26 mmol), K2CO3 (523 mg, 3.79 mmol), and Pd(dppf)Cl2 (92 mg, 0.13 mmol) were added. The reaction mixture was stirred at 90 °C under N2 for 4 h. After completion of the reaction, H2O (20 mL) was added to the reaction mixture, and then it was extracted with DCM (20 mL x 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 Combi-flash (DCM / MeOH = 0 - 10%) to give the product (250 mg, 34%) as a yellow oil. Mass (m / z): 578.3 [M+H] + 。

[0614] 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: According to Steps 3 and 4 of General Synthetic Procedure I, from 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, 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] + . 11H 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).

[0615] 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

[0616]

[0617]

[0618] Preparation of 1.3-(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 K3PO4 (69 mg, 0.33 mmol) in 1,4-dioxane / H2O (10:1, 3 mL) was added Pd(dppf)Cl2 (8 mg, 0.011 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 x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4. Then the filtrate was concentrated by filtration. The residue was purified by preparative HPLC [Gemini-C18, 50 x 21.2 mm, 5um; ACN--H2O (0.1% FA), 5-50] to give the product as a yellow solid (2 mg, 2.5%). Mass (m / z): 730.3 [M+H] + .

[0619] 11H 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).

[0620] 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

[0621]

[0622] Preparation of (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: To a solution 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 (100 mg, 0.15 mmol), 3-bromo-4-chloro-5-(2,2-difluoroethyl)-7H-pyrrolo[2,3-b]pyridine (55 mg, 0.18 mmol) and K3PO4 (99 mg, 0.46 mmol) in 1,4-dioxane / H2O (5 mL) was added Pd(dppf)Cl2 (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 x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4. Then the filtrate was concentrated by filtration. The crude product was purified by preparative HPLC [Gemini-C18, 150 x 21.2 mm, 5 µm; ACN--H2O (0.1% FA), 30-50] to give the product as a yellow solid (6 mg, 5.1%). Mass (m / z): 730.3 [M+H] + . 11H 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).

[0623] Compound E: 5 - ({2 - [3 - (3 - {4 - chloro - 5 - ethyl - 7H - pyrrolo[2,3 - b]pyridin - 3 - yl}phenyl)-2 - oxo - 1,3 - dioxazin - 1 - yl]ethyl}amino)-2 - (2,6 - dioxopiperidin - 3 - yl)isoindole - 1,3 - dione

[0624]

[0625] Step 1. Preparation of tert - butyl N - {2 - [3 - (3 - bromophenyl)-2 - oxo - 1,3 - dioxazin - 1 - yl]ethyl}carbamate: According to Steps 1 and 2 of General Synthetic Procedure I, from N - (3 - aminopropyl)-3 - bromoaniline, the compound tert - butyl N - {2 - [3 - (3 - bromophenyl)-2 - oxo - 1,3 - dioxazin - 1 - yl]ethyl}carbamate was obtained as a yellow solid (0.93 g, 85%). Mass (m / z): 420.0 [M + Na] + 。

[0626] 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-diazin-1-yl}ethyl)carbamate: To a mixture of tert-butyl N-{2-[3-(3-bromophenyl)-2-oxo-1,3-diazin-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)Cl2 (171 mg, 0.233 mmol). The reaction was degassed with N2 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 x 3), washed with brine (100 mL), dried over Na2SO4 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-diazin-1-yl}ethyl)carbamate as a yellow solid (0.53 g, 46%). Mass (m / z): 445.3 [M+H] + .

[0627] 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 / H2O (10:1, 10.0 mL), K2CO3 (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)Cl2 (82 mg, 0.112 mmol) were added. The reaction was degassed with N2 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 x 3), washed with brine (100 mL), dried over Na2SO4 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] + .

[0628] 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, from 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, 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 was obtained as a yellow solid (5 mg, 5%). Mass (m / z): 654.0 [M+H] + . 11H 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).

[0629] 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

[0630]

[0631] Step 1. Preparation of tert-butyl 3-(2-(3-(3-bromophenyl)-2-oxotetrahydropyrimidin-1(2H)-yl)ethyl)azetidine-1-carboxylate: According to Steps 1 and 2 of General Synthetic Procedure I, from N 1 -(3-bromophenyl)propane-1,3-diamine, 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] + .

[0632] 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)Cl2 (62 mg, 0.08 mmol). 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 Combi-flash (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] + .

[0633] 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 / H2O (10:1, 15 mL), 5-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (240 mg, 0.93 mmol), K2CO3 (383 mg, 2.78 mmol) and Pd(dppf)Cl2 (68 mg, 0.09 mmol) were added. The reaction mixture was stirred at 90 °C under N2 for 4 h. After completion of the reaction, H2O (20 mL) was added to the reaction mixture, and then the mixture was extracted with DCM (20 mL x 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 Combi-flash (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] + 。

[0634] 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, from 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, the compound 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 was obtained as a yellow solid (136 mg, 21%). Mass (m / z): 694.1 [M+H] + . 11H 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).

[0635] General determination procedure:

[0636] GSPT1 degradation assay

[0637] HL-60 cells (4 x 10^ 6 cells / well) were seeded in 6-well culture plates (Costar, 3516) and treated with different concentrations of the test compound. After incubation for 2 hours, the cells were collected and lysed. The protein concentration was determined using the BCA Protein Assay Kit (23227) from Thermo. The GSPT1 protein level was determined by Western blotting using a GSPT1 polyclonal antibody. The protein was added to each well of the precast gel and separated by SDS-PAGE electrophoresis. The protein separated by SDS-PAGE was transferred to PVDF, blocked with 5% skim milk, and detected using the following standard Western blotting procedure with an anti-GSPT1 antibody (Proteintech, 10763-1-AP) or an anti-β-actin antibody (CST, 3700S). The blot intensity was quantified using ImageJ software, and the intensity of the GSPT1 band was normalized to the β-actin band respectively. Then the GSPT1 degradation results were 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.

[0638] Table 2. Results of compounds in the GSPT1 protein degradation assay

[0639]

[0640]

[0641]

[0642]

[0643] The above results indicate that most of the compounds in Table 2 have better GSPT1 degradation effects than the previously reported compound C84971 (see WO2021126974A1 and WO2021126973A1).

[0644] Cell viability assay

[0645] HL-60 cells were seeded in a 96-well culture plate (Corning 3903) at a density of 7000 cells per well, cultured in IMDM, and treated with the test compounds by 6-point serial dilution. RPMI 1640 (0.1% DMSO) was used as the control for each well. After incubation for 72 hours, cell viability was measured using the CellTiter-Glo assay kit (Promega, G9242) according to the manufacturer's instructions. The dose-response curve was determined using GraphPad Prism software by non-linear regression method, and the IC 50 value was calculated. The results of the cell viability assay are shown in Table 3 below.

[0646] Table 3. Results of the compounds in the cell viability assay

[0647]

[0648]

[0649] Other embodiments

[0650] The present disclosure only provides exemplary embodiments. Those skilled in the art will readily recognize that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

1. A compound of formula (I), its tautomer, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing substances, wherein: (xvii) each R’ is independently selected from: hydrogen, a halogen group, a straight-chain alkyl group, a branched-chain alkyl group, and a cycloalkyl group; (xviii) m and n are independently selected from: 0, 1, and 2; (xix) X and Z are independently absent or selected from: a straight-chain alkylene group, a branched-chain alkylene group, a cycloalkylene group, a straight-chain heteroalkylene group, a branched-chain heteroalkylene group, a cycloheteroalkylene group, and a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group; (xx)Y and W are independently absent or selected from: –O–, –C(O)–, –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, where p is selected from: 1, 2, 3, 4, 5, and 6; and R x is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, and cycloalkyl, carbocyclic group, heterocyclic group, aryl, and heteroaryl; (xxi) Ring A is selected from: wherein R a is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, and prodrug groups; each R 1 and each R 2 is independently selected from: hydrogen, halogen groups, OR z and straight-chain alkyl, branched-chain alkyl, and cycloalkyl; further, wherein R z is selected from: hydrogen, straight-chain alkyl, branched-chain alkyl, cycloalkyl, carbocyclic group, heterocyclic group, aryl, and heteroaryl; (xxii) Ring B is absent or selected from: an optionally substituted cycloalkyl group and a heterocycloalkyl group; (xxiii) Ring C is absent or selected from: an optionally substituted aryl group and a heteroaryl group; (xxiv) Ring D is absent or selected from: an optionally substituted cycloalkyl group, a heterocycloalkyl group, and a heteroaryl group; wherein the straight-chain alkyl group, branched-chain alkyl group, and cycloalkyl group, straight-chain alkenyl group, branched-chain alkenyl group, and cycloalkenyl group, straight-chain alkylene group, branched-chain alkylene group, and cycloalkylene group, carbocyclic group, straight-chain and branched-chain heteroalkenyl group, straight-chain alkynyl group, branched-chain alkynyl group, and cycloalkynyl group, heterocyclic group, aryl group, and heteroaryl group are optionally substituted with at least one group selected from the following groups: a halogen group, hydroxyl, mercapto, amino, cyano, -OC(O)C1-C6 straight-chain, branched-chain, and cycloalkyl groups, -C(O)OC1-C6 straight-chain, branched-chain, and cycloalkyl groups, -NHC1-C6 straight-chain, branched-chain, and cycloalkyl groups, -N(C1-C6 straight-chain, branched-chain, and cycloalkyl groups)2, -NHC(O)C1-C6 straight-chain, branched-chain, and cycloalkyl groups, -C(O)NHC1-C6 straight-chain, branched-chain, and cycloalkyl groups, -C(O)N(C1-C6)2 straight-chain, branched-chain, and cycloalkyl groups, -NH aryl group, -N(aryl group)2, -NHC(O) aryl group, -C(O)NH aryl group, -NH heteroaryl group, -N(heteroaryl group)2, -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, -S(O)2C1-C6 straight-chain, branched-chain, and cycloalkyl groups, C1-C6 straight-chain, branched-chain, and cycloalkyl groups, C2-C6 straight-chain, branched-chain, and cycloalkenyl groups, C1-C6 straight-chain, branched-chain, and cycloalkylhydroxy groups, C1-C6 straight-chain, branched-chain, and cycloalkylamino groups, C1-C6 straight-chain, branched-chain, and cycloalkoxy groups, C1-C6 straight-chain, branched-chain, and cycloalkylthio groups, C1-C6 straight-chain, branched-chain, and cycloalkylhalo groups, C1-C6 straight-chain, branched-chain, and cycloalkylhaloamino groups, C1-C6 straight-chain, branched-chain, and cycloalkylhalothio groups, C1-C6 straight-chain, branched-chain, and cycloalkylhaloalkoxy groups, benzyloxy, benzylamino, and benzylthio groups, 3- to 6-membered heteroalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.

2. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 - 46, wherein ring A is 3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1-46, wherein ring A is 4. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1-46, wherein ring A is 5. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 - 46, wherein ring A is 6. A compound selected from the following compounds: its tautomer, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing substances.

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

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

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

10. A method for treating or alleviating a disease, disorder or condition mediated by GSPT1 protein degradation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, its tautomer, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound is selected from:

11. A method for reducing the GSPT1 protein activity in a disease, disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, its tautomer, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound is selected from:

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

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