Compounds with two azaheterocycles substituted isoindolinone skeleton and uses thereof

Abstract

The present disclosure relates to a compound represented by formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof and a use thereof. The present disclosure also relates to pharmaceutical compositions comprising, as an active ingredient, the compound represented by formula (I) or the salt, enantiomer, stereoisomer, solvate, polymorph thereof, and a use thereof. In the present disclosure, the compounds designed and synthesized can effectively prevent or treat diseases or conditions related to celeblon protein, including tumors or cancers.

Description

Technical Field

[0001] The present disclosure relates to a compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof and uses thereof, especially their use in the prevention or treatment of diseases or disorders associated with cereblon protein, including tumors or cancers. Formula (I) Background

[0002] Immunomodulatory drugs (IMiDs) of the phthalimide class, such as thalidomide and lenalidomide, have shown remarkable efficacy in treating multiple myeloma and autoimmune diseases. However, it was not until 2010 that their direct binding target was identified as the E3 ubiquitin ligase cereblon (CRBN). Subsequent studies confirmed that upon binding to CRBN, these drugs act as molecular glues, recruiting substrate proteins (e.g., the transcription factors IKZF1 / 3) and inducing protein-protein interactions between CRBN and the substrates. This leads to the ubiquitination of the substrate proteins, which are then recognized and degraded by the proteasome, thereby eliciting pharmacological effects such as antitumor and immunomodulatory activities. Molecular glue degraders directly target and degrade specific proteins, offering potential advantages such as targeting "undruggable" proteins. Moreover, molecular glues typically exhibit low molecular weight and favorable drug-like properties, making their development highly challenging. Based on the CRBN E3 ubiquitin ligase and the molecular glue degradation mechanism, a series of compounds have been developed, including the approved pomalidomide and several candidates currently in clinical trials, such as Bristol Myers Squibb's CC-122, CC-220, CC-90009, CC-99282, CC-92480, and BMS-986470; Novartis's DKY709; C4 Therapeutics's CFT7455; and Monte Rosa's MRT-6160. The substrates degraded by these molecular glues have also expanded from the initially identified transcription factors IKZF1 / 3 to casein kinase 1a (CK1a), zinc finger protein 91 (ZFP91), WIZ, transcription factor IKZF2, translation factor GSPT1, and immune disease target Vav1, among others. Degradation of these protein substrates enables molecular glues to exert immunomodulatory, anti-inflammatory, and antitumor activities. Currently, the structural novelty of designed molecular glue candidates remains quite limited, making the diversification of molecular scaffolds and the development of novel molecular glues a key research focus in the field.

[0003] Therefore, the present application designs and develops a series of novel molecular glue degraders based on CRBN E3 ubiquitin ligase, which can be used for treating and / or preventing a disease or disorder mediated by or associated with a degradation protein. Summary of Invention

[0004] In view of the foregoing, the objectvies of the present disclosure are to provide provide novel protein degradation compounds having two azaheterocycles substituted isoindolinone skeleton, methods for their preparation, uses thereof, and methods of using the same.

[0005] To achieve the above objectives and other related goals, in one aspect, the present disclosure provides a compound of Formula (I): Formula (I) or salts, stereoisomers (including enantiomers and diastereoisomer), solvates, or polymorphs thereof, wherein Zi represents C(O), C(S), CH2, or CD2, and Z2, Z3, and Z4 each independently represent C(O) or C(S); Z5 represents CH or N; Ra1, Ra2, Ra3, and Ra4 each independently represent hydrogen, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy or halogenated C1-6 alkoxy; (Ra5)m indicates that the isoindoline ring to which it is attached is optionally substituted with m Ra5, with each Ra5 being identical or different and each independently representing deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, or C2-6 alkynyl; m represents an integer of 0, 1, 2, or 3; R represents C(O) or optionally substituted linear or branched C1-5 alkylene; X represents: (Rdl)n1 (Rd2)n2 y ml (Rd3)n3   (Rd4)n4 wherein ring A represents nitrogen-containing heterocyclylene, and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0-20; ring B represents nitrogen-containing heterocyclylene, and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0-20; Rc represents C(O), CRc1Rc2, or a bond, wherein Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; ring C represents cycloalkylene, heterocyclylene, arylene, or heteroarylene, m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0-20; and ring D represents heterocyclyl, cycloalkyl, aryl, or heteroaryl, and (Rd4)n4 indicates that ring D is optionally substituted with n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0-20.

[0006] In a further aspect, the present disclosure provides a pharmaceutical composition comprising the compound of Formula (I) or pharmaceutically acceptable salts, stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, and at least one pharmaceutically acceptable carrier.

[0007] In a further aspect, the present disclosure further provides a medicine kit or reagent kit comprising: the compound of Formula (I) or a pharmaceutically acceptable salt, or the pharmaceutical composition comprising the same.

[0008] In a further aspect, the present disclosure provides the compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, prodrugs, or polymorphs thereof, for use as a medicament.

[0009] In a further aspect, the present disclosure provides the compound of Formula (I) or pharmaceutically acceptable salts, stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, or the pharmaceutical composition of the present disclosure, for use in the treatment or prevention of a disease or disorder associated with cereblon protein.

[0010] In a further aspect, the present disclosure provides the compound of Formula (I) or pharmaceutically acceptable salts, stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, or the pharmaceutical composition of the present disclosure, for use in the treatment or prevention of a disease or disorder selected from the group consisting of: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

[0011] In a further aspect, the present disclosure provides the use of the compound of Formula (I) or pharmaceutically acceptable salts, stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, or the pharmaceutical composition of the present disclosure, for the manufacture of a medicament for the prevention or treatment of a disease or disorder associated with cereblon protein.

[0012] In a further aspect, the present disclosure provides the use of the compound of Formula (I) or pharmaceutically acceptable salts, stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, or the pharmaceutical composition of the present disclosure, for the manufacture of a medicament for the prevention or treatment of a disease or disorder selected from the group consisting of: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

[0013] In a further aspect, the present disclosure provides a method for treating or preventing a disease or disorder associated with cereblon protein, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I) or pharmaceutically acceptable salts, stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, or the pharmaceutical composition of the present disclosure.

[0014] In a further aspect, the present disclosure provides a method for treating or preventing a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I) or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present disclosure, wherein the disease or disorder is selected from the group consisting of: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

[0015] In a further aspect, the present disclosure provides a method for preparing the compound of Formula (I), comprising reacting a compound of Formula (M1) with a compound of Formula (M2) to obtain the compound of Formula (I): wherein Rai, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, Z5, nitrogen-containing heterocycle A, (Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure; and R represents optionally substituted linear or branched C1-5 alkylene; LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, o-nitrobenzenesulfonyl, C(O)Cl, or COOH; and Xa of the compound of Formula (I) correspondingly represents a structure represented by the following formula: (Rdl)n1 (Rd2)n2      (Rd3)n3   (^d4)n4 , wherein nitrogen-containing heterocyclylene A is a divalent group obtained by removing a hydrogen atom from the nitrogen atom of said nitrogen-containing heterocycle A, wherein said nitrogen-containing heterocyclylene A represents a 4- to 30-membered nitrogen-containing heterocyclylene (preferably, 4- to 20-membered nitrogen-containing heterocyclylene; more preferably, 4- to i5-membered nitrogen-containing heterocyclylene), and said nitrogen-containing heterocycle A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably, 4- to 20-membered nitrogen-containing heterocycle; more preferably, 4- to i5-membered nitrogen-containing heterocycle), and (Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. Detailed Description of the Invention

[0016] The following detailed description is provided as exemplary specific embodiments to assist those skilled in the art in understanding and practicing the present disclosure. It should be appreciated, however, that such description is not intended to limit the scope of the present disclosure, and that various modifications and changes may be made to the specific embodiments described in the present disclosure without departing from the spirit and scope of the present disclosure. Such changes and modifications are to be understood as being included within the scope of the present invention as defined by the appended claims. I. Compounds Compounds of Formula (I)

[0017] The present disclosure provides a compound of Formula (I) or salts (including pharmaceutically acceptable salts), stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof: (Ra5)m Z4   Z5—n' 7 R—X HN-Z3 Zi5^ Formula (I) wherein Zi, Z2, Z3, Z4, Z5, Rai, Ra2, Ra3, Ra4, (Ra5)m, R, and X are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure.

[0018] The compounds of Formula (I) of the present disclosure, or salts thereof (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, exhibit binding affinity to CRBN, facilitate the recruitment of substrate proteins, and can act as molecular glues binding to the CRBN E3 ubiquitin ligase. These compounds of Formula (I), or salts thereof (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, can also degrade substrate proteins (e.g., IKZFi / 2 / 3 / 4 proteins, WEEi protein, CKla protein, GSPT1 protein, ZFP91 protein, etc.). The compounds of Formula (I) of the present disclosure, or salts thereof (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, has anti-tumor activity or excellent pharmacokinetic properties, rendering them suitable for use as therapeutic agents for tumor patients.

[0019] In some embodiments of the present disclosure, Rai, Ra2, Ra3, and Ra4 are identical or different and each independently represent H, deuterium (i.e., D), Ci-6 alkyl (e.g., Ci-3 alkyl, such as methyl, ethyl, or propyl), halogenated Ci-6 alkyl (e.g., halogenated Ci-4 alkyl, such as trifluoromethyl), deuterated Ci-6 alkyl, Ci-6 alkoxy (e.g., Ci-4 alkoxy, such as methoxy), deuterated Ci-6 alkoxy, or halogenated Ci-6 alkoxy (e.g., halogenated Ci-4 alkoxy, such as trifluoromethoxy). In some subembodiments of the present disclosure, Rai, Ra2, Ra3, and Ra4 each independently represent H.

[0020] In some embodiments of the present disclosure, Zi represents C(O), C(S), CH2, or CD2.

[0021] In some embodiments of the present disclosure, Z2, Z3, and Z4 represent C(O), or C(S).

[0022] In some embodiments of the present disclosure, Zi, Z2, Z3, and Z4 represent C(O).

[0023] In some embodiments of the present disclosure, Zi represents CH2, and Z2, Z3, and Z4 represent C(O).

[0024] In some embodiments of the present disclosure, Zi represents CH2, Z2 represents C(S), and Z3 and Z4 represent C(O).

[0025] In some embodiments of the present disclosure, Zi represents CH2, Z3 represents C(S), and Z2 and Z4 represent C(O).

[0026] In some embodiments of the present disclosure, Zi represents CH2, Z4 represents C(S), and Z2 and Z3 represent C(O).

[0027] In some embodiments of the present disclosure, Z1 represents CH2, Z2 and Z4 represent C(S), and Z3 represents C(O).

[0028] In some embodiments of the present disclosure, Z1 represents CH2, Z2 and Z3 represent C(S), and Z4 represents C(O).

[0029] In some embodiments of the present disclosure, Z1 represents CH2, and Z2, Z3, and Z4 represent C(S).

[0030] In some embodiments of the present disclosure, Z1 represents C(S), and Z2, Z3, and Z4 represent C(O).

[0031] In some embodiments of the present disclosure, Z2 represents C(S), and Z1, Z3, and Z4 represent C(O).

[0032] In some embodiments of the present disclosure, Z3 represents C(S), and Z1, Z2, and Z4 represent C(O).

[0033] In some embodiments of the present disclosure, Z4 represents C(S), and Z1, Z2, and Z3 represent C(O).

[0034] In some represent C(O).

[0035] In some represent C(O).

[0036] In some represent C(O). embodiments embodiments embodiments of the of the of the present disclosure, Z1 present disclosure, Z1 present disclosure, Z1 and and and Z2 represent C(S), and Z3 Z3 represent C(S), and Z2 Z4 represent C(S), and Z2 and and and Z4 Z4 Z3

[0037] In some embodiments of the present disclosure, Z1, Z2, and Z3 represent C(S), and Z4 represents C(O).

[0038] In some embodiments of the present disclosure, Z1, Z2, and Z4 represent C(S), and Z3 represents C(O).

[0039] In some embodiments of the present disclosure, Z1, Z3, and Z4 represent C(S), and Z2 represents C(O).

[0040] In

[0041] In

[0042] In some embodiments of the present disclosure, Z1, Z2, Z3, and Z4 represent C(S). some embodiments of the present disclosure, Z5 represents CH or N. some embodiments of the present disclosure, (Ra5)m indicates that the isoindoline ring in Formula (I) to which it is attached is optionally substituted with m Ra5, wherein each Ra5 is identical or different and each independently represents deuterium, halogen (e.g., fluorine, chlorine, bromine, or iodine), hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), deuterated C1-6 alkyl (e.g., perdeuterated C1-6 alkyl, perdeuterated C1-5 alkyl or perdeuterated C1-4 alkyl, such as CD3, CD3CD2-, CD3CD2CD2- etc.), C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tertbutoxy), deuterated C1-6 alkoxy, halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-), C2-6 alkenyl (e.g., vinyl), or C2-6 alkynyl (e.g., ethynyl), and m represents an integer of 0, 1, 2, or 3. In some sub-embodiments of the present disclosure, m represents an integer of 0, 1 or 2. In some sub-embodiments of the present disclosure, each Ra5 is identical or different and each independently represents deuterium, halogen (e.g., fluorine, chlorine, bromine, or iodine), hydroxy, mercapto, nitro, amino, cyano, C1-4 alkyl (e.g., C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), halogenated C1-4 alkyl (e.g., halogenated C1-3 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), C1-4 alkoxy (e.g., C1-3 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy), or halogenated C1-4 alkoxy (e.g., halogenated C1-3 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-).

[0043] In the embodiments of the present disclosure, the number of substituents is not theoretically limited in any way, or is automatically limited by the size of the building units.

[0044] In some embodiments of the present disclosure, R represents C(O) or optionally substituted linear or branched C1-5 alkylene (e.g., C1-4 alkylene, C1-3 alkylene, C1-2 alkylene, or methylene). The C1-5 alkylene is optionally substituted with a substituent(s) selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl.

[0045] In some embodiments of the present disclosure, R represents C(O).

[0046] In some embodiments of the present disclosure, R represents -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-; wherein the above groups are optionally substituted with a substituent selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl.

[0047] In some embodiments of the present disclosure, X represents: wherein ring A represents nitrogen-containing heterocyclylene, and (Rdi)ni indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0-20; ring B represents nitrogen-containing heterocyclylene, and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0-20; Rc represents C(O), CRc1Rc2, or a bond, wherein Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; ring C represents cycloalkylene, heterocyclylene, arylene, or heteroarylene, m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0-20; and ring D represents heterocyclyl, cycloalkyl, aryl, or heteroaryl, and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0-20.

[0048] In some embodiments of the present disclosure, ring A represents 4- to 30-membered nitrogencontaining heterocyclylene (including 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene). Ring A is optionally substituted with n1 Rd1 groups, each Rd1 independently being deuterium, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl, or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C1-6 alkyl (e.g., perdeuterated C1-6 alkyl, perdeuterated C1-5 alkyl, or perdeuterated C1-4 alkyl, such as CD3, CD3CD2-, CD3CD2CD2- etc.), halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy), halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-), halogen (e.g., fluorine, chlorine, bromine, or iodine), amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl), or C2-6 alkenyl (e.g., vinyl), and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0049] In some embodiments of the present disclosure, ring A represents azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, piperidinylene, piperazinylene, azacycloheptanylene, diazacycloheptanylene, azacyclooctylene, diazacyclooctylene, azabicyclo[3.1.1]heptanylene, azabicyclo[2.2.1]heptanylene, azabicyclo[3.2.1]octanylene, azabicyclo[2.2.2]octanylene, diazabicyclo[3.1.1]heptanylene, diazabicyclo[2.2.1]heptanylene, diazabicyclo[3.2.1]octanylene, diazabicyclo[2.2.2]octanylene, quinuclidinylene, 2,6-diazaspiro[3.3]heptanylene, 2,7-diazaspiro[3.5]nonanylene, 2,8-diazaspiro[4.5]decanylene, 3,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 7-azaspiro[3.5]nonanylene, 8-azaspiro[4.5]decanylene, or octahydropyrrolo[3,4-c]pyrrolylene, each optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-5, 1-4, or 1-3) substituents selected from the group consisting of deuterium, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl, or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C1-6 alkyl, halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy), halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-), halogen (e.g., fluorine, chlorine, bromine, or iodine), amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl), and C2-6 alkenyl (e.g., vinyl).

[0050] In some embodiments of the present disclosure, ring B represents 4- to 30-membered nitrogencontaining heterocyclylene (including 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene). Ring B is optionally substituted with n2 Rd2 groups, each Rd2 independently being deuterium, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl, or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C1-6 alkyl (e.g., perdeuterated C1-6 alkyl, perdeuterated C1-5 alkyl, or perdeuterated C1-4 alkyl, such as CD3, CD3CD2-, CD3CD2CD2- etc.), halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy), halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-), halogen (e.g., fluorine, chlorine, bromine, or iodine), amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl), or C2-6 alkenyl (e.g., vinyl), and n2 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0051] In some embodiments of the present disclosure, ring B represents azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, piperidinylene, piperazinylene, azacycloheptanylene, diazacycloheptanylene, azacyclooctylene, diazacyclooctylene, azabicyclo[3.1.1]heptanylene, azabicyclo[2.2.1]heptanylene, azabicyclo[3.2.1]octanylene, azabicyclo[2.2.2]octanylene, diazabicyclo[3.1.1]heptanylene, diazabicyclo[2.2.1]heptanylene, diazabicyclo[3.2.1]octanylene, diazabicyclo[2.2.2]octanylene, quinuclidinylene, 2,6-diazaspiro[3.3]heptanylene, 2,7-diazaspiro[3.5]nonanylene, 2,8-diazaspiro[4.5]decanylene, 3,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene,     7-azaspiro[3.5]nonanylene,     8-azaspiro[4.5]decanylene, or octahydropyrrolo[3,4-c]pyrrolylene, each optionally substituted with one or more (e.g., 1-20, 1-15, 110, 1-5, 1-4, or 1-3) substituents selected from the group consisting of deuterium, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl, or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C1-6 alkyl, halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy), halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-), halogen (e.g., fluorine, chlorine, bromine, or iodine), amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl), and C2-6 alkenyl (e.g., vinyl).

[0052] In some embodiments of the present disclosure, Rc represents C(O).

[0053] In some embodiments of the present disclosure, Rc represents a bond. When Rc represents a bond, ring B is directly connected to ring C.

[0054] In some embodiments of the present disclosure, Rc represents CRc1Rc2, wherein Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched C1-10 alkyl (e.g., optionally substituted linear or branched C1-6 alkyl, or optionally substituted linear or branched C1-3 alkyl), optionally substituted C3-30 cycloalkyl (e.g., optionally substituted C3-20 cycloalkyl, or optionally substituted C3-15 cycloalkyl), optionally substituted C5-30 aryl (e.g., optionally substituted C5-20 aryl, or optionally substituted C5-15 aryl), optionally substituted 4- to 30-membered heterocyclyl (e.g., optionally substituted 4- to 20-membered heterocyclyl, or optionally substituted 4-to 15-membered heterocyclyl), or optionally substituted 5- to 30-membered heteroaryl (e.g., optionally substituted 5- to 20-membered heteroaryl, or optionally substituted 5- to 15-membered heteroaryl). In some embodiments, examples of linear or branched C1-10 alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, and octyl. In some embodiments, the linear or branched C1-10 alkyl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkynyl, and C2-6 alkenyl. In some embodiments, examples of C3-30 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro-cycloalkyl (e.g., C5-C20 spiro-cycloalkyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, and spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g., C6-C20 bridged cycloalkyl, such as adamantanyl, noradamantanyl, bornyl, norbornyl, bicyclo[2.2.1]heptanyl, 2-oxobicyclo[2.2.1]heptyl, or bicyclo[2.2.1]heptenyl). In some embodiments, the C3-30 cycloalkyl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 26, or 1) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, examples of 4- to 30-membered heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxy-piperidinyl, difluoro-piperidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, azacyclooctyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptanyl, 4,5-diazacycloheptanyl, 1,3-diazacycloheptanyl), diazacyclooctyl, bridged heterocyclyl (e.g., 6- to 20-membered bridged heterocyclyl, such as 6-azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, and quinuclidinyl), and azaspirocycloalkyl (e.g., 5- to 20-membered azaspirocycloalkyl, such as 2,6-diazaspiro[3.3]heptanyl,      2,7-diazaspiro[3.5]nonanyl,      2,8-diazaspiro[4.5]decanyl,      3,9- diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, and 7-azaspiro[3.5]nonanyl), or octahydropyrrolo[3,4-c]pyrrolyl. In some embodiments, 4- to 30-membered heterocyclyl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, amino, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, examples of C5-30 aryl include, but are not limited to, phenyl or naphthyl. In some embodiments, the C5-30 aryl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, examples of 5- to 30-membered heteroaryl include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl,quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl. In some embodiments, the 5- to 30-membered heteroaryl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.

[0055] In some embodiments of the present disclosure, m1 represents an integer of 1, and ring C represents 4- to 30-membered heterocyclylene (e.g., 4- to 20-membered heterocyclylene, or 4- to 15membered heterocyclylene), C3-30 cycloalkylene (e.g., C3-20 cycloalkylene, or C3-15 cycloalkylene), C5-30 arylene (e.g., C5-20 arylene, or C5-15 arylene), or 5- to 30-membered heteroarylene (e.g., 5- to 20membered heteroarylene, or 5- to 15-membered heteroarylene). Ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl, or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C1-6 alkyl, halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tertbutoxy), halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-), halogen (e.g., fluorine, chlorine, bromine, or iodine), amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl), or C2-6 alkenyl (e.g., vinyl), and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0056] In some embodiments, ring C represents 4- to 30-membered heterocyclylene, examples of which include but are not limited to 4- to 20-membered, 4- to 15-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6membered, 5- to 15-membered, and 5- to 9-membered heterocyclylene, such as azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, azacycloheptanylene, azacyclooctylene, dioxacyclohexylene, azacycloheptanylene, azacyclooctylene, diazacycloheptanylene (e.g., 1,4-diazacycloheptanylene, 4,5-diazacycloheptanylene, 1,3-diazacycloheptanylene), diazacyclooctylene, bridged heterocyclylene (e.g., 6- to 20-membered bridged heterocyclylene, such as 6-azabicyclo[3.1.1]heptanylene, 2,5-diazabicyclo[2.2.1]heptanylene, 3,6-diazabicyclo[3.1.1]heptanylene,               3-azabicyclo[3.2.1]octanylene,               3,8- diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, and quinuclidinylene), azaspirocycloalkylene (e.g., 5- to 20-membered azaspirocycloalkylene, such as 2,6-diazaspiro[3.3]heptanylene, 2,7-diazaspiro[3.5]nonanylene, 2,8-diazaspiro[4.5]decanylene, 3,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, and 7-azaspiro[3.5]nonanylene), or octahydropyrrolo[3,4-c]pyrrolylene. The heterocyclylene is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.

[0057] In some embodiments, ring C represents C3-30 cycloalkylene, examples of which include but are not limited to C3-20 cycloalkylene, C3-15 cycloalkylene, and C3-11 cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, spiro-cycloalkylene (e.g., C5-C20 spiro-cycloalkylene and C5-15 spirocycloalkylene, such as spiro[3.3]heptylene, spiro[2.5]octylene, spiro[3.5]nonylene, spiro[4.4]nonylene, spiro[4.5]decylene, and spiro[5.5]undecylene), p-menthanylene, m-menthanylene, or bridged cycloalkylene (e.g., C6-C20 bridged cycloalkylene, such as adamantanylene, noradamantanylene, bornylene, norbornylene, bicyclo[2.2.1]heptylene, 2-oxobicyclo[2.2.1]heptylene, and bicyclo[2.2.1]heptentylene). The cycloalkylene is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.

[0058] In some embodiments, ring C represents C5-30 arylene, examples of which include but are not limited to C5-20 arylene, C6-20 arylene, C5-15 arylene, and C6-15 arylene, such as phenylene or naphthylene. The arylene is optionally substituted with one or more (e.g., 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.

[0059] In some embodiments, ring C represents 5- to 30-membered heteroarylene, examples of which include but are not limited to 5- to 20-membered heteroarylene, 5- to 15-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, and 5- to 6-membered heteroarylene, such as furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, triazinylene, indolylene, isoindolylene, indolinylene, benzofuranylene, chromanylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolylene,          benzo[b][1,4]oxazinylene,          3,4-dihydro-2H- benzo[b][1,4]oxazinylene, quinolinylene, isoquinolinylene, 1,2,3,4-tetrahydroquinolinylene, naphthyridinylene, cinnolinylene,       quinazolinylene,       quinoxalinylene, 1,2,3,4- tetrahydroquinoxalinylene, phthalazinylene, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinylene, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinylene, thieno[2,3-d]pyrimidinylene,       thieno[3,2-d]pyrimidinylene,       isoxazolo[4,5-c]pyridinylene, isoxazolo[4,5-c]pyrimidinylene,     isoxazolo[4,5-d]pyrimidinylene,    pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, pyrrolo[2,1-b]thiazolylene, imidazo[2,1-b]thiazolylene, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinylene, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinylene. The heteroarylene is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxysubstituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.

[0060] In some embodiments of the present disclosure, when m1 represents 0 (i.e., ring C is absent), Rc is directly bonded to ring D.

[0061] In some embodiments of the present disclosure, ring D represents C3-30 cycloalkyl (e.g., C3-20 cycloalkyl, or C3-15 cycloalkyl), 4- to 30-membered heterocyclyl (e.g., 4- to 20-membered heterocyclyl, or 4- to 15-membered heterocyclyl), C5-30 aryl (e.g., C5-20 aryl, or C5-15 aryl), or 5- to 30-membered heteroaryl (e.g., 5- to 20-membered heteroaryl, or 5- to 15-membered heteroaryl). Ring D is optionally substituted with n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0062] In some embodiments, ring D represents C3-30 cycloalkyl, examples of which include but are not limited to C3-20 cycloalkyl, C3-15 cycloalkyl, and C3-11 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro-cycloalkyl (e.g., C5-C20 spiro-cycloalkyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, and spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g., C6-C20 bridged cycloalkyl, such as adamantanyl, noradamantanyl, bornyl, norbornyl, bicyclo[2.2.1]heptanyl, 2- oxobicyclo[2.2.1]heptyl, or bicyclo[2.2.1]heptenyl). The cycloalkyl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl.

[0063] In some embodiments, ring D represents 4- to 30-membered heterocyclyl, examples of which include but are not limited to 4- to 20-membered, 4- to 15-membered, 4- to 12-membered, 4- to 11membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6membered, 5- to 15-membered, and 5- to 9-membered heterocyclyl, such as azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxy-piperidinyl, difluoro-piperidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, azacyclooctyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptanyl, 4,5-diazacycloheptanyl, 1,3-diazacycloheptanyl), diazacyclooctyl, bridged heterocyclyl (e.g., 6- to 20-membered bridged heterocyclyl, such as 6-azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, and quinuclidinyl), and azaspirocycloalkyl (e.g., 5- to 20-membered azaspirocycloalkyl, such as 2,6-diazaspiro[3.3]heptanyl,      2,7-diazaspiro[3.5]nonanyl,      2,8-diazaspiro[4.5]decanyl,      3,9- diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, and 7-azaspiro[3.5]nonanyl), and octahydropyrrolo[3,4-c]pyrrolyl. The heterocyclyl is optionally substituted with one or more (e.g., 120, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl.

[0064] In some embodiments, ring D represents C5-30 aryl, examples of which include but are not limited to C5-20 aryl, C6-20 aryl, C5-15 aryl, and C6-15 aryl, such as phenyl or naphthyl, optionally substituted with one or more (e.g., 1-7, 1-6, 1-4, 1-3, 2-6, or 1) substituent(s) selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, and C2-6 alkenyl.

[0065] In some embodiments, ring D represents 5- to 30-membered heteroaryl, examples of which include but are not limited to 5- to 20-membered, 5- to 15-membered, 5- to 10-membered, 5- to 9membered, 5- to 8-membered, 5- to 7-membered, and 5- to 6-membered heteroaryl, such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H- benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl,quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl. The heteroaryl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, and C2-6 alkenyl.

[0066] In some embodiments of the present disclosure, X represents: (^dl)nl (Rd2)n2 wherein ring A represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogen-containing heterocyclylene, 4- to   25-membered   nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; ring B represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogencontaining heterocyclylene, 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; Rc represents C(O), CRc1Rc2, or a bond, wherein Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-10 alkyl, optionally substituted linear or branched C1-6 alkyl, or optionally substituted linear or branched C1-3 alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C3-30 cycloalkyl, optionally substituted C3-20 cycloalkyl, or optionally substituted C3-15 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted 4- to 30-membered heterocyclyl, optionally substituted 4- to 20-membered heterocyclyl, or optionally substituted 4- to 15-membered heterocyclyl), optionally substituted aryl (e.g., optionally substituted C5-30 aryl, optionally substituted C5-20 aryl, or optionally substituted C5-15 aryl), or optionally substituted heteroaryl (e.g., optionally substituted 5- to 30membered heteroaryl, optionally substituted 5- to 20-membered heteroaryl, or optionally substituted 5- to 15-membered heteroaryl); ring C represents cycloalkylene (e.g., C3-30 cycloalkylene, C3-20 cycloalkylene, or C3-15 cycloalkylene), heterocyclylene (e.g., 4- to 30-membered heterocyclylene, 4- to 20membered heterocyclylene, or 4- to 15-membered heterocyclylene), arylene (e.g., C5-30 arylene, C5-20 arylene, or C5-15 arylene), or heteroarylene (e.g., 5- to 30-membered heteroarylene, 5- to 20-membered heteroarylene, or 5- to 15-membered heteroarylene), m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and ring D represents heterocyclyl (e.g., 4- to 30-membered heterocyclyl, 4- to 20-membered heterocyclyl, or 4- to 15-membered heterocyclyl), cycloalkyl (e.g., C3-30 cycloalkyl, C3-20 cycloalkyl, or C3-15 cycloalkyl), aryl (e.g., C5-30 aryl, C5-20 aryl, or C5-15 aryl), or heteroaryl (e.g., 5- to 30-membered heteroaryl, 5- to 20-membered heteroaryl, or 5- to 15-membered heteroaryl), and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, wherein each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0067] In some embodiments of the present disclosure, X represents: (^ds)n3   (^d4)n4 (Rdl)n1 (Rd2)n2 wherein ring A represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogen-containing heterocyclylene, 4- to   25-membered   nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15- membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; ring B represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogencontaining heterocyclylene, 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-10 alkyl, optionally substituted linear or branched C1-6 alkyl, or optionally substituted linear or branched C1-3 alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C3-30 cycloalkyl, optionally substituted C3-20 cycloalkyl, or optionally substituted C3-15 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted 4- to 30-membered heterocyclyl, optionally substituted 4- to 20-membered heterocyclyl, or optionally substituted 4- to 15membered heterocyclyl), optionally substituted aryl (e.g., optionally substituted C5-30 aryl, optionally substituted C5-20 aryl, or optionally substituted C5-15 aryl), or optionally substituted heteroaryl (e.g., optionally substituted 5- to 30-membered heteroaryl, optionally substituted 5- to 20-membered heteroaryl, or optionally substituted 5- to 15-membered heteroaryl); ring C represents cycloalkylene (e.g., C3-30 cycloalkylene, C3-20 cycloalkylene, or C3-15 cycloalkylene), heterocyclylene (e.g., 4- to 30-membered heterocyclylene, 4- to 20membered heterocyclylene, or 4- to 15-membered heterocyclylene), arylene (e.g., C5-30 arylene, C5-20 arylene, or C5-15 arylene), or heteroarylene (e.g., 5- to 30-membered heteroarylene, 5- to 20-membered heteroarylene, or 5- to 15-membered heteroarylene), m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and ring D represents heterocyclyl (e.g., 4- to 30-membered heterocyclyl, 4- to 20-membered heterocyclyl, or 4- to 15-membered heterocyclyl), cycloalkyl (e.g., C3-30 cycloalkyl, C3-20 cycloalkyl, or C3-15 cycloalkyl), aryl (e.g., C5-30 aryl, C5-20 aryl, or C5-15 aryl), or heteroaryl (e.g., 5- to 30-membered heteroaryl, 5- to 20-membered heteroaryl, or 5- to 15-membered heteroaryl), and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, wherein each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0068] In some embodiments of the present disclosure, X represents: ^^rci X?y (Rd4)n4 (Rdl)nl (Rd2)n2 wherein ring A represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogen-containing heterocyclylene, 4- to   25-membered   nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; ring B represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogencontaining heterocyclylene, 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; Rc1 represents H, deuterium, halogen, or optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-10 alkyl, optionally substituted linear or branched C1-6 alkyl, or optionally substituted linear or branched C1-3 alkyl); Rc2 represents H, deuterium, halogen, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-10 alkyl, optionally substituted linear or branched C1-6 alkyl, or optionally substituted linear or branched C1-3 alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C3-30 cycloalkyl, optionally substituted C3-20 cycloalkyl, or optionally substituted C3-15 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted 4- to 30-membered heterocyclyl, optionally substituted 4- to 20membered heterocyclyl, or optionally substituted 4- to 15-membered heterocyclyl), optionally substituted aryl (e.g., optionally substituted C5-30 aryl, optionally substituted C5-20 aryl, or optionally substituted C5-15 aryl), or optionally substituted heteroaryl (e.g., optionally substituted 5- to 30-membered heteroaryl, optionally substituted 5- to 20-membered heteroaryl, or optionally substituted 5- to 15-membered heteroaryl); and ring D represents heterocyclyl (e.g., 4- to 30-membered heterocyclyl, 4- to 20-membered heterocyclyl, or 4- to 15-membered heterocyclyl), cycloalkyl (e.g., C3-30 cycloalkyl, C3-20 cycloalkyl, or C3-15 cycloalkyl), aryl (e.g., C5-30 aryl, C5-20 aryl, or C5-15 aryl), or heteroaryl (e.g., 5- to 30-membered heteroaryl, 5- to 20-membered heteroaryl, or 5- to 15-membered heteroaryl), and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, wherein each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0069] In some embodiments of the present disclosure, X represents: (^dl)nl (Rd2)n2   (^d3)n3   (^d4)n4 ring A represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogencontaining heterocyclylene, 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; ring B represents nitrogen-containing heterocyclylene (including 4- to 30-membered nitrogencontaining heterocyclylene, 4- to 25-membered nitrogen-containing heterocyclylene, 4- to 20-membered nitrogen-containing heterocyclylene, 4- to 15-membered nitrogen-containing heterocyclylene, and 5- to 20-membered nitrogen-containing heterocyclylene), and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; ring C represents cycloalkylene (e.g., C3-30 cycloalkylene, C3-20 cycloalkylene, or C3-15 cycloalkylene), heterocyclylene (e.g., 4- to 30-membered heterocyclylene, 4- to 20membered heterocyclylene, or 4- to 15-membered heterocyclylene), arylene (e.g., C5-30 arylene, C5-20 arylene, or C5-15 arylene), or heteroarylene (e.g., 5- to 30-membered heteroarylene, 5- to 20-membered heteroarylene, or 5- to 15-membered heteroarylene), m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and ring D represents heterocyclyl (e.g., 4- to 30-membered heterocyclyl, 4- to 20-membered heterocyclyl, or 4- to 15-membered heterocyclyl), cycloalkyl (e.g., C3-30 cycloalkyl, C3-20 cycloalkyl, or C3-15 cycloalkyl), aryl (e.g., C5-30 aryl, C5-20 aryl, or C5-15 aryl), or heteroaryl (e.g., 5- to 30-membered heteroaryl, 5- to 20-membered heteroaryl, or 5- to 15-membered heteroaryl), and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, wherein each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0070] In some embodiments of the present disclosure, examples of X include but are not limited to:

[0071] In some embodiments of the present disclosure, the compound of Formula (I) is also represented by Formula (I-1), Formula (I-2), Formula (I-3), or Formula (I-4): Ra2 Ra3        R X Z4 z5-n hn—z3 ; (Ra5)m Formula (1-1) Ra2 Ra3D Ra1^J / Ra4 / ; z4 z5-n ' HN-Z3 z (^a5)m Formula (1-2) Ra2 Ra3 Ra1^-^Ra4 Z; z4 z5-n ' hn-z3 z (Ra5)m R—X Formula (1-3) _ RfR|3R.      (Ra5)m Rai^)—a4;      ' z5-\ hn-z3 ; R—X Formula (1-4) wherein Rai, Ra2, Ra3, Ra4, Zi, Z2, Z3, Z4, Z5, (Ra5)m, R, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0072] In some embodiments of the present disclosure, the compound of Formula (I) is also represented by Formula (I-5): (Ra5), Z4 Z5-\ I  4pR—X HN-Z3 Zi1^ Formula (I-5) wherein Zi, Z2, Z3, Z4, Z5, (Ra5)m, R, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0073] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-i): Formula (I-5-1) wherein Zi, (Ra5)m, R, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0074] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-iA): (Ra5)m o=(        ^r—x O Formula (I-5-1A) wherein (Ra5)m, R, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0075] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-iB): S (Ra5)rn o s Formula (I-5-1B) wherein (Ra5)m, R, L, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0076] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-2): Formula (I-5-2) wherein Zi, (Ra5)m, R, L, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0077] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-2A): o Formula (I-5-2A) wherein (Ra5)m, R, L, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0078] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-2B): o s Formula (I-5-2B) wherein (Ra5)m, R, L, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0079] In some embodiments of the present disclosure, the compound of Formula (I-5) is also represented by Formula (I-5-3): Formula (I-5-3) wherein Zi, (Ra5)m, R, and X are as defined in the compound of Formula (I) and its various embodiments in the present disclosure.

[0080] Preferably the compounds of the present invention and their salts (especially pharmaceutically acceptable salts, such as hydrochloride, etc.), enantiomers, diastereomers, solvates, or polymorphs thereof in Table i below are provided: Table i. The compounds of the present invention Compo und No. Structure of the compounds The compounds’ name Chinese translation of the compounds’ name GT-04329 ■' 0 Q O^z^o ° 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1- 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione oxoisomdolm-2-yl)piperidme-2,6-dione GT-04330 a V} nJ o z^o ° 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-4-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-04331 X 9 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-6-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-04597 o °YV 0 D 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-7-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-04598 3-(4-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-04599 A / K rp 0 PP\PX 3-(6-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09194 hQ, ?       O nA / - n \ / \ / = / o k0 3-(7-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09195 3-(5-(2-(4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(2-(4-(4- benzhydrylpiperazin-1- yl)piperidin-1-yl)ethyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09196 X    0 °Pp     u U^nU 3-(5-(3-(4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(3-(4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09335 4-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1 -yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09334 o vy , A'z'^A-K / VP Q q =?VA W 5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1 -yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-04376 o kA PXJ Z— X X^vP W 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-04377 o °YV° / / Mb 99 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-4-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-04378 b 9 939999 1                  F F 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-6-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-04379 o ■ ■ 39 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-7-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-04380 OyO 0 9 b°° 3-(4-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09188 9 „ 9 9 r / ' 0 F 3-(6-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09189 z 9^0 ex, 99 0 c9o 3-(7-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09190 3-(5-(2-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09191 Hb9        Q °oAb ^OXl XX / ^nJXf F 3-(5-(3-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)propyl)-1-oxoisomdolm-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09193 4-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09192 O My \— / o '0 x 5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-05037 o \ Y '0 w 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09336 o °yY / / =\^ w 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09337 o W £ Jv w 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09338 o °VL° ■? % / =\ w 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09339 3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09340 O, •      9 O “9 ^“MO My “yf 3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09341 V^Y<q 3-(7-((3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-((3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09342 Y„   P ^Yy9"9 3-(5-(2-(3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09343 Hq      q dq ^0¾ F 3-(5-(3-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09345 °rx o hn qqq^^^qA 4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2- 4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09344 Hb . 9 F 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-04595 "b Xjx^nXvf F 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-04596 XM° % cr z o 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fuoro-1- oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-4-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09346 1                   F F 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fuoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-6-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09347 k O N—i             ( N O '-^'ci <N 9kk-N krF 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fuoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-7-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09348 kkxkk^b o / \= /                    Cl 3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09349 I o. z,,o r\A \_ / o cHJ< ( / 3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09350 V4kko^ 3-(7-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- 3-(7-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09351 Cl 3-(5-(2-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(2-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09378 °u       x O=K 1               1 N :'O X^'"'CI UI rU^ VV^n^f F 3-(5-(3-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09352 HU> -U' / / °        uXU 0 N—y            [ N 0 XjUnUvf F 5-((4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09353 °¥> o O A W ™ X     / “N Xn na. Xa o xU3 FF     M 4-((4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-05160 H_H’ O^XX-s / "vN'-^ X3XNXvF F 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09379 CX 5^0 Oil X Z—\ XK O 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-4-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09380 CX 5^,0 Oli -X X 'XXx o 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-6-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09381 aX A X ° o z o 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-7-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09382 0 3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09383 HN ) Y\ ,°        ) XX 0 N— /          [ N X Jk  Z\zkJ uxCX F 3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09384 k* 0 c> Vi okV z—' / x=° \— z o 1 3-(7-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difuoropiperidm-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09385 Cl 3-(5-(2-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09386 O °YV ^yjk yj Q 3-(5-(3-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09387 I o. z_ ,o ° I T r\A \_ / o - hx o 5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09388 ¢) c> V) zA £r 4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-04604 CI XXO 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-04605 O Cr' O p z'X o Z c 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-04606 '        XX O N—1              f N p Cl oXX       N'''^ Cl F 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-04607 X   r-N-^X qXX,           Cl XXnU 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-04609 ° o^o     X, 3-(4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-04608 "P , O N—p          f N p Cl X X            Cl 1X0 3-(6-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09389 VnA / -O~G-D o L / X      M XX           ci ci 3-(7-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09390 Vx / a      / =\ o              Nv^N vX o \_ / —                  Cl Cl 3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09391 cP Q Q rX ° 3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09393 XxXx^^^ o xTX         Cl Cl o V / 4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09392 cP Q Q rX o z o I 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-05212 HqX^    Pn-XX o'ssX<X\                  ci XJX,nXvf F 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1- 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09417 XX-nXf F 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fuoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09418 Hk XX-nXf 1                F F 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fuoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09419 Hk     r-N'Q'c. TxXtX 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fuoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09420 °YX     _ HN n N^YV-Vy 0 o^O f F   cHc, 3-(4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09421 X' »   „ jtX O N—?          f N Y Cl ( A. z\AJ Cl XuCX F 3-(6-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09422 Ao "AaXA Xn n~O o UY ^f  M XX    F      Cl Cl 3-(7-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09430 °YX hnAn--n     X      / =\ J xhxvvi) o \— /    A’-F     AA —        F         Cl Cl 3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09431 HPn o^axy    Xi 3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisomdolm-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09433 Vy o „ _ HN' nN  N N 0 X-H X    )—( 0 XX F       Cl Cl 4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09432 I,  ,- XX 0 N-A           | N c ci KJ^N--^rF F 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-05333 Cu Z ,O o Y Y Y Q 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09599 O, Z_ ,O o i r ■ z 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09600 hnh ,9,, 0 N~z         1 Y 1 c oY\        ci Xj^n-Yf T             F F 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09601 rXk, OX>X / \zNY Cl zxtx 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09602 VZ       ^a / =\ HN     N        N      N 0 <X\ /   F F Cl Cl 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09635 Y Y . Y 0 nY     yy y c YY / vY ci F 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09636 " W~N> >-n'X / =\ 0 xH Y / F     ci^ci 3-(7-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09637 °YZ 0   \__ /           F        2 —        F r      Cl Cl 3-(5-(2-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09638 H,Z X?” 0 Y            1 I J. X \         / \ ^N-Y CI oAY  YY 3-(5-(3-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)propyl)-1-oxoisomdolm-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridm-1(2H)-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09640 hn A. s     / —\ X wX Xnz~\a=\ r            Cl XC| 4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09639 X hn /             in Of N ^     (11“ O—  ,     A'A-'N'-^ Cl XXX OrF F 5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-04989 0 HX 0 N—,           [ N \ VF O^XaX     N-X XXJj 3-(5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1- oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09641 0 0 N—,           [ N \ VF oZ1,f         's= / ULnJ 3-(4-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09642 0 0 N—,           [ N \ Xf X A, / "\zN'X UJJ 3-(6-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09643 0 HN >                  N'Q 0 N—,          ( N y' VF o=XX\ / ^ / NX WJ 3-(7-fluoro-5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1- oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-fluoro-5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09644 Vl     AA AA N.0 HN^kN- / ^N / N      Y o Xm     (X o \= /        VA F 3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09645 0 HN )                      N'°. / 0       zCX o            a n xz Vf X X / \.N^ J xxo 3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09646 x Q 0 0 / n 3-(7-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09647 X1—   -A- 3-(5-(2-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin- 3-(5-(2-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1- 1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09648 HN>              N'Q oXX 3-(5-(3-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(3-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09650 A o n   n-o hnani rN / N nXY o XX      kX o \_ /         AA F 2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione GT-09649 0 HN )                    N'O 0Xy  pyyF AA ~ 2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione GT-04931 o HN )                  N'Q XX        xXa ° n—,            n y VF oXX       a / XJX- N-ArF F 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09655 o HN )                  N'Q dy  pAf qaa / vA XA-m-Af F 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09656 0 A 0 N—,           [ N \ Xf XP^nJ—F 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09657 0 HX     Ay 0 Ny         1 N \ Xf qAA-.    / \zn-X   " ax 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09658 A      xo hny\y An / n n \_1 °yX X^ X F 3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09659 0 HN )                  N'O XX. o        xXa o nA       A N \ Xf X X / \^NyA ''^ axCa F 3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09660 A / ?   ^A_  ^-0 “y^nA An / n n \A o Qy X a q F 3-(7-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin- 3-(7-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1- 1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09661 a I1 3-(5-(2-(3,3-difluoro-4-(4- (6-fuorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09662 l)                 N'°\ .rL 0RR 3-(5-(3-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09664 0 PAO Cp A 0 n 4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09663 0 HN \                  N'O ohnr    pNAfi AoP F 5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-04932 0 HNA AtA 0 nr         i i \ Af ORR'. Z‘vNA " X3^n'J-vf F 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09665 o HN P                   N'O Ar      ^AAAr ° n a         ।      \ Af oAAf / RzNA rXzPA F 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘-yl)methyl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09666 o HN P                  N'Q Ar       z^AAAr ° n~a        | A^ v Af PuP ' 1                 F F 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09667 0 HN )                       N'°x Ar     rArA 0 NA         1      \ Af oAA zxRzN'A 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09668 XkrPar F 3-(4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09669 O HN P                    N'O. AX / zo     z^AaAr 0 N A       i     \ Af P A z\ ^N. J Ap.CP F 3-(6-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09670 ° YY Df Q F 3-(7-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09671 VlX^QKXX, 3-(5-(2-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(2-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione GT-09672 "A   YY o                    1 I V Af »Aa aV^ 3-(5-(3-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09674 nVNAzVnJ-Aj 0 oHJ af   Q F 4-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘-yl)methyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione GT-09673 o HN )                   N'O p9 / / ° o NP        1 1  \ pF oPJ\  ^\yNxP F 5-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09944 ■ • .. PP^nP 3-(5-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione GT-09946 P 9 v° 3-(5-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09945 ■ . 3-(5-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09947 Ya o     O hnHnaa aa vaA Ap  D 3-(4-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione GT-09948 ■A. ,-D 3-(6-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione GT-09949 °YA o o       O HNyA 3-(7-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-(4-(4- benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione GT-09950 "Pxp 4-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09951 X X AJPnP o 5-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09675 • XX^nXf 3-(5-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09710 Z., ,O °       1       1 op A ppp XX1 3-(5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difuoropiperidme-1-carbonyl)-6-fuoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-6-fuoro-1- oxoisomdolm-2-yl)piperidme-2,6-dione GT-09676 b 9 0 / Nx      PNPPb 0^1, X~\x-NxA PA AAA 0 3-(5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difuoropiperidme-1-carbonyl)-7-fuoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-7-fuoro-1- oxoisomdolm-2-yl)piperidme-2,6-dione GT-09678 X ”......9.....' 3-(4-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09677 ° Xp° 3-(6-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09711 Apxx| 3-(7-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09712 °Y9 o o _    O ^XpX'p^P 4-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione GT-09713 O^ z .O ° T i \—) % op % V / 5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione GT-09714 I o. z,,o °       1 I pp Op r\^ w 3-(5-(3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09716 0 HN~~\ o OA A       J \J UvQf F 0     F 3-(5-(3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisomdolm-2-yl)piperidine-2,6-dione 3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09715 % Ao r^w zq \ A A. o O Z ’O 3-(5-(3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisomdolm-2-yl)piperidine-2,6-dione 3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09717 V / o     Q 3-(4-(3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09718 0 HN X                  <N X~\ 0         A _ ° ^q° 3-(6-(3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09719 !—\ ’—'■ _X^ AAAAd 3-(7-(3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-(3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09720 « %. ’—V1—* _x*^ ""rAA"^ 4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09721 <q\ fVx ■ % Ao °x VU / x ,z. / ' X A o o z o 5-(3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09722 o. z. ,o °       1       1 fyJ op X oq o o 3-(5-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3- difluoropiperidine-1- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09724 o q( Xm° % v° rXZ^ z. / 1 L o o z o 3-(5-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1- oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09723 £ r$a o N~\        INO C o=\Jy r^^N^ i J N F O 3-(5-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1- oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09733 "n ^y^A. 0 irvJ F         a 3-(4-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3- difluoropiperidine-1- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09725 °k      Civ HN A ,.o     ^„,XnXA O nY      INO C Xiay O 3-(6-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09726 CC F          a 3-(7-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09727 X^J^X^oXq o^xy F            tci 4-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 4-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione GT-09728 ‘h HN yX / .o       - X^XX. O n~A        'NO     Cl o^Xzy      N-^ XXX- nXX n f O 5-(4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione GT-09729 I O. ,,2. / 0 °        1       1 o=\ A \—z ,---. / -X o a 3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09731 a JA o N—,        A      ^^Cl XxcT F O 3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1- 3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1- carbonyl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione oxoisomdolm-2-yl)piperidme-2,6-dione GT-09730 O N—N     ^'-''Xl o-\Xx  <"VN^ i         J O 3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1- oxoisomdolm-2-yl)piperidme-2,6-dione GT-09732 z / ? z-x o=^ 0 3-(4-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09828 ‘H      du. HN yd z,o         J XJX 0 N-f          f N         XI U U 0 3-(6-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09829 x^ Ci X Ux oVY z— / y=o Xz o 1 3-(7-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09830 xY” 0 x ° xJ Z^X __ / o / \— z o 1 4-(4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09831 u    du HN >             Ux / X. X\ &       y Xx. O N—X            [           '''^"Cl U^Y'^ Udd-N^JdF Y    F o 5-(4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09832 o Hd       UCI O N—.           f N X^ Cl O^X / ^X             ci X\nCJ o 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09834 z. ,o °      1      [ "'Oj o=( Q Q q^D Q 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09833 o HNX       XX. O N—>                      f Cl y-"\yNy-X ci fX\nCj 0 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fuoro-1-oxoisoindolm-2-yl)piperidine-2,6-dione GT-09835 a-x HNXN-\rvXvjX\ ) 0 oHj    X 3-(4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09836 o 0 0 x° O' / =X xx <x^Y'Z'X ' o^z^o 3-(6-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09837 VnAH / v "W o AAA       crci 3-(7-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(7-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisomdolm-2-yl)piperidme- 2,6-dione GT-09838 °YA o o nVNAh'vHX ) °         X. 4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09839 o CX 0 0 x° ox / ^X yxx 1 X o cr z 'O 5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09840 o % x° Xxx X X o o z o T 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09842 <9    Y XA O N—>             X N I Cl oXA. / ^N^X Cl X> jL, N^XF in   f F O 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09841 Hk pn'Qx. / ''yN^X C fX3Lyn^\ f o F 3-(5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisomdolm-2-yl)piperidme-2,6-dione GT-09843 ^^xxXQx^-O <y~~\_ /               ci bi 3-(4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09844 0 N—< N y ci b X / \yXX ci xxqx 0 3-(6-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09845 YXYYkYYY1 o XYY? F F cr ci 3-(7-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09846 (J    \__ /      F           Cl 4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09847 & % O, / \ WJ 1 L b o z o 5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09952 "W       Q.o oYX      N^Jl Cl XX^CXr 0 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09954 I CK 2^,0 ° । r ox ■ o 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-6-fuoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fuoro-1- oxoisomdolm-2-yl)piperidme-2,6-dione GT-09953 ”k       Q,, o4k      N'Y Cl FXX.CP O     F 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-7-fuoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fuoro-1- oxoisomdolm-2-yl)piperidme-2,6-dione GT-09955 °Y^i o _ O     A        r / y, O \ /     F          Cl Cl 3-(4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09956 Y YYo   <jaci ° nY            i ii    i   c 4 k         A J*   ci UY T F 0 3-(6-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09957 °*O u V hn y^n ArNvh nvH? o '\h /           C| / 3-(7-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09958 Yiw. 4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1- 4-(4-(4-(2,3-dichlorophenyl)- 3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1- carbonyl)-2-(2,6- carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09959 °       1       1 AvA o oA 5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidme-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09848 o HN \                  N'° AJA ° na         i n \ Af X\nJ o 3-(5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09850 o HN^ O N~\          1 N \ Af cA z\          " F O 3-(6-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09849 HNS O N-,          I N \ VF cA X_ / ’-^N-A ^= / fX\nJ o 3-(7-fluoro-5-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-fluoro-5-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09851 °ya v ^a_ nN^AN^ An An nAi ° XX     XX o V /       XA F 3-(4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09896 o HN )                  N"O A\ O O nA       A N \ Vc -' o 3-(6-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09897 0 0 oAO 0=^7^ .A 3-(7-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09898 °Y7 » V      A-o HNsAA AN / N NA Y o A / A,        XX o \= /        VA F 2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione GT-09899 0 HN \                  N'O o n^        ( N \ Af XaO 0 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione GT-09900 o HN )                     N'°x ° N~A          1 N \ ^F f T F o 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09902 o HN )                   N'Q 0                     r N \ F O 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09901 0 HN )                  N'Q 0  N—,        ( N ¥ VF c¥z\   / 'Xz^x^ Wi 0 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09903 °VX 0           N.o ™XN^. / n / n N vl Q F 3-(4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09904 o HN )                  N'Q / °       zx AJ¥\ o n-X          n ¥z VF ri ¥   F o 3-(6-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09905 C) X oAn c¥¥ ¥ 3-(7-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09906 ¥¥¥ d 4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09907 o HN )                  N-O / °          Jl¥¥\ o n-¥      pN ¥ VF o¥ zL X^XN      "" ¥   F o 5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09908 0 HN )                   N'Q 0 Nx     M\ Z'F o¥xx Z'VI¥  '^~ / / 0 3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09910 z¥¥a 0 Nx       ¥ ¥ \ ¥f O=¥z¥ XOLn^J-f ¥ ¥ f F O 3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione GT-09909 O HN )                  N'Q 0 N~A           1       \ ¥-F x''-XN'- / ^     ' A4 3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09911 °oHJ f   Q F 3-(4-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'- 3-(4-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘- carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09912 o HN )                   N'Q o 3-(6-(3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09913 3-(7-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(7-(3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione GT-09914 °YA » V         / N'O q F 4-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09915 °>A             o HN )                   N-0 z,° 0 N~f                 \ cAzy..                ~~~ ^J^NyAVF 0 5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1‘-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione GT-09941 I O..Z, ,O co t r A Q VaZ 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione GT-09938 3-(4-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09862 aa “ Q Q co / =\ T^J O^Z^O I 3-(6-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-05105 / “A % riA O Z ^o I 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09617 N 3-(4-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09691 Ja     Q A\ ZS        „ JL 0 / N~f \Ay / "y .N. J ILA XXyCP 3-(6-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-05208 -z „9" O 7N^ saa     m F 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09618 3-(4-((3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-05042 o HN \ M / S o n~y      yn F 3-(6-((3,3-difuoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09679 -X / Xi X^\^N JrF F 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difuoropiperidin-1- yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09619 "O '-v-A 0 sXJ F          'ci 3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09692 ‘h X\ ,s       XnXX 0 N~k          [ N 0 "—^xci ulCX f 3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09680 k Jrk 0 N—i             | N ''^ 5=^ J\ / VN"- / ' X3y.-n JrF F 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09576 XL "V-Xl 0 sYJ F          'ci 3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09863 °x HN )             V XX, S       „ J V y 0   N— /           ( N     Xs'"x3l ( Jk          J kk-Ck F 3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09934 ckL    ^N^C, CI XXxJ 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione GT-09939 °k            / =\ hnXaoXV / X ° skj    X 3-(4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09935 "X ,..0,, 0 Nk       kN <T c ( X / -\X-xk Cl kkO 3-(6-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(6-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione GT-09687 ck^     Pn-^C, skk         ci UAxOy 3-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09575 3-(4-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1- thioxoisoindolin-2- yl)piperidine-2,6-dione 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09693 "X rJQ. o No;           । n      Cl ( X zxzkk ci kkCk F 3-(6-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09688 k      jQlo S=< 1      / •- N-X CI kkkXF 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09614 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09694 X kL .A 0 Nk            1 11   1 c Cl F 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1- 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09861 0 HX     aX 0   N~\           [ N \   / ~F sX XX^nJ 3-(5-((4-(4-(6- fuorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09940 x A ¢1 n 3-(4-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09864 O HN )                     N'°x X^ / S          JX^X. 0 NX       f N    VF EXO 3-(6-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09689 o X   ^ix ° nx        r n \ Xf sXX,         ^= / XjXnXvf F 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09615 3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09695 0 HN \                  N"O X\ ,s       xXx 0 NX        i n \ Xf XxCX F 3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09690 HX   Xh 0 X       i X \ Xf sX a. / •'.N-X ' / XX 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(5-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09616 0 SX f X F 3-(4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(4-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-09936 O HN 5                  N'Q X\ / zs      / \Xxx 0 NX      11^ \ ^x lxXe F 3-(6-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1‘- yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione GT-04941 XX of ■ 0 Q 1-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-05255 0 HN ^N. o           T 0 ,N~f ULX 5-((4-(4- benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1 -yl)methyl)-2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-04942 b 9 bN.              _ I . °         XN ib obk   b bb UL-nXf F 1-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-05256 -b 9 ■X ob F 5-((4-(4- benzhydrylpiperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-05082 X    o HN )            Xn XN.               T °.<1 rr0 U UVnJ-f F 1-(5-((3,3-difluoro-4-(4- (phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-05257 x    n HN )            XX Xb / O 0 Xf           iTX °XA F F 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-05335 0 HN )          ^X'b bN.         / -, XnXb 0 N—>                [ N 0 '''-^''c| ob^   .-,N X9XNbvF F 1-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-05271 °               xb HN )            XXx^. ^n / 0      z\ X XI 0 N-b          | N 0 ^^ '"ci obb\      . bJh,NXrF F 5-((4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-(4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-05334 °               jy ^N.             -J X X 0 N—>               [ N OX / XjYNxYF F 1-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin- 2-yl)dihydropyrimidine- 2,4(1H,3H)-dione 1-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-05270 0                  Y\t hn / YN o          „ J |l J 0 N—Y           | N      "'^^Cl o^..^   'rN ■ iYYn^Vf F 5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-09355 o HN /              YY <Xv    pNYY q^Y .Y.                 ci XYnJ 1-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-09357 0 HN )             YY ^N' / / °          XxAn 0 N—f N y Cl OYJ 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-09205 o hn               YY O^Y       / 'x / N'xY CI jXJJY 1-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine- 2,4(1H,3H)-dione GT-05258 0 HN               YY oHn /   PnYY O^YvjYx / ^x^N-xY ci u3Lx^n-xJvf F 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-(2,3- dichlorophenyl)piperazin-1-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-09206 o HN X              OY )^N.      xYd O N—>           < if Y CI oYX / v^y ci XJJJY 1-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1- yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-09358 0 HN )                 YYi ^N. ,p      / xJ^An ° n~Y               i ii i c °^YYx    / -x.NxY' Cl k;>Ax^Nx^VF F 5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difuoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-09356 O HN                    N"P O N—,                    V F O^\ Jx, XXJj 1-(5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((4-(4-(6- fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine- 2,4(1H,3H)-dione GT-09359 o HN )                    N-°x ,p O N—|       \  7—F 2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione 2-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione GT-09207 o HN ;                  N'P 0 Nx        f N p VF XjCN S^F F 1-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-09360 O HN ;                  N"O O N—| N \ Af F 5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin- 1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione GT-09208 O HN )                     N"°\ ZN.        / / Ox. 0 N~A           1 I \ Af AJL^N^-F F 1-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(5-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'- yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione GT-09361 O HN )                  N-0 0 N~f          I       \ Z^F F 5-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione 5-((3',3'-difluoro-4-(6- fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione II. Other Forms of Compounds (including salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs of compounds)

[0081] The compounds of the present disclosure have the structures of any one of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I-5-1), Formula (I-5-1A), Formula (I-5-1B), Formula (I-5-2), Formula (I-5-2A), Formula (I-5-2B), or Formula (I-5-3). Unless otherwise specified, all references to the compounds of the present disclosure also include compounds of any one of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I-5-1), Formula (I-5-1A), Formula (I-5-1B), Formula (I-5-2), Formula (I-5-2A), Formula (I-5-2B), or Formula (I-5-3) and specific compounds within the scope of these general formulae.

[0082] It should be recognized that the compounds of the present disclosure (including the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I- 5-1), Formula (I-5-1A), Formula (I-5-1B), Formula (I-5-2), Formula (I-5-2A), Formula (I-5-2B), or Formula (I-5-3)) may have a stereo-configuration and thus can exist in more than one stereoisomeric form. The present disclosure also relates to optically enriched compounds having a stereoconfiguration, e.g., greater than about 90% enantiomeric / diastereomeric excess ("ee"), such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures. As used herein, "optically enriched" means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer, and can be described by enantiomeric excess (ee%). Purification of isomers and separation of mixtures of isomers can be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates) and / or or chiral resolution, etc.).

[0083] In some embodiments, polymorph forms or salts of the compounds of the present disclosure are also provided. Salts of the compounds of the present disclosure may be pharmaceutically acceptable salts including, but not limited to, hydrohalide (including hydrochloride, hydrobromide), sulfate, citrate, maleate, besylate, glycolate, a-D-glucoheptonate, D-gluconate, L-lactate, L-malate, malonate, mandelate, phosphate, propionate, succinate, tartrate, tosylate, valerate, palmitate, sebacate, stearate, laurate, acetate, adipate, carbonate, 4-chlorobenzenesulfonate, edisylate, fumarate, D-glucuronate, a-ketoglutarate, hippurate, 2-hydroxyethanesulfonate, lactobionate, 2-naphthalenesulfonate, oleate, cholate, terephthalate, L-ascorbate, camphorate, ethanesulfonate, formate, hydrobromide, methanesulfonate, oxalate, benzoate, salicylate, pyruvate, dihydrogen phosphate, pyrophosphate, metaphosphate, p-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, 3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, 2-naphthalenesulfonate, trifluoroacetate, and hydroxyacetate, etc., of the compounds of the present disclosure. The compounds of the present disclosure can exist in nonsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In some embodiments, the compounds of the present disclosure can be prepared as prodrugs or precursor drugs. Prodrugs can be converted into the parent drug in vivo to exert their therapeutic effects. In some embodiments, isotopically-labeled compounds of the present disclosure are also provided, examples of which include deuterium (D or 2H). III. Compositions / Formulations

[0084] In some embodiments, the present disclosure provides a pharmaceutical composition comprising as active ingredient the compound of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.

[0085] In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: 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; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; polyethylene oxide, polyvinylpyrrolidone, polyacrylamide, poloxamer; and other common non-toxic compatible substances used in pharmaceutical formulations.

[0086] The pharmaceutical composition of the present disclosure can further comprise at least one second therapeutic agent, e.g., an anticancer agent. The second therapeutic agent may be used in combination with the compounds of Formula (I) described in the present disclosure to treat the diseases or disorders as disclosed herein. The second therapeutic agent includes, but is not limited to, chemotherapeutic agents, immunotherapeutic agents, gene therapy agents, and the like.

[0087] The pharmaceutical composition of the present disclosure comprising, as an active ingredient, the compounds of Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof can be formulated into any suitable formulations such as sprays, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (such as soft capsules, hard capsules, enteric-coated capsules), dragees, troches, powders, granules, powder injections, suppositories, or liquid formulations (such as suspensions (e.g., aqueous or oily suspensions), solutions, emulsions, or syrups), or conventional injection dosage forms such as injectable solutions (e.g., sterile injectable solutions formulated according to methods known in the art using water, Ringer's solution, or isotonic sodium chloride solution or the like as a vehicle or solvent) or lyophilized injectable formulation and the like, depending upon a suitable route of administration (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, intraperitoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration). Those skilled in the art can also formulate the compounds of Formula (I) of the present disclosure into conventional, dispersible, chewable, orally disintegrating or rapidly dissolving formulations, or sustained-release capsules or controlled-release capsules as needed.

[0088] The compounds of Formula (I) of the present disclosure, as an active ingredient, is contained in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount for the indication to be treated, without causing serious toxic effects in the subject treated. A dosage of the active compound for all diseases or disorders mentioned herein ranges, for example, from about 5ng / kg to 500mg / kg, from about 10ng / kg to 300mg / kg per day, such as from 0.1 to 100 mg / kg, or from 0.5 to about 25mg per kilogram body weight of the subject per day.

[0089] The compounds of Formula (I) of the present disclosure or pharmaceutically acceptable salts thereof may be conveniently administered in any suitable unit dosage form. Suitable unit dosage form specifications include, but are not limited to, less than 1mg, 1mg to 3000mg, 5mg to 1000mg, for example, 5 to 500mg, 25 to 250mg of active ingredient per unit dosage form. IV. Kits / Packaged Products

[0090] The compounds of Formula (I) of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof is used as a medicament. The medicament of the present disclosure or the pharmaceutical composition of the present disclosure may be presented in a kit / packaged product. The kit / packaged product may include a package or container including, but not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes and dispensing devices, and the like. The kit / packaged product may contain instructions for use of the product. V. Treatment Methods and Uses

[0091] The compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof can be used as a medicament. Especially the compound of Formula (I) of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof can be used for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder. The disease or disorder includes a disease or disorder associated with a cereblon protein.

[0092] In some embodiments, the disease or disorder comprises: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

[0093] In some embodiments, the disease or disorder includes, but is not limited to, myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplantation-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, acute B-lymphoblastic leukemia, T-lymphoblastic leukemia, acute T-lymphoblastic leukemia, lymphoma cell leukemia, monocytic leukemia, myelomonocytic leukemia; lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, immunoblastic T-Cell lymphoma, CD20 positive lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Burkitt’s lymphoma, marginal zone lymphoma (MZL), primary lymphoma, B-cell lymphoma, recurrent B-cell nonHodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma, recurrent mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, recurrent transformed nonHodgkin’s lymphoma, refractory B-cell non-Hodgkin’s lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin’s lymphoma; Burkitt’s lymphoma (Burkitt’s lymphoma); thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, and small cell lung cancer; inflammatory myofibroblastoma; colorectal cancer; intestinal cancer; brain glioma; astroblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer, ductal carcinoma of the breast, and patients with Cowden syndrome; pancreatic cancer; central nervous system tumor; neuroblastoma; glioma; peripheral neuroepithelioma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; metrocarcinoma; head and neck cancer; brain cancer; oral cancer; sarcoma, including rhabdomyosarcoma, various lipogenic tumors, Ewing’s sarcoma / primitive neuroectodermal tumors (Ewing / PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; Richter syndrome (RS); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren’s syndrome, atopic dermatitis, hidradenitis suppurativa, gout, type I diabetes, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis; inflammatory diseases, including pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, Acquired immunodeficiency syndrome (AIDS), COVID-19 novel coronavirus infection, gram-negative bacteria infection, gram-positive bacteria infection, tuberculosis, etc; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplantation rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; pediatric aplastic anemia; cardiovascular diseases (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ dysfunction caused by cachexia and septic shock; and acute liver failure.

[0094] The present disclosure provides a method for preventing and / or treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compounds of Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure comprising as an active ingredient the compounds of Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, In some embodiments, the disease or disorder includes a disease or disorder associated with a cereblon protein. The disease or disorder is as defined herein.

[0095] In the method for preventing and / or treating a disease or disorder (associated with a cereblon protein) in a subject, the compound of Formula (I) of the present disclosure or the pharmaceutical composition comprising as an active ingredient the compound of Formula (I) of the present disclosure is administered to the subject through at least one mode of administration selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, intramuscular administration, subcutaneous, transdermal, epidural, intrathecal, and intravenous administration.

[0096] The term "treatment" or "treating" refers to administering to a subject the compound of Formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising, as an active ingredient, the compound of Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, to mitigate (alleviate) undesirable diseases or conditions, such as the development of a cancer or tumor. The beneficial or desired clinical results of the present disclosure include, but are not limited to: alleviating symptoms, reducing the severity of the disease, stabilizing the state of the disease, slowing down or delaying the progression of the disease, improving or alleviating the condition, and alleviating the disease.

[0097] A "therapeutic effective amount" of the compound of the present disclosure depends on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the duration of its action, the age, sex and weight of the patient, the patient's current medical condition, the route and duration of administration, the excretion rate, the combined administration of additional drugs, and the progression of the diseases or conditions of the patient being treated. Those skilled in the art will be able to determine appropriate dosages based on these and other factors.

[0098] It is to be understood that the choice of using one or more active compounds and / or compositions and their dosage depends on the basic situations of the individual (which should generally render the individual situation to achieve the best effect). Dosing and dosing regimens should be within the ability of those skilled in the art, and the appropriate dosage depends on many factors including the knowledge and ability of the physicians, veterinarians or researchers (see e.g., Jun Li (chief editor), "Clinical Pharmacology", 4th edition, People’s Public Health Press, 2008).

[0099] As used herein, the term “patient” or “subject” to be treated refers to animal, for example mammal, including but not limited to primate (such as human being), cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mice, etc. VI. Preparation Method

[00100] The compound of Formula (I) of the present disclosure may be prepared by reacting a compound of Formula (M1) with a compound of Formula (M2): wherein Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, Z5, (Rd1)n1, ring B, (Rd2)n2, Rc, ring C, ml, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure; nitrogen-containing heterocycle A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably a 4- to 20-membered nitrogen-containing heterocycle; more preferably a 4- to 15-membered nitrogen-containing heterocycle); R represents optionally substituted linear or branched C1-5 alkylene; LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, o-nitrobenzenesulfonyl, C(O)Cl, or COOH; and Xa of the compound of Formula (I) correspondingly represents a structure represented by the following formula: (Rdl)n1 (Rd2)n2      (^d3)n3   (^d4)n4 , wherein nitrogen-containing heterocyclylene A represents 4- to 30-membered nitrogen-containing heterocyclylene (preferably, 4- to 20-membered nitrogen-containing heterocyclylene; more preferably, 4- to 15-membered nitrogen-containing heterocyclylene), (Rd1)n1, ring B, (Rd2)n2, Rc, ring C, m1, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure.

[00101] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, R represents -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-; wherein the above-mentioned group is optionally substituted with a substituent selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl.

[00102] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, the nitrogen-containing heterocycle A, after removal of the hydrogen atom on the nitrogen atom through a reaction, gives a nitrogen-containing heterocyclylene A. In some embodiments, the nitrogen-containing heterocycle A represents 4- to 30-membered nitrogen-containing heterocycle (preferably, 4- to 20-membered nitrogen-containing heterocycle; more preferably, 4- to 15-membered nitrogen-containing heterocycle). The nitrogen-containing heterocyclylene A represents 4- to 30membered nitrogen-containing heterocyclylene (preferably, 4- to 20-membered nitrogen-containing heterocyclylene; more preferably, 4- to 15-membered nitrogen-containing heterocyclylene).

[00103] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, when LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, or o-nitrobenzenesulfonyl, the compound of Formula (M1) and the compound of Formula (M2) undergo an amine alkylation reaction. In some embodiments, the amine alkylation reaction may be carried out, for example, in the presence of an organic base and sodium iodide at a temperature ranging from room temperature to 80°C (e.g., 40°C to 60°C, 40°C to 50°C, or 50°C to 60°C). Examples of the organic base include, but are not limited to, DIEA or triethylamine. In some embodiments, the molar ratio of the compound of Formula (M1) to the compound of Formula (M2) may be, for example, 1:1.0 to 2, 1:1.1 to 2, 1:1.1 to 1.5, 1:1.1 to 1.2, or 1:1.2 to 1.3, and the like.

[00104] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, when LE represents COOH, the compound of Formula (M1) and the compound of Formula (M2) undergo an amide condensation reaction. In some embodiments, the amide condensation reaction may be carried out, for example, in the presence of an organic base and HATU at room temperature. Examples of the organic base include, but are not limited to, DIEA or triethylamine. In some embodiments, the molar ratio of the compound of Formula (M1) to the compound of Formula (M2) may be, for example, 1:1.0 to 2, 1:1.1 to 2, 1:1.1 to 1.5, 1:1.1 to 1.2, or 1:1.2 to 1.3, and the like.

[00105] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, when the group LE represents methanesulfonyloxy, the compound of Formula (M1) is prepared by reacting a compound of Formula (M3) with methanesulfonic anhydride or methanesulfonyl chloride: D ^3.2 R?3 R (Ra5)m Rai^-d^a^^V z4 z5-n' T R HN-Z3 'zAz XOH (M3) wherein Rai, Ra2, Ra3, Ra4, (Ra5)m, Zi, Z2, Z3, Z4, Z5, and R are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. In some embodiments, R may represent CH2.

[00106] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, when the group LE represents Cl, Br or I, the compound of Formula (M1) may be prepared by reacting a compound of Formula (M3) with a hydrohalic acid through a halogenation reaction: wherein Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, Z5, and R are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. In some embodiments, R may represent CH2.

[00107] In some embodiments of the method for preparing the compound of Formula (I) of the present disclosure, the compound of Formula (M3), wherein R represents CH2, may be prepared by subjecting a compound of Formula (M4) to a coupling reaction with (tributylstannyl)methanol in the presence of a palladium catalyst: Ra2 Ra3 D Ra1^L4 / Ra4^ Z4 Z5-N ‘ HN-Z3 z (M4) wherein Rai, Ra2, Ra3, Ra4, (Ra5)m, Zi, Z2, Z3, Z4, and Z5 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure.

[00108] In some embodiments, the coupling reaction may be carried out, for example, in the presence of tetrakis(triphenylphosphine)palladium and 1,4-dioxane (or DMF) at a temperature ranging from 40°C to 120°C.

[00109] In some embodiments, when Z5 in the compound of Formula (M4) represents N, and Z1 represents C(O), CH2, or CD2, and Z2, Z3, and Z4 each independently represent C(O), the compound of Formula (M4) is prepared by subjecting a compound of Formula (M5) and a compound of Formula (M6) to an amine-ester exchange reaction: wherein Rai, Ra2, Ra3, Ra4, and (Ra5)m are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure.

[00110] In some embodiments, the amine-ester exchange reaction may be carried out in the presence of CH3ONa and methanol at room temperature. Alternatively, the amine-ester exchange reaction may also be carried out in the presence of CH3OLi or Cs2CO3 and methanol at a temperature ranging from 40°C to 90°C, or in the presence of DBU and THF at a temperature ranging from 40°C to 90°C.

[00111] In some embodiments, when Z1 in the compound of Formula (M4) represents C(O), C(S), CH2, or CD2; Z2, Z3, and Z4 each independently represent C(O) or C(S); and at least one of Z1, Z2, Z3, and Z4 represents C(S), the compound of Formula (M4) is prepared by subjecting a compound of Formula (M7) to a thionation reaction with a thionating reagent: wherein Z6 in the compound of Formula (M7) represents C(O), CH2, or CD2; and the Ra1, Ra2, Ra3, Ra4, and (Ra5)m are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. When Z6 in the starting material compound of Formula (M7) represents CH2 or CD2, the corresponding Z1 in the product thiocarbonyl compound of Formula (M4) represents CH2 or CD2. When Z6 in the starting material compound of Formula (M7) represents C(O), the corresponding Z1 in the product thiocarbonyl compound of Formula (M4) represents C(O) or C(S).

[00112] In some embodiments, examples of the thionating reagent include, but are not limited to, carbon disulfide, hexamethyldisilathiane, sulfur, thiourea, hydrogen sulfide, phosphorus pentasulfide, Lawesson's Reagent (CAS No.:19172-47-5), Belleau’s reagent (CAS No.: 88816-02-8), and Davy’s reagent (CAS No.: 82737-61-9) etc.

[00113] In some embodiments, the compound of Formula (M7) is reacted with the thionating reagent (e.g., Lawesson's reagent) in a solvent (e.g., 1,4-dioxane) at a temperature ranging from 40°C to 150°C to give the thiocarbonyl compound of Formula (M4).

[00114] In some embodiments, at least one of Z1, Z2, Z3, and Z4 in the thiocarbonyl compound of Formula (M4) represents C(S). In some embodiments, at least two of Z1, Z2, Z3, and Z4 in the thiocarbonyl compound of Formula (M4) represent C(S). In some embodiments, at least three of Z1, Z2, Z3, and Z4 represent C(S). In some embodiments, all of Z1, Z2, Z3, and Z4 represent C(S). VII. Definitions

[00115] Unless otherwise specified, the following words, phrases and symbols used herein generally have the meanings as described below.

[00116] In general, the nomenclature used herein (including the IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, and pharmacology, etc.) are those well-known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in connection with the present disclosure described herein have the same meaning as commonly understood by one skill in the art. In addition, the use of the word “a” or “an” when used in conjunction with the term “comprising” or a noun in the claims and / or the specification may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the terms "another" or "other" can mean at least a second or more.

[00117] It should be understood that whenever the term "comprise" or "include" is used herein to describe various aspects, other similar aspects described by "consisting of" and / or "consisting essentially of" are also provided.

[00118] As used herein, the term "about" used alone or in combination refers to approximately, roughly, nearly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical value. In general, the term "about" can modify a numerical value above and below the stated value by an upward or downward (increasing or decreasing) variation, e.g., 10%, 5%, 2%, or 1%.

[00119] As used herein, the wording "...represents a bond" used alone or in combination means that the referenced group is a bond linker (that is, the referenced group is absent). For example, the wording "Rc represents a bond" means that Rc is a bond linker. In other words, when Rc represents a bond, the ring B in the structure of Formula (I) is directly connected to the ring C in the structure of Formula (I).

[00120] In this document, the term "optionally substituted" used alone or in combination means that the referenced group may be unsubstituted or substituted with one or more substituents as defined here. Herein, the wording "optionally substituted with..." and "unsubstituted or substituted" can be used interchangeably. The term "substituted" generally represents the replacement of one or more hydrogen atoms in the referenced structure by identical or different specific substituents. The number of substituents is not theoretically limited in any way, or is automatically limited by the size of the building units (i.e., the total number of replaceable hydrogen atoms in the building units), or as clearly defined herein.

[00121] Herein, a bond interrupted by a wavy line shows the point of attachment of the depicted group to the rest of the molecule. For example, the monovalent group X depicted below (Rdl)n1 (Rd2)n2 ml (Rd3)n3   (Rd4)n4 shows the point of attachment of ring A in said group X to group R in the structure of Formula (I).

[00122] As used herein, the term "one or more" in the expression "substituted with one or more substituents selected from the group consisting of ...", whether used alone or in combination, means that some or all of the hydrogen atoms of the referenced group are replaced by a substituent or substituents. The number of substituents includes but is not limited to 1 to 40, such as 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1. The number of hydrogens to be replaced is in principle not limited in any way, or is automatically limited by the size of the building unit. For example, where the referenced group is a methyl group, the number of substituents may be 1 to 3.

[00123] As used herein, the term "deuterated" used alone or in combination, indicates that one or more hydrogen atoms in the referenced group are replaced by deuterium atoms.

[00124] As used herein, the term "oxo" or "oxo group" used alone or in combination, refers to =O.

[00125] As used herein, the term “C(O)” or “C(=O)” used alone or in combination, refers to a carbonyl group.

[00126] As used herein, the term "thiocarbonyl", whether used alone or in combination, refers to C(S) or C(=S).

[00127] As used herein, the term "halogen atom" or "halogen", used alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[00128] As used herein, the term "alkyl", used alone or in combination, refers to a linear or branched alkyl group. The term "Cx-Cy alkyl" or "Cx-y alkyl" (x and y each being an integer) refers to a linear or branched alkyl group containing from x to y carbon atoms. The term "C1-10 alkyl" used alone or in combination in the present disclosure refers to a linear or branched alkyl group containing from 1 to 10 carbon atoms. Examples of the C1-10 alkyl of the present disclosure may include a C1-9 alkyl, C1-8 alkyl, C2-8 alkyl, C1-7 alkyl, C1-6alkyl, C1-5 alkyl, C1-4 alkyl, C1-C3 alkyl, and C1-C2 alkyl. Representative examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl. The term "C1-3 alkyl" or "C1-C3 alkyl" in the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms, and representative examples thereof include methyl, ethyl, propyl, and isopropyl. In the present disclosure, the "alkyl" is optionally substituted, and the substituents are optionally one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from the group consisting of e.g., halogen, hydroxyl, cyano, C1-3 alkyl, C1-3 alkoxy, halogenated C1-6 alkoxy, halogenated C1-6 alkyl (e.g., trifluoromethyl), C3-6 cycloalkyl, and 4- to 7membered heterocyclyl.

[00129] As used herein, the term "halogenated alkyl", used alone or in combination, refers to a linear or branched alkyl group substituted with one or more halogens, wherein one or more hydrogen atoms of the alkyl group are replaced with one or more halogens. The term "halogenated Cx-Cy alkyl" or "halogenated Cx-y alkyl" (x and y are each an integer) refers to a linear or branched alkyl containing from x to y carbon atoms substituted with one or more halogens. The term "halogenated C1-10 alkyl" used alone or in combination in the present disclosure refers to a linear or branched alkyl group containing from 1 to 10 carbon atoms substituted with one or more halogens. Examples of the halogenated C1-10 alkyl group of the present disclosure include halogenated C1-9 alkyl group, e.g., halogenated C1-8 alkyl group, halogenated C2-8 alkyl group, halogenated C1-7 alkyl group, halogenated C1-6 alkyl, halogenated C1-5 alkyl, or halogenated C1-4 alkyl. Representative examples include halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halo-sec-butyl, halo-tert-butyl, halopentyl, haloisoamyl, haloneopentyl, halo-tert-pentyl, halohexyl, haloheptyl, halooctyl, halononyl, and halodecyl. The term "halogenated C1-3 alkyl" or "halogenated C1-C3 alkyl" of the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms substituted with one or more halogens, and its representative examples include halomethyl (e.g., trifluoromethyl), haloethyl, halopropyl and haloisopropyl.

[00130] As used herein, the term "deuterated alkyl", used alone or in combination, refers to a linear or branched alkyl group substituted with one or more deuterium atoms, wherein one or more hydrogen atoms of the alkyl group are replaced with one or more deuterium atoms. The term "deuterated Cx-Cy alkyl" or "deuterated Cx-y alkyl" (x and y are each an integer) refers to a linear or branched alkyl containing from x to y carbon atoms substituted with one or more deuterium atoms. The term "deuterated C1-10 alkyl" used alone or in combination in the present disclosure refers to a linear or branched alkyl group containing from 1 to 10 carbon atoms substituted with one or more deuterium atoms. Examples of the deuterated C1-10 alkyl group of the present disclosure include deuterated C1-9 alkyl group, e.g., deuterated C1-8 alkyl group, deuterated C2-8 alkyl group, deuterated C1-7 alkyl group, deuterated C1-6 alkyl, deuterated C1-5 alkyl, or deuterated C1-4 alkyl. Representative examples include perdeuterated methyl (CD3), perdeuterated ethyl (CD3CD2), perdeuterated propyl, perdeuterated isopropyl, perdeuterated butyl, perdeuterated isobutyl, perdeuterated sec-butyl, perdeuterated tertbutyl, perdeuterated pentyl, perdeuterated isopentyl, perdeuterated neopentyl, perdeuterated tert-pentyl, and perdeuterated hexyl. The term "deuterated C1-3 alkyl" or "deuterated C1-C3 alkyl" of the present disclosure refers to an alkyl group containing from 1 to 3 carbon atoms substituted with one or more deuterium atoms, and its representative examples include perdeuterated methyl (CD3) and perdeuterated ethyl (CD3CD2).

[00131] As used herein, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms, which is the divalent form of a linear or branched alkyl group. The term "Cx-Cy alkylene" or "Cx-y alkylene" (x and y each being an integer) refers to a linear or branched alkylene group containing from x to y carbon atoms. The term "C1-C5 alkylene" as used herein, whether alone or in combination, refers to a linear or branched alkylene containing 1 to 5 carbon atoms, examples of which include, but are not limited to, C1-C4 alkylene, C1-C3 alkylene, and C1-C2 alkylene. Representative examples include, but are not limited to, methylene (i.e., -CH2-), ethylene (e.g., -CH2CH2-), propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, and tert-pentylene. In the present disclosure, the "alkylene" is optionally substituted, and the substituents are optionally one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00132] As used herein, the term "alkoxy", used alone or in combination, refers to a linear or branched alkoxy group having structural formula of alkyl-O-. Optionally, the alkyl portion of the alkoxy group may contain 1-10 (e.g., 1-6, 1-4, or 1-3) carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc. The term "C1-C6 alkoxy" or "C1-6 alkoxy" refers to a linear or branched alkoxy group containing from 1 to 6 carbon atoms. Representative examples of C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, and hexyloxy.

[00133] As used herein, the term "halogenated alkoxy", used alone or in combination, refers to an alkoxy group substituted with one or more halogen atoms. Optionally, the alkyl portion of the alkoxy group may contain 1-10 (e.g., 1-6, 1-4, or 1-3) carbon atoms. Examples of "halogenated alkoxy" include halogenated C1-6 alkoxy or halogenated C1-4 alkoxy. Representative examples include, but are not limited to, F3C-O-, FCH2-O-, F2CH-O-, ClCH2-O-, Cl2CH-O-, CF3CF2-O-, CF3CHF-O-, CHF2CF2-O-, CHF2CHF-O-, CF3CH2-O-, or CH2ClCH2-O-.

[00134] As used herein, the term "heteroaryl", used alone or in combination, refers to a 5- to 30membered (e.g., 5- to 20-membered, 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5-to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15membered, 6- to 9-membered, or 6- to 20-membered) monocyclic, bicyclic, or polycyclic cyclic hydrocarbon radical containing at least one aromatic ring having one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic or tetracyclic heteroaryl groups, which contain one aromatic ring having one or more (e.g., 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from O, S and N, and the remaining rings which may be a saturated, partially unsaturated or aromatic ring and can be carbocyclic ring or contain one or more (e.g., 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from O, S and N. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridyl, furopyridyl, pteridyl, purinyl, pyridopyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridyl,    1H-pyrrolo[3,2-b]pyridyl,    1H-pyrrolo[2,3-b]pyridyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, chromanyl, and 6,7-dihydrothieno[3,2-d]pyrimidinyl. Examples of tricyclic or polycyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, xanthyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, and 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl. The heteroaryl group may be unsubstituted or substituted. A substituted heteroaryl refers to heteroaryl substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) by a substituent(s) optionally selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00135] As used herein, the term "heteroarylene", used alone or in combination, refers to a 5- to 30membered (e.g., 5- to 20-membered, 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5-to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15membered, 6- to 9-membered, or 6- to 20-membered) bivalent monocyclic, bicyclic, or polycyclic cyclic hydrocarbon radical containing at least one aromatic ring having one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroarylene groups include bicyclic, tricyclic, tetracyclic or polycyclic heteroarylene groups, which contain one aromatic ring having one or more (e.g., 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from O, S and N, and the remaining ring(s) which may be a saturated, partially unsaturated or aromatic ring and can be carbocyclic ring or contain one or more (e.g., 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from O, S and N. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Examples of bicyclic heteroarylene include, but are not limited to, indolylene, isoindolylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, oxazolopyridylene, furopyridylene, pteridylene, purinylene, pyridopyridylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, pyrrolo[2,1-b]thiazolylene, imidazo[2,1-b]thiazolylene, chromanylene, and 6,7-dihydrothieno[3,2-d]pyrimidinylene. Examples of tricyclic or polycyclic heteroarylene include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, xanthylene, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinylene, and 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinylene. The heteroarylene may be unsubstituted or substituted. A substituted heteroarylene refers to heteroarylene substituted one or more times (e.g., 14, 1-3, or 1-2 times) by a substituent(s) optionally selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00136] As used herein, the term "aryl", used alone or in combination, refers to a monovalent aromatic hydrocarbon group containing from 5 to 30 (e.g., from 5 to 20, from 5 to 15, from 5 to 12, from 5 to 10, from 5 to 9, from 5 to 8, from 5 to 7, from 5 to 6, from 6 to 15, from 6 to 9, or from 6 to 20) carbon atoms and optionally one or more fused rings, such as phenyl group, naphthyl group, or fluorenyl group. As used herein, the "aryl" is optionally substituted. A substituted aryl group refers to an aryl group substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent(s). For example, aryl is mono-, di-, tri-, or poly-substituted with a substituent(s) optionally selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00137] As used herein, the term "arylene", used alone or in combination, refers to a divalent aromatic hydrocarbon group containing from 5 to 30 (e.g., from 5 to 20, from 5 to 15, from 5 to 12, from 5 to 10, from 5 to 9, from 5 to 8, from 5 to 7, from 5 to 6, from 6 to 15, from 6 to 9, or from 6 to 20) carbon atoms and optionally one or more fused rings, such as phenylene (e.g.,      ' ,       , and ^^Z / ), naphthylene, or fluorenylene. As used herein, the "arylene" is optionally substituted. A substituted arylene refers to an arylene group substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent(s). For example, arylene is mono-, di-, tri-, or poly-substituted with a substituent(s) optionally selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00138] As used herein, the term "cycloalkyl", used alone or in combination, refers to a saturated or partially unsaturated (i.e., containing one or more double bonds but not fully conjugated) monocyclic or bicyclic or tricyclic or polycyclic cyclic hydrocarbon radical, and the number of carbon atoms thereof includes, but is not limited to, from 3 to 30 carbon atoms (i.e., C3-30 cycloalkyl), or from 3 to 25 carbon atoms (i.e., C3-25 cycloalkyl), or from 3 to 20 carbon atoms (i.e., C3-20 cycloalkyl), or from 3 to 15 carbon atoms (i.e., C3-15 cycloalkyl), or from 3 to 12 carbon atoms (i.e., C3-12 cycloalkyl), or from 3 to 11 carbon atoms (i.e., C3-11 cycloalkyl), or from 3 to 10 carbon atoms (i.e., C3-10 cycloalkyl), or from 3 to 8 carbon atoms ( i.e., C3-8 cycloalkyl), or from 3 to 7 carbon atoms (i.e., C3-7 cycloalkyl), or from 3 to 6 carbon atoms (i.e., C3-6 cycloalkyl), or from 4 to 20 carbon atoms ( i.e., C4-20 cycloalkyl), or from 4 to 15 carbon atoms ( i.e., C4-15 cycloalkyl), or from 4 to 12 carbon atoms (i.e., C4-12 cycloalkyl), or from 4 to 10 carbon atoms (i.e., C4-10 cycloalkyl). The term "cycloalkyl" includes monocyclic, bicyclic, tricyclic, and polycyclic cyclic hydrocarbon radical having from 3 to 30 carbon atoms. Examples of the term "cycloalkyl" include, but are not limited to, monocyclic cycloalkyl, bridged cycloalkyl (e.g., C5-30 bridged cycloalkyl, C5-20 bridged cycloalkyl, C5-15 bridged cycloalkyl, and C7-15 bridged cycloalkyl), fused cycloalkyl (e.g., C5-30 fused cycloalkyl, C5-20 fused cycloalkyl, C5-15 fused cycloalkyl, C6-30 fused cycloalkyl, C6-20 fused cycloalkyl, C6-15 fused cycloalkyl, C7-30 fused cycloalkyl, C7-20 fused cycloalkyl, C7-15 fused cycloalkyl, and C8-15 fused cycloalkyl), and spiro-cycloalkyl (e.g., C5-30 spiro-cycloalkyl, C5-20 spiro-cycloalkyl, C5-15 spiro-cycloalkyl, C6-30 spiro-cycloalkyl, C6-20 spirocycloalkyl, C6-15 spiro-cycloalkyl, C7-30 spiro-cycloalkyl, C7-20 spiro-cycloalkyl, C7-15 spiro-cycloalkyl, and C8-15 spiro-cycloalkyl). Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl, spiro-cycloalkyl, and bridged cycloalkyl groups include, but are not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, C5-20 spiro-cycloalkyl, C5-15 spiro-cycloalkyl, adamantanyl, noradamantanyl, bornyl, and norbornyl (also named as bicyclo[2.2.1]heptyl by the IUPAC system). As used herein, the "cycloalkyl" is optionally mono- or poly-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkyl" are optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl. Examples of the terms “C3-6 cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[00139] As used herein, the term "Cx-y spiro-cycloalkyl" (x and y each being an integer), used alone or in combination, refers to a spiro-cycloalkyl group containing from x to y carbon atoms. As used herein, the term "C5-30 spiro-cycloalkyl", used alone or in combination, refers to a spiro-cycloalkyl group containing from 5 to 30 carbon atoms (e.g., but not limited to, 5-20, 5-15, 7-20, 7-15, 5-11, 5-10, and 7-9 carbon atoms). The term "C5-30 spirocycloalkyl" includes "C5-20 spirocycloalkyl", "C5-15 spirocycloalkyl", "C7-15 spirocycloalkyl" and "C7-20 spirocycloalkyl", and representative examples of which include, but are not limited to, spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, and spiro[5.5]undecyl. The "C5-30 spiro-cycloalkyl" is optionally further substituted with one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00140] As used herein, the term "Cx-y bridged cycloalkyl" (where x and y are integers) used alone or in combination, refers to a bridged cycloalkyl group containing x to y carbon atoms. In the present invention, the term "C5-30 bridged cycloalkyl" used alone or in combination, refers to a bridged cycloalkyl group containing from 5 to 30 carbon atoms (e.g., but not limited to, 5-20, 6-20, 7-20, 5-15, 7-15, 5-11, 5-10, and 7-9 carbon atoms). The term "C5-30 bridged cycloalkyl" includes "C5-20 bridged cycloalkyl", "C6-20 bridged cycloalkyl", "C7-20 bridged cycloalkyl", "C5-15 bridged cycloalkyl", and "C7-15 bridged cycloalkyl", and representative examples of which include, but are not limited to, adamantanyl, noradamantanyl, bornyl, norbornanyl (systematically named bicyclo[2.2.1]heptanyl), 2-oxobicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, and cubanyl. Said " C5-30 bridged cycloalkyl" is optionally substituted with 1-10 (e.g., 1-6, 1-5, 1-4, or 1-3) substituents selected from the group consisting of e.g., deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00141] As used herein, the term "cycloalkylene", used alone or in combination, refers to a saturated or partially unsaturated (i.e., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic, tricyclic or polycyclic divalent cyclic hydrocarbon radical, and the number of carbon atoms thereof includes, but is not limited to, from 3 to 30 carbon atoms (i.e., C3-30 cycloalkylene), or from 3 to 25 carbon atoms (i.e., C3-25 cycloalkylene), from 3 to 20 carbon atoms (i.e., C3-20 cycloalkylene), or from 3 to 15 carbon atoms (i.e., C3-15 cycloalkylene), or from 3 to 12 carbon atoms (i.e., C3-12 cycloalkylene), or from 3 to 11 carbon atoms (i.e., C3-11 cycloalkylene), or from 3 to 10 carbon atoms (i.e., C3-10 cycloalkylene), or from 3 to 8 carbon atoms ( i.e., C3-8 cycloalkylene), or from 3 to 7 carbon atoms (i.e., C3-7 cycloalkylene), or from 3 to 6 carbon atoms (i.e., C3-6 cycloalkylene), or from 4 to 20 carbon atoms (i.e., C4-20 cycloalkylene), or from 4 to 15 carbon atoms ( i.e., C4-15 cycloalkylene), or from 4 to 12 carbon atoms (i.e., C4-12 cycloalkylene), or from 4 to 10 carbon atoms (i.e., C4-10 cycloalkylene). The term "cycloalkylene" includes monocyclic, bicyclic, tricyclic and polycyclic divalent cyclic hydrocarbon radical having from 3 to 30 carbon atoms. Examples of the term "cycloalkylene" include, but are not limited to, monocyclic cycloalkylene, bridged cycloalkylene (e.g., C5-30 bridged cycloalkylene, C5-20 bridged cycloalkylene, C5-15 bridged cycloalkylene, and C7-15 bridged cycloalkylene), fused cycloalkylene (e.g., C5-30 fused cycloalkylene, C5-20 fused cycloalkylene, C5-15 fused cycloalkylene, C6-30 fused cycloalkylene, C6-20 fused cycloalkylene, C6-15 fused cycloalkylene, C7-30 fused cycloalkylene, C7-20 fused cycloalkylene, C7-15 fused cycloalkylene, and C8-15 fused cycloalkylene), and spiro-cycloalkylene (e.g., C5-30 spiro-cycloalkylene, C5-20 spirocycloalkylene, C5-15 spiro-cycloalkylene, C6-30 spiro-cycloalkylene, C6-20 spiro-cycloalkylene, C6-15 spiro-cycloalkylene, C7-30 spiro-cycloalkylene, C7-20 spiro-cycloalkylene, C7-15 spiro-cycloalkylene, and C8-15 spiro-cycloalkylene). Representative examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Examples of fused cycloalkylene, spiro-cycloalkylene, and bridged cycloalkylene groups include, but are not limited to, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, C5-20 spirocycloalkylene (e.g., C5-15 spiro-cycloalkylene), adamantanylene, noradamantanylene, and norbornylene also named as bicyclo[2.2.1]heptylene by the IUPAC system). As used herein, the "cycloalkylene" is optionally mono- or poly-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexylene. The substituents of the substituted "cycloalkylene" are optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00142] As used herein, the term "Cx-y spiro-cycloalkylene" (x and y each being an integer), used alone or in combination, refers to a spiro-cycloalkylene group containing from x to y carbon atoms. As used herein, the term "C5-30 spiro-cycloalkylene", used alone or in combination, refers to a spirocycloalkylene group containing from 5 to 30 carbon atoms (e.g., 5-20, 5-15, 7-20, 7-15, 5-11, 5-10, or 7-9 carbon atoms). The term "C5-30 spiro-cycloalkylene" includes "C5-20 spiro-cycloalkylene", "C5-15 spiro-cycloalkylene", "C7-15 spiro-cycloalkylene", and "C7-20 spiro-cycloalkylene", and representative examples of which include, but are not limited to, spiro[3.3]heptylene, spiro[2.5]octylene, spiro[3.5]nonylene, spiro[4.4]nonylene, spiro[4.5]decylene, and spiro[5.5]undecylene. The "C5-30 spiro-cycloalkylene" is optionally further substituted with one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 13) substituents selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00143] As used herein, the term "Cx-y bridged cycloalkylene" (where x and y are integers) used alone or in combination, refers to a bridged cycloalkylene group containing x to y carbon atoms. In the present invention, the term "C5-30 bridged cycloalkylene" used alone or in combination, refers to a bridged cycloalkylene group containing 5 to 30 (e.g., but not limited to, 5-20, 6-20, 7-20, 5-15, 7-15, 5-11, 5-10, and 7-9) carbon atoms. The term "C5-30 bridged cycloalkylene" includes "C5-20 bridged cycloalkylene", "C6-20 bridged cycloalkylene", "C7-20 bridged cycloalkylene", "C5-15 bridged cycloalkylene", and "C7-15 bridged cycloalkylene", and representative examples of which include, but are not limited to, adamantanylene, noradamantanylene, bornylene, bicyclo[2.2.1]heptanylene, 2-oxobicyclo[2.2.1]heptanylene, bicyclo[2.2.1]heptenylene, and cubanylene. Said "C5-30 bridged cycloalkylene" is optionally substituted with one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00144] As used herein, the term "heterocyclyl" or "heterocyclic group", used alone or in combination, refers to a 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) saturated or partially unsaturated (i.e., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic, tricyclic or polycyclic cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of the heterocyclyl group include, but not limited to, monocyclic heterocyclyl (e.g., 4- to 30-membered monocyclic heterocyclyl, and 4- to 20-membered monocyclic heterocyclyl), bridged heterocyclyl (e.g., 5- to 30-membered bridged heterocyclyl, 5- to 20-membered bridged heterocyclyl, 7- to 20-membered bridged heterocyclyl, and 7- to 15-membered bridged heterocyclyl), fused heterocyclyl (e.g., 5- to 30-membered fused heterocyclyl, and 5- to 20membered fused heterocyclyl), and spiro-heterocyclyl groups (e.g., 5- to 30-membered spiro-heterocyclyl, and 5- to 20-membered spiro-heterocyclyl). Representative examples of the monocyclic heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptan-1-yl), and diazacyclooctyl. Examples of bridged heterocyclyl, fused heterocyclyl and spiro-heterocyclyl groups include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, octahydro-1H-indolyl, and azaspirocycloalkyl (e.g., 5- to 20-membered azaspirocycloalkyl, such as 3-azaspiro[5.5]undecan-3-yl). The heterocyclyl may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) by a substituent(s) optionally selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00145] As used herein, the term "nitrogen-containing heterocyclyl", used alone or in combination, refers to 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) saturated or partially unsaturated (i.e., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic, tricyclic or polycyclic cyclic hydrocarbon group containing one nitrogen atom and optionally one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of the nitrogen-containing heterocyclyl group include, but not limited to, nitrogen-containing monocyclic heterocyclyl (e.g., 4- to 30-membered nitrogen-containing monocyclic heterocyclyl, and 4- to 20-membered nitrogencontaining monocyclic heterocyclyl), nitrogen-containing bridged heterocyclyl (e.g., 5- to 30membered nitrogen-containing bridged heterocyclyl, 5- to 20-membered nitrogen-containing bridged heterocyclyl, 5- to 15-membered nitrogen-containing bridged heterocyclyl, 7- to 20-membered nitrogen-containing bridged heterocyclyl, and 7- to 15-membered nitrogen-containing bridged heterocyclyl), nitrogen-containing fused heterocyclyl (e.g., 5- to 30-membered nitrogen-containing fused heterocyclyl, and 5- to 20-membered nitrogen-containing fused heterocyclyl), and nitrogencontaining spiro-heterocyclyl groups (e.g., 5- to 30-membered nitrogen-containing spiro-heterocyclyl, and 5- to 20-membered nitrogen-containing spiro-heterocyclyl). Representative examples of the nitrogen-containing monocyclic heterocyclyl include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptan-1-yl), and diazacyclooctyl. Examples of nitrogen-containing bridged heterocyclyl, nitrogen-containing fused heterocyclyl and nitrogen-containing spiro-heterocyclyl groups include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, octahydro-1H-indolyl, and azaspirocycloalkyl (e.g., 5- to 20membered azaspirocycloalkyl, such as 3-azaspiro[5.5]undecan-3-yl). The nitrogen-containing heterocyclyl may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or polysubstituted) by a substituent(s) optionally selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00146] As used herein, the term "heterocyclylene", used alone or in combination, refers to a 4- to 30membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4-to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) saturated or partially unsaturated (i.e., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic, tricyclic or polycyclic bivalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of the heterocyclylene groups include, but are not limited to, monocyclic heterocyclylene (e.g., 4- to 30-membered monocyclic heterocyclylene, and 4- to 20-membered monocyclic heterocyclylene), bridged heterocyclylene (e.g., 5- to 30-membered bridged heterocyclylene, 5- to 20-membered bridged heterocyclylene, 7- to 20-membered bridged heterocyclylene, and 7- to 15-membered bridged heterocyclylene), fused heterocyclylene (e.g., 5- to 30-membered fused heterocyclylene, and 5- to 20-membered fused heterocyclylene), and spiro-heterocyclylene groups (e.g., 5- to 30-membered spiro-heterocyclylene, and 5- to 20-membered spiro-heterocyclylene). Representative examples of the monocyclic heterocyclylene include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene,      azacycloheptanylene,      azacyclooctylene, dioxacyclohexylene, diazacycloheptanylene (e.g., 1,4-diazacycloheptanylene, 4,5-diazacycloheptanylene, 1,3-diazacycloheptanylene), and diazacyclooctylene. Examples of the bridged heterocyclylene, fused heterocyclylene and spiro-heterocyclylene groups include, but are not limited to, 6-azabicyclo[3.1.1]heptanylene,                2,5-diazabicyclo[2.2.1]heptanylene,                3,6- diazabicyclo[3.1.1]heptanylene, 3-azabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, octahydro-1H-indolylene, and azaspirocycloalkylene (e.g., 5- to 20-membered azaspirocycloalkylene, such as 3-azaspiro[5.5]undecanylene). The heterocyclylene may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) by a substituent(s) optionally selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00147] As used herein, the term "nitrogen-containing heterocyclylene", used alone or in combination, refers to a 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9- membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) saturated or partially unsaturated (i.e., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic, tricyclic or polycyclic bivalent cyclic hydrocarbon group containing one nitrogen atom and optionally one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of the nitrogen-containing heterocyclylene group include, but not limited to, nitrogen-containing monocyclic heterocyclylene (e.g., 4- to 30-membered nitrogen-containing monocyclic heterocyclylene, and 4- to 20-membered nitrogen-containing monocyclic heterocyclylene), nitrogen-containing bridged heterocyclylene (e.g., 5- to 30-membered nitrogen-containing bridged heterocyclylene, 5- to 20-membered nitrogen-containing bridged heterocyclylene, 7- to 20-membered nitrogen-containing bridged heterocyclylene, and 7- to 15membered nitrogen-containing bridged heterocyclylene), nitrogen-containing fused heterocyclylene (e.g., 5- to 30-membered nitrogen-containing fused heterocyclylene, and 5- to 20-membered nitrogencontaining fused heterocyclylene), and nitrogen-containing spiro-heterocyclylene (e.g., 5- to 30membered nitrogen-containing spiro-heterocyclylene, and 5- to 20-membered nitrogen-containing spiro-heterocyclylene). Representative examples of the nitrogen-containing monocyclic heterocyclylene include, but are not limited to, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, azacycloheptanylene, azacyclooctylene, diazacycloheptanylene (e.g., 1,4-diazacycloheptanylene, 4,5-diazacycloheptanylene, 1,3-diazacycloheptanylene), and diazacyclooctylene. Examples of nitrogen-containing bridged heterocyclylene, nitrogen-containing fused heterocyclylene, and nitrogen-containing spiro-heterocyclylene groups include, but are not limited to, 6-azabicyclo[3.1.1]heptanylene, 2,5-diazabicyclo[2.2.1]heptanylene, 3,6-diazabicyclo[3.1.1]heptanylene, 3-azabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, octahydro-1H-indolylene, and azaspirocycloalkylene (e.g., 5- to 20-membered azaspirocycloalkylene, such as 3-azaspiro[5.5]undecanylene). The nitrogen-containing heterocyclylene may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) by a substituent(s) optionally selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH-, NH2-C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)-, optionally deuterated C1-6 alkyl-C(O)NH-, C2-6 alkynyl, and C2-6 alkenyl.

[00148] As used herein, the term "alkynyl", used alone or in combination, refers to a linear or branched monovalent hydrocarbon group containing from 2 to 8 (e.g., from 2 to 6, from 2 to 5, from 2 to 4, or preferably 2) carbon atoms and having one or more (e.g., from 1 to 3, from 1 to 2, or 1) carbon-carbon triple bonds. Examples of alkynyl include C2-8 alkynyl, C2-6 alkynyl, or C2-4 alkynyl, with representative but non-limiting examples including ethynyl, 1-propynyl, 1-butynyl, and 1,3-diynyl.

[00149] As used herein, the term "alkenyl", used alone or in combination, refers to a linear or branched monovalent hydrocarbon group containing from 2 to 8 (e.g., from 2 to 6, from 2 to 5, from 2 to 4, from 2 to 3, or 2) carbon atoms and having one or more (e.g., from 1 to 3, from 1 to 2, or 1) carbon-carbon double bonds. Examples of “alkenyl” include C2-8 alkenyl, C2-6 alkenyl or C2-4 alkenyl, with representative but non-limiting examples including, vinyl (e.g., CH2=CH-), 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, n-pent-2,4-dienyl, 1-methyl-but-1-enyl, 2-methyl- but-1-enyl, 3-methyl-but-1-enyl, 1-methyl-but-2-enyl, 2-methyl-but-2-enyl, 3-methyl-but-2-enyl, 1-methyl-but-3-enyl, 2-methyl-but-3-enyl, 3-methyl-but-3-enyl, and hexenyl.

[00150] As used herein, "bornylane" or "bornane" (also known as 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane) has a definition known to those skilled in the art. As used herein, "camphanyl" or "bornyl" refers to a monovalent group of bornane, i.e., the group remaining after any one of the hydrogens in bornane is removed. Representative examples of "bornyl" include, but are not limited to, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-3-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-4-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-5-yl, 1,7,7- trimethylbicyclo[2.2.1]heptan-6-yl, V , and V .

[00151] As used herein, "bicyclo[2.2.1]heptane" also known as "norbornane", has a definition known to those skilled in the art. As used herein, "bicyclo[2.2.1]heptyl" or "norbornyl" refers to a monovalent group of bicyclo[2.2.1]heptane, i.e., the group remaining after any hydrogen in bicyclo[2.2.1]heptane is removed. Representative examples of “bicyclo[2.2.1]heptyl” include, but are not limited to, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-3-yl, bicyclo[2.2.1]heptan-4-yl, bicyclo[2.2.1]heptan-5-yl, or bicyclo[2.2.1]heptan-6-yl.

[00152] As used herein, the term "bicyclo[2.2.1]heptene" has a definition known to those skilled in the art. As used herein, "bicyclo[2.2.1]heptenyl" refers to a monovalent group of bicyclo[2.2.1]heptene, i.e., the group remaining after any hydrogen in bicyclo[2.2.1]heptene is removed. Representative examples of “bicyclo[2.2.1]heptenyl” include, but are not limited to, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]hept-5-en- 3-yl, or bicyclo[2.2.1]hept-5-en-7-yl.

[00153] As used herein, "adamantane" (also known as tricyclo[3.3.1.13,7]decane) has a definition known to those skilled in the art, and its structural formula is e.g., as follows: jAs^. As used herein, "adamantanyl" refers to a monovalent group of adamantane, that is, the group remaining after any hydrogen in adamantane is removed. Representative examples of “adamantanyl” include, but are not limited to, 1-adamantanyl, 2-adamantanyl, 3-adamantanyl, 4-adamantanyl, 5-adamantanyl, 6-adamantanyl, 7-adamantanyl, 8-adamantanyl, 9-adamantanyl, or 10-adamantanyl.

[00154] As used herein, "noradamantane" has a definition known to those skilled in the art, and its structural formula is e.g., as follows: or Kl_^. As used herein, "noradamantanyl" refers to a monovalent group of noradamantane, that is, the group remaining after any hydrogen in noradamantane is removed. Representative examples of "noradamantanyl" include, but are not limited to, 1-noradamantanyl, 2-noradamantanyl, 3-noradamantanyl, 4-noradamantanyl, 5-noradamantanyl, 6-noradamantanyl, 7-noradamantanyl, 8-noradamantanyl or 9-noradamantanyl.

[00155] As used herein, "adamantanamine" has the definitions known to those skilled in the art, namely referring to an adamantane having an amino substituent, wherein the amino substituent can replace a hydrogen on a carbon at any position in the adamantane. An example of "adamantanamine" can be adamantan-1-amine (corresponding English chemical name is adamantan-1-amine or Tricyclo[3.3.1.13,7]decan-1-amine; CAS No.: 768-94-5), with the following structural Formula: nh2

[00156] Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of Formula (I) of the present disclosure are also encompassed within the scope of the present invention.

[00157] In all embodiments of the present disclosure, the salts or pharmaceutically acceptable salts of the compounds of Formula (I) refer to non-toxic inorganic or organic acid and / or base addition salts. Examples include: sulfates, hydrohalides (including hydrochlorides and hydrobromates), maleate, sulfonate, citrate, lactate, lactobionate, L-tartrate, fumarate, L-malate, L-lactate, a-ketoglutarate, hippurate, D-glucuronate, D-gluconate, a-D-glucoheptonate, glycolate, mucate, L-ascorbate, orotate, picrate, glycinate, alaninate, arginate, cinnamate, laurate, pamoate, sebacate, besylate, methanesulfonate, ethanesulfonate, edisylate, formate, acetate, 2,2-dichloroacetate, trimethylacetate, propionate, valerate, palmitate, triphenylacetate, 2-ethyl-butane-1,4-dioate, iodate, nicotinate, L-pyroglutamate, L-prolinate, ferulate, 2-hydroxyethanesulfonate, nitrate, gentisate, cholate, salicylate, terephthalate, glutarate, adipate, stearate, oleate, undecylenate, camphorate, camsylate, dodecylsulfate, phosphate, thiocyanate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, carbonate, malonate, benzoate, mandelate, succinate, pyruvate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, 3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, 2-naphthalenesulfonate, glycolate, trifluoroacetate, terephthalate, or 4-methylbenzenesulfonate, etc.

[00158] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, with which the useful compounds according to the present disclosure are carried or transported into or administered to a patient so that they can perform their intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not harmful to the patient, and the carrier must be "acceptable". Some examples of materials that can be used as pharmaceutically acceptable carriers include 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; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other common nontoxic compatible substances used in pharmaceutical formulations.

[00159] As used herein, the term "room temperature" refers to the ambient temperature, such as 20-30oC.

[00160] As used herein, "stereoisomer" refers to a compound with the same chemical structural formula, but a different arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and so on.

[00161] As used herein, the term "solvate" refers to an association or complex formed by the interaction between one or more solvent molecules and the compounds of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" means that a complex formed with water.

[00162] As used herein, the term "chiral" refers to a molecule that is nonsuperimposable on its mirror image; whereas "achiral" refers to a molecule that can be superimposed on its mirror image.

[00163] As used herein, the term "enantiomers" refers to two isomers of a compound that are non-superimposable mirror images.

[00164] As used herein, the term "diastereomers" refers to stereoisomers that have two or more chiral centers but are not mirror images of each other. The diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. The diastereomeric mixture can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.

[00165] As used herein, "p-menthane" has the definitions known to those skilled in the art, and its structural formula is e.g., as follows:           . As used herein, "p-menthanyl" refers to a monovalent group of p-menthane, that is, the group remaining after any hydrogen in p-menthane is removed. Representative examples of “p-menthanyl” include, but are not limited to,          ¢, "vZ / Z, -o4 -04 '—' \,    '—' \ , and    '—'    ' .

[00166] As used herein, "m-menthane" has the definitions known to those skilled in the art, and its ■ structural formula is e.g., as follows: /       . As used herein, "m-menthanyl" refers to a monovalent group of m-menthane, that is, the group remaining after any hydrogen in m-menthane is removed. Representative examples of “m-menthanyl” include, but are not limited to, , , , , , and

[00167] As used herein, "Quinuclidine" (also known as 1-azabicyclo[2.2.2]octane) has the definitions known to those skilled in the art, and its structural formula is e.g., as follows: . As used herein, "quinuclidinyl" refers to a monovalent group of Quinuclidine, that is, the group remaining after any hydrogen in Quinuclidine is removed. Representative examples of “quinuclidinyl” include, but are not limited to, and Descriptionof the Drawings

[00168] FIG. 1 shows the Western Blot results of target substrate protein degradation induced by the compounds of the present invention in hPBMCs. Examples

[00169] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. In other cases, well-known process operations have not been described in detail in order not to unnecessarily obscure the present disclosure. Although the present disclosure will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the present disclosure to these embodiments.

[00170] The following abbreviations are used throughout the specification and examples: AcOH acetic acid Boc t-Butyloxy carbonyl DCM dichloromethane DIEA or DIPEA N, N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate ESI electrospray ionization equiv EtOH equivalent ethanol EtOAc ethyl acetate HPLC high performance liquid chromatography HRMS high resolution mass spectrometry LC-MS liquid chromatography-mass spectrometry LRMS low resolution mass spectrometry LC liquid chromatography Me methyl MeCN acetonitrile MeOH methanol MS mass spectrometry MsCl methanesulfonyl chloride MsO- methanesulfonyloxy Ms2O methanesulfonic anhydride 1H NMR Proton nuclear magnetic resonance MeO- methoxy ONs o-nitrobenzenesulfonyl rt room temperature tBu tert-butyl TEA triethylamine TFA trifluoroacetic acid TfO- trifluoromethanesulfonate TLC thin layer chromatography TMS tetramethylsilane TsO- tosyloxy Xantphos X-Phos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[00171] In the present disclosure, the 1H NMR spectrum was recorded on a Bruker-500MHz nuclear magnetic resonance instrument, by using, as a solvent, CD3OD (8 = 3.31 ppm) containing 0.1% TMS (as an internal standard); or using, as a solvent, CDCh (8 = 7.26 ppm) containing 0.1% TMS (as an internal standard); or using, as a solvent, DMSO-d6 (8 = 2.50 ppm) containing 0.03% TMS (as an internal standard). LC-MS spectra were recorded on a Sciex API 2000 mass spectrometer equipped with an Agilent 1100 binary pump, DAD and ELSD detectors, or on an Agilent 1260-6125B single quadrupole LC-MS system equipped with an Agilent 1260 quaternary pump, DAD and ELSD detectors. HPLC preparative purification was performed using a SHIMADZU LC-20AP system. HPLC purity was determined using either a SHIMADZU LC-30AP or Waters 1525 system. All reactions were carried out under ambient atmosphere unless otherwise specified. Reaction progress was monitored by TLC or LC-MS.

[00172] Solvents and reagents are processed as follows: DCM, DMF, anhydrous EtOH and anhydrous MeOH used in the reactions were purchased from Sinopharm Group; and preparative HPLC was performed using HPLC-grade CH3CN and deionized water. Unless otherwise specified, other reaction substrates, reagents and chemicals are either commercially available or may be synthesized by methods known in the art.

[00173] Unless otherwise specified, the materials and reagents used in the following examples are commercially available and used directly, or can be synthesized by using methods known in the art.

[00174] General synthesis methods

[00175] Compounds and / or pharmaceutically acceptable salts thereof of the present disclosure can be synthesized using commercially available raw materials by synthetic techniques known in the art. The synthetic schemes described below illustrate the preparation of most compounds. The starting materials or reagents used in each scheme can be purchased from commercial sources or prepared by methods known to those skilled in the art. One skilled in the art can prepare the salts, racemates, enantiomers, phosphates, sulfates, hydrochlorides and prodrug forms of the compounds of Formula (I) of the present disclosure according to routine techniques in the art.

[00176] Scheme 1: Ra2 Ra3 D Ra1^L^Ra4z Z4 HN—Z3   Z 1 LE (Ra5)m amine alkylation (Rdl)n1 (Rd2)n2      (Rd3)n3   (Rd4)n4 2 NH A Ra2 Ra3 Ra1^_ Z4 z5-n ' HN—Z3 Z (Rd2)n2      (Rd3)n3   (Rd4)n4 Scheme 1

[00177] In Scheme 1, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, Z5, nitrogen-containing heterocycle A, (Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. The group LE of Substrate 1 represents Cl, Br, I, OMs, Ots, or ONs. Substrate 2 is a compound corresponding to the moiety X containing a nitrogen-containing heterocycle in the compound of Formula (I).

[00178] The amine alkylation reaction in Scheme 1 may be carried out, for example, in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide, at a temperature ranging from room temperature to 80 °C (e.g., 40 °C to 60 °C, 40 °C to 50 °C, or 50 °C to 60 °C). The molar ratio of Substrate 1 to Substrate 2 may be, for example, 1:1.1 to 2, 1:1.1 to 1.5, 1:1.1 to 1.2, or 1:1.2 to 1.3, and the like.

[00179] For example, the specific procedure for Scheme 1 may be as follows:

[00180] To a solution of bromo-substituted substrate 1 (1.3 eq.) and substrate 2 (1.0 eq.) in anhydrous DMF (2 mL) are added triethylamine (3.0 eq.) and sodium iodide (1.0 eq.). The reaction mixture is stirred at 50 oC for 2 hours. After monitoring the reaction via LCMS and confirming its completion, the reaction mixture is filtered, and the filtrate is separated and purified by high-performance liquid chromatography to give the target compound.

[00181] Scheme 2: (Sulfonate ester formation) (Ra5)m HO z2 zz3-nh n-z5   Z4 Zi       r—p / |   \ Ka1 Ra4Ra3 Ra2 MsCI, DIEA DCM, r.t. MsO (Ra5)m z2 zz3-nh n-z5 Z4 Zi \   —p / |   \ Rai ^a4Ra3Ra2 Scheme 2

[00182] In Scheme 2, Rai, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, and Z5 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. (1)Ms2O, DIEA DCM, DMF, rt (2)substrate 2, DIEA Nai, DMF, rt

[00183] In Scheme 2, the substituent -CH2-OH of the reaction substrate may be at the 4-, 5-, 6- or 7-position on the benzene ring of the isoindolinyl group, and the substituent -CH2-OMs of the resulting products 2-2 and 2-3 is correspondingly at the 4-, 5-, 6- or 7-position on the benzene ring of the isoindolinyl group.

[00184] Scheme 3: Ra2 Ra3 Ra1^L_^Ra4^ Z4 Z5-N HN-Z3 z Scheme 3

[00185] In Scheme 3, Rai, Ra2, Ra3, Ra4, (Ra5)m, Zi, Z2, Z3, Z4, Z5, nitrogen-containing heterocycle A, (Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure. The substrate 2 in step (2) is the same compound as substrate 2 in Scheme i.

[00186] For example, the specific procedure for Scheme 3 may be as follows:

[00187] To a solution of hydroxyl substrate (i.0 eq.) in anhydrous DMF (0.5 mL) and dichloromethane (5 mL) are added diisopropylethylamine (3.0 eq.) and methanesulfonic anhydride (0.9 eq.). The reaction mixture is stirred at room temperature for 5 minutes. After monitoring the reaction via TLC and confirming its completion, a solution of the corresponding amine substrate (i.0 eq.) in DMF (0.5 mL) is added to the reaction mixture, and the mixture is then stirred at room temperature for 3 hours. After monitoring the reaction via LCMS and confirming its completion, the reaction mixture is filtered and concentrated, and the residue is separated and purified by high-performance liquid chromatography to give the target compound.

[00188] Scheme 4: Ra2 Ra3 D Ra1^4 / Ra4 z4 z5-n HN—Z3 1 amide condensation (Rdl)n1 (Rd3)n3   (Rd4)n4 Ra2 Ra3 Ra1^4 / Ra4z Z4 z5-n ' HN—Z3   z (Ra5). Scheme 4

[00189] In Scheme 4, Rai, Ra2, Ra3, Ra4, (Ra5)m, Zi, Z2, Z3, Z4, Z5, nitrogen-containing heterocycle A, (Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure.

[00190] The specific procedure for Scheme 4 may be as follows:

[00191] To a solution of carboxylic acid substrate i (i.i eq.) and substrate 2 (i.0 eq.) in anhydrous DMF (2 mL) are added triethylamine (3.0 eq.) and HATU (i.3 eq.). The reaction mixture is stirred at room temperature for 2 hours. After monitoring the reaction via LCMS and confirming its completion, the reaction mixture is filtered, and the filtrate is separated and purified by high-performance liquid chromatography to give the target compound.

[00192] Scheme 5: Br NH )=0 Ra4Ra3 Ra^1 5-1 (Ra5)r Lawesson's reagent --------------► Br 1,4-dioxane, 110 °C, 12 h HO-Sn Zq'NH Ra1 ' Ka3 Ra2 5-2 Xphos Pd G3 1,4-dioxane, 100 °C, 12 h HO (Ra5)m Ra1 Scheme 5

[00193] In Scheme 5, Z6 represents C(O), CH2, or CD2. Zi represents C(O), C(S), CH2, or CD2, and Z2, Z3, and Z4 each independently represents C(O) or C(S), wherein at least one of Zi, Z2, Z3, and Z4 represents C(S). When Z6 represents C(O), Zi represents C(O) or C(S). When Z6 represents CH2 or CD2, Zi correspondingly represents CH2 or CD2.

[00194] The thionation reagent Lawesson's reagent in Scheme 5 may also be replaced with other suitable thionation reagents, such as, but not limited to, carbon disulfide, hexamethyldisilthiane, sulfur, thiourea, hydrogen sulfide, phosphorus pentasulfide, Belleau's reagent, and Davy's reagent, and the like.

[00195] In Scheme 5, the substituent Br of the reaction substrate 5-i in step i may be at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolinyl group, and the substituent Br of the resulting intermediate product and the substituent -CH2-OMs of the product of step 2 are correspondingly at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolinyl group. Ra1, Ra2, Ra3, Ra4, and (Ra5)m are as defined in the compound of Formula (I) and its various sub-embodiments in the present disclosure.

[00196] In some embodiments of scheme 5, at least one of Z1, Z2, Z3, and Z4 in the compound of Formula (I) represents C(S). In some embodiments, at least two of Z1, Z2, Z3, and Z4 in the compound of Formula (I) represent C(S). In some embodiments, at least three of Z1, Z2, Z3, and Z4 represent C(S). In some embodiments, all of Z1, Z2, Z3, and Z4 represent C(S).

[00197] Depending upon the target compounds, the above schemes and their reaction substrates, reaction conditions (including reaction dosage, temperature, duration, etc.), work up, etc. can be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compounds. The obtained target compounds can be further modified by the substituents and the like to obtain subsequent target compounds through methods well known to those skilled in the art. Examples

[00198] Intermediate Example 1: Preparation of 3-(5-(hydroxymethyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GTC00170)

[00199] The target compound (GTC00170) was prepared by referring to the method of Scheme 5.

[00200] Step 1: To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20 g, 61.891 mmol) in 1,4-dioxane (200 mL) was added Lawesson's reagent (11.26 g, 27.851 mmol). The reaction mixture was stirred at 110°C for 12 hours. After monitoring the reaction via TLC and confirming its completion, the reaction mixture was concentrated, and the residue was purified by column chromatography to afford 3-(5-bromo-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (10 g, 29.480 mmol, yield 47.64%) as an off-white solid.

[00201] Step 2: To a solution of 3-(5-bromo-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (6 g, 17.688 mmol) and (tributyl-^4-stannyl)methanol (8.52 g, 26.532 mmol) in 1,4-dioxane (60 mL) was added XPhos Pd G3 (0.1 g, 0.147 mmol). The reaction mixture was stirred at 100°C for 3 hours under an argon atmosphere. The reaction mixture was concentrated, and the residue was purified by column chromatography to afford 3-(5-(hydroxymethyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (1 g, yield 19.46%) as a gray solid. 1H NMR (400 MHz, DMSO) 5 11.17 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 6.09 - 5.91 (m, 1H), 5.49 (t, J = 5.7 Hz, 1H), 4.91 - 4.67 (m, 4H), 3.13 - 2.93 (m, 1H), 2.79 - 2.58 (m, 2H), 2.16 (dd, J = 8.9, 3.6 Hz, 1H). LCMS (ESI) calcd. for C14H15N2O3S+ [M+H]+: 291.08, found, 291.0.

[00202] Intermediate Example 2: Preparation of 3-(4-(hydroxymethyl)-1-thioxoisoindolin-2- yl)piperidine-2,6-dione (GTC00504)

[00203] With reference to the method of Scheme 5 or Intermediate Example 1, the target compound (GTC00504) was obtained as a gray solid (0.8 g, yield 33.32%). 1HNMR (400 MHz, DMSO) 8 11.12 (s, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 5.98 (d, J = 8.3 Hz, 1H), 5.37 (d, J = 5.4 Hz, 1H), 4.79 (dd, J = 49.7, 20.2 Hz, 2H), 4.65 (d, J = 4.1 Hz, 2H), 2.96 (s, 1H), 2.64 (d, J = 18.4 Hz, 2H), 2.09 (dd, J = 8.9, 3.5 Hz, 1H). LCMS (ESI) calcd. for C14H15N2O3S+ [M+H]+: 291.08, found, 291.0.

[00204] Intermediate Example 3: Preparation of 3-(6-(hydroxymethyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GTC00505)

[00205] With reference to the method of Scheme 5 or Intermediate Example 1, the target compound (GTC00505) was obtained as a gray solid (1 g, yield 38.91%). 1HNMR (400 MHz, DMSO) 8 11.06 (d, J = 31.4 Hz, 1H), 7.86 (d, J = 19.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 5.95 (d, J = 8.9 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.82 - 4.60 (m, 4H), 3.00 - 2.90 (m, 1H), 2.64 (d, J = 17.9 Hz, 1H), 2.54 (s, 1H), 2.16 - 2.05 (m, 1H). LCMS (ESI) calcd. for CMH15N2O3S+ [M+H]+: 291.08, found, 291.0.

[00206] Intermediate Example 4: Preparation of (2-(2,6-dioxopiperidin-3-yl)-1-thioxoisoindolin-5-yl)methyl methanesulfonate (GTC00505) MsO'

[00207] With reference to the method of Scheme 5 or Intermediate Example 1, the target compound (GTC00505) was obtained as a gray solid (1 g, yield 38.91%). 1HNMR (400 MHz, DMSO) 8 11.06 (d, J = 31.4 Hz, 1H), 7.86 (d, J = 19.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 5.95 (d, J = 8.9 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.82 - 4.60 (m, 4H), 3.00 - 2.90 (m, 1H), 2.64 (d, J = 17.9 Hz, 1H), 2.54 (s, 1H), 2.16 - 2.05 (m, 1H). LCMS (ESI) calcd. for C14H15N2O3S+ [M+H]+: 291.08, found, 291.0.

[00208] Example 1: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04329)

[00209] With reference to the method of Scheme 1, the target compound (GT-04329) was obtained as a white solid (28 mg, yield 37%). 1H NMR (400 MHz, MeOD) 8 7.82 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.61 - 7.50 (m, 4H), 7.32 - 7.29 (m, 4H), 7.25 - 7.22 (m, 2H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 5.04 - 4.88 (m, 1H), 4.48 - 4.40 (m, 4H), 3.60 - 3.56 (m, 2H), 3.51 - 3.42 (m, 5H), 3.18 - 3.01 (m, 5H), 2.88 - 2.67 (m, 2H), 2.48 - 2.23 (m, 4H), 2.17 - 1.97 (m, 3H). LCMS (ESI) calcd. for C36H42N5O3+ [M+H]+: 592.23, found, 592.3.

[00210] Example 2: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)- 4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04330)

[00211] With reference to the method of Scheme 1, the target compound (GT-04330) was obtained as a white solid (34 mg, yield 43%). 1H NMR (400 MHz, MeOD) 5 7.76 - 7.70 (m, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.58 - 7.55 (m, 4H), 7.33 - 7.29 (m, 4H), 7.25 - 7.22 (m, 2H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 5.04 - 4.89 (m, 1H), 4.60 - 4.48 (m, 4H), 3.70 - 3.61 (m, 2H), 3.59 - 3.40 (m, 5H), 3.20 - 2.98 (m, 6H), 2.91 - 2.75 (m, 1H), 2.73 - 2.66 (m, 1H), 2.51 - 2.39 (m, 1H), 2.38 - 2.31 (m, 2H), 2.17 -1.95 (m, 3H). LCMS (ESI) calcd. for C36H41FN5O3+ [M+H]+: 610.32, found, 610.3.

[00212] Example 3: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04331)

[00213] With reference to the method of Scheme 1, the target compound (GT-04331) was obtained as a white solid (34 mg, yield 43%). 1H NMR (400 MHz, MeOD) 5 7.82 (d, J = 6.0 Hz, 1H), 7.65 - 7.50 (m, 5H), 7.35 - 7.29 (m, 4H), 7.25 - 7.22 (m, 2H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 5.04 - 4.89 (m, 1H), 4.55 - 4.36 (m, 4H), 3.68 - 3.62 (m, 2H), 3.57 - 3.38 (m, 5H), 3.20 - 2.94 (m, 6H), 2.88 - 2.75 (m, 1H), 2.72 - 2.66 (m, 1H), 2.49 - 2.26 (m, 3H), 2.12 - 2.03 (m, 3H). LCMS (ESI) calcd. for C36H41FN5O3+ [M+H]+: 610.32, found, 610.3.

[00214] Example 4: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04597)

[00215] With reference to the method of Scheme 1, the target compound (GT-04597) was obtained as a white solid (39 mg, yield 45%). 1H NMR (400 MHz, MeOD) 5 7.54 (s, 1H), 7.52 - 7.40 (m, 4H), 7.37 (d, J = 9.6 Hz, 1H), 7.27 (t, J = 6.9 Hz, 4H), 7.23 - 7.16 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.71 (s, 2H), 4.48 (q, J = 17.9 Hz, 2H), 4.39 (s, 2H), 3.60 - 3.54 (m, 2H), 3.41 - 3.23 (m, 5H), 3.14 -3.06 (m, 3H), 3.01 - 2.92 (m, 1H), 2.89 - 2.76 (m, 2H), 2.69 (d, J = 15.5 Hz, 1H), 2.48 - 2.36 (m, 1H), 2.36 - 2.22 (m, 2H), 2.16 - 1.88 (m, 3H). LCMS (ESI) calcd. for C36H41FN5O3+ [M+H]+: 610.32, found, 610.3.

[00216] Example 5: Preparation of 3-(4-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04598)

[00217] With reference to the method of Scheme 1, the target compound (GT-04598) was obtained as a white solid (46 mg, yield 54%). 1H NMR (400 MHz, MeOD) 5 7.97 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63 - 7.52 (m, 4H), 7.41 - 7.37 (m, 4H), 7.34 - 7.21 (m, 2H), 5.24 (dd, J = 13.4, 5.1 Hz, 1H), 4.80 (d, J = 17.4 Hz, 1H), 4.67 (d, J = 17.4 Hz, 1H), 4.58 - 4.42 (m, 2H), 3.82 - 3.65 (m, 2H), 3.56 - 3.49 (m, 1H), 3.46 - 3.37 (m, 4H), 3.32 - 3.27 (m, 5H), 3.26 - 3.20 (m, 1H), 3.03 - 2.90 (m, 2H), 2.83 (d, J = 15.8 Hz, 1H), 2.61 - 2.53 (m, 1H), 2.46 - 2.38 (m, 2H), 2.31 - 2.20 (m, 1H), 2.18 - 2.09 (m, 2H). LCMS (ESI) calcd. for C36H42N5O3+ [M+H]+: 592.33, found, 592.3.

[00218] Example 6: Preparation of 3-(6-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04599)

[00219] With reference to the method of Scheme 1, the target compound (GT-04599) was obtained as a white solid (8 mg, yield 9%). 1H NMR (400 MHz, MeOD) 5 7.98 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 6.3 Hz, 4H), 7.40 (t, J = 7.2 Hz, 4H), 7.34 - 7.32 (m, 2H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 - 4.52 (m, 4H), 3.70 - 3.67 (m, 2H), 3.61 - 3.40 (m, 6H), 3.24 - 3.05 (m, 5H), 3.03 - 2.86 (m, 2H), 2.87 - 2.75 (m, 1H), 2.59 - 2.51 (m, 1H), 2.48 - 2.41 (m, 2H), 2.28 -2.16 (m, 1H), 2.14 - 2.03 (m, 2H). LCMS (ESI) calcd. for C36H42N5O3+ [M+H]+: 592.33, found, 592.3.

[00220] Example 7: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04376)

[00221] With reference to the method of Scheme 1, the target compound (GT-04376) was obtained as a white solid (31 mg, yield 45%). 1H NMR (400 MHz, MeOD) 5 7.82 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.60 - 7.58 (m, 5H), 7.40 - 7.37 (m, 4H), 7.34 - 7.30 (m, 2H), 5.36 (s, 1H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 4.56 - 4.36 (m, 4H), 3.68 - 3.61 (m, 1H), 3.53 - 3.50 (m, 1H), 3.43 - 3.31 (m, 2H), 3.14 - 3.09 (m, 9H), 2.88 - 2.78 (m, 1H), 2.73 - 2.65 (m, 1H), 2.44 - 2.31 (m, 1H), 2.17 - 2.01 (m, 3H). LCMS (ESI) calcd. for C36H40F2N5O3+ [M+H]+: 628.31, found, 628.3.

[00222] Example 8: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04377)

[00223] With reference to the method of Scheme 1, the target compound (GT-04377) was obtained as a white solid (41 mg, yield 58%). 1H NMR (400 MHz, MeOD) 5 7.68 - 7.62 (m, 2H), 7.59 - 7.55 (m, 4H), 7.40 - 7.36 (m, 4H), 7.34 - 7.30 (m, 2H), 5.35 (s, 1H), 5.08 (dd, J = 13.4, 5.1 Hz, 1H), 4.62 -4.44 (m, 3H), 4.36 (brs, 2H), 3.70 - 3.62 (m, 1H), 3.53 - 3.40 (m, 1H), 3.35 - 3.28 (m, 1H), 3.16 -3.01 (m, 9H), 2.87 - 2.78 (m, 1H), 2.74 - 2.64 (m, 1H), 2.48 - 2.38 (m, 1H), 2.16 - 1.99 (m, 3H). LCMS (ESI) calcd. for C36H39F3N5O3+ [M+H]+: 646.30, found, 646.3.

[00224] Example 9: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04378)

[00225] With reference to the method of Scheme 1, the target compound (GT-04378) was obtained as a white solid (40 mg, yield 57%). 1H NMR (400 MHz, MeOD) 5 7.74 (d, J = 5.9 Hz, 1H), 7.60 - 7.58 (m, 4H), 7.54 (d, J = 8.6 Hz, 1H), 7.40 - 7.36 (m, 4H), 7.35 - 7.29 (m, 2H), 5.35 (s, 1H), 5.12 - 5.03 (m, 1H), 4.53 - 4.39 (m, 2H), 4.36 (brs, 2H), 3.68 - 3.59 (m, 1H), 3.53 - 3.39 (m, 1H), 3.36 - 3.23 (m, 2H), 3.20 - 2.93 (m, 9H), 2.88 - 2.76 (m, 1H), 2.74 - 2.64 (m, 1H), 2.43 - 2.36 (m, 1H), 2.15 - 1.97 (m, 3H). LCMS (ESI) calcd. for C36H39F3N5O3+ [M+H]+: 646.30, found, 646.3.

[00226] Example 10: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04379)

[00227] With reference to the method of Scheme 1, the target compound (GT-04379) was obtained as a white solid (35 mg, yield 50%). 1H NMR (400 MHz, MeOD) 5 7.57 (d, J = 7.4 Hz, 4H), 7.42 - 7.36 (m, 5H), 7.34 - 7.32 (m, 2H), 7.29 - 7.23 (m, 1H), 5.35 (s, 1H), 5.03 (dd, J = 13.2, 6.6 Hz, 1H), 4.53 - 4.34 (m, 2H), 4.16 (brs, 2H), 3.48 - 3.39 (m, 1H), 3.33 - 3.22 (m, 2H), 3.20 - 2.95 (m, 9H), 2.82 - 2.77 (m, 2H), 2.74 - 2.63 (m, 1H), 2.44 - 2.33 (m, 1H), 2.10 - 1.94 (m, 3H). LCMS (ESI) calcd. for C36H39F3N5O3+ [M+H]+: 646.30, found, 646.3.

[00228] Example 11: Preparation of 3-(4-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04380)

[00229] With reference to the method of Scheme 1, the target compound (GT-04380) was obtained as a white solid (19 mg, yield 28%). 1H NMR (400 MHz, MeOD) 5 7.79 - 7.77 (m, 1H), 7.65 (t, J = 7.0 Hz, 1H), 7.60 - 7.55 (m, 4H), 7.54 - 7.50 (m, 1H), 7.40 - 7.36 (m, 4H), 7.35 - 7.28 (m, 2H), 5.35 (brs, 1H), 5.18 - 5.04 (m, 1H), 4.68 - 4.47 (m, 2H), 4.31 - 4.03 (m, 2H), 3.52 - 3.43 (m, 1H), 3.41 - 3.25 (m, 2H), 3.20 - 2.94 (m, 9H), 2.94 - 2.75 (m, 2H), 2.72 - 2.68 (m, 1H), 2.51 - 2.29 (m, 1H), 2.19 -2.06 (m, 1H), 2.06 - 1.90 (m, 2H). LCMS (ESI) calcd. for C36H40F2N5O3+ [M+H]+: 628.31, found, 628.3.

[00230] Example 12: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-5037)

[00231] With reference to the method of Scheme 1, the target compound (GT-5037) was obtained as a white solid (49 mg, yield 52%). 1H NMR (400 MHz, DMSO-d6) 5 11.00 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.87 - 7.78 (m, 2H), 7.74 - 7.70 (m, 4H), 7.50 - 7.36 (m, 4H), 5.89 (s, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.52 - 4.36 (m, 4H), 3.63 - 3.52 (m, 4H), 3.47 - 3.23 (m, 4H), 3.21 -3.12 (m, 4H), 2.98 - 2.82 (m, 2H), 2.61 (d, J = 16.8 Hz, 1H), 2.43 (dd, J = 13.2, 4.5 Hz, 1H), 2.26 -2.09 (m, 1H), 2.03 - 1.99 (m, 2H). LCMS (ESI) calcd. for C35H39F2N6O3+ [M+H]+: 629.30, found, 629.3.

[00232] Example 13: Preparation of 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04595)

[00233] With reference to the method of Scheme 1, the target compound (GT-04595) was obtained as a white solid (16 mg, yield 35%). 1H NMR (400 MHz, MeOD) 5 7.91 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.20 (dd, J = 13.4, 5.0 Hz, 1H), 4.64 - 4.50 (m, 2H), 4.43 - 4.25 (m, 2H), 3.65 - 3.56 (m, 2H), 3.31 - 3.09 (m, 6H), 3.01 - 2.86 (m, 3H), 2.84 - 2.78 (m, 2H), 2.72 - 2.66 (m, 1H), 2.59 - 2.44 (m, 4H), 2.28 - 2.11 (m, 2H), 2.09 -1.93 (m, 3H), 1.62 - 1.48 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H). LCMS (ESI) calcd. for C38H45ClF2N5O4+ [M+H]+: 708.31, found, 708.3.

[00234] Example 14: Preparation of 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04596)

[00235] With reference to the method of Scheme 1, the target compound (GT-04596) was obtained as a white solid (17 mg, yield 37%). 1H NMR (400 MHz, MeOD) 5 7.77 - 7.68 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 5.20 (dd, J = 13.3, 5.0 Hz, 1H), 4.63 (q, J = 17.3 Hz, 2H), 4.33 -4.21 (m, 2H), 3.66 - 3.56 (m, 2H), 3.47 - 3.39 (m, 3H), 3.29 - 3.18 (m, 2H), 3.07 - 2.88 (m, 3H), 2.85 - 2.78(m, 3H), 2.70 - 2.42 (m, 4H), 2.29 - 2.14 (m, 2H), 2.04 - 1.95 (m, 4H), 1.57 - 1.52 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H). LCMS (ESI) calcd. for C38H44ClF3N5O4+ [M+H]+: 726.30, found, 726.3.

[00236] Example 15: Preparation of 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-05160)

[00237] With reference to the method of Scheme 1, the target compound (GT-05160) was obtained as a white solid (50 mg, yield 48%). 1H NMR (400 MHz, DMSO-d6) 5 11.01 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.60 - 7.54 (m, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.48 (d, J = 16.8 Hz, 1H), 4.35 (d, J = 16.8 Hz, 1H), 4.15 - 3.87 (m, 1H), 3.55 (brs, 3H), 3.28 - 3.20 (m, 3H), 3.05 - 2.97 (m, 4H), 2.91 - 2.82 (m, 4H), 2.66 - 2.59 (m, 4H), 2.47 - 2.36 (m, 1H), 2.34 - 2.21 (m, 3H), 2.02 (brs, 3H), 1.96 - 1.84 (m, 1H), 1.83 - 1.73 (m, 1H), 1.44(m, 2H), 0.96 (s, 6H). LCMS (ESI) calcd. for C38H47ClF2N5O3+ [M+H]+: 694.33, found, 694.4.

[00238] Example 16: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04604)

[00239] With reference to the method of Scheme 1, the target compound (GT-04604) was obtained as a white solid (29 mg, yield 33%). 1H NMR (400 MHz, MeOD) 5 7.94 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.17 - 7.15 (m, 1H), 5.19 (dd, J = 13.7, 4.9 Hz, 1H), 4.64 - 4.46 (m, 4H), 3.79 - 3.58 (m, 7H), 3.50 - 3.43 (m, 2H), 3.20 - 3.13 (m, 4H), 3.01 - 2.86 (m, 1H), 2.84 - 2.78 (m, 1H), 2.60 - 2.45 (m, 3H), 2.25 - 2.12 (m, 3H). LCMS (ESI) calcd. for C29H34Cl2N5O3+ [M+H]+: 570.20, found, 570.2.

[00240] Example 17: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04605)

[00241] With reference to the method of Scheme 1, the target compound (GT-04605) was obtained as a white solid (30 mg, yield 34%). 1H NMR (400 MHz, MeOD) 5 7.82 - 7.77 (m, 2H), 7.35 - 7.27 (m, 2H), 7.18 - 7.16 (m, 1H), 5.19 (dd, J = 13.4, 5.2 Hz, 1H), 4.72 - 4.50 (m, 4H), 3.78 - 3.73 (m, 3H), 3.68 - 3.54 (m, 4H), 3.49 - 3.47 (m, 2H), 3.28 - 3.11 (m, 4H), 3.02 - 2.85 (m, 2H), 2.84 - 2.74 (m, 1H), 2.59 - 2.44 (m, 3H), 2.22 - 2.13 (m, 3H). LCMS (ESI) calcd. for C29H33Cl2FN5O3+ [M+H]+: 588.19, found, 588.2.

[00242] Example 18: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04606)

[00243] With reference to the method of Scheme 1, the target compound (GT-04606) was obtained as a white solid (23 mg, yield 26%). 1H NMR (400 MHz, MeOD) 5 7.93 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.19 (dd, J = 7.1, 2.5 Hz, 1H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 - 4.46 (m, 4H), 3.83 - 3.72 (m, 3H), 3.68 - 3.59 (m, 4H), 3.52 - 3.41 (m, 2H), 3.30 - 3.12 (m, 4H), 2.97 - 2.88 (m, 1H), 2.85 - 2.78 (m, 1H), 2.57 - 2.50 (m, 3H), 2.30 - 2.13 (m, 3H). LCMS (ESI) calcd. for C29H33Cl2FN5O3+ [M+H]+: 588.19, found, 588.2.

[00244] Example 19: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04607)

[00245] With reference to the method of Scheme 1, the target compound (GT-04607) was obtained as a white solid (25 mg, yield 28%). 1H NMR (400 MHz, MeOD) 5 7.64 (s, 1H), 7.46 (d, J = 9.6 Hz, 1H), 7.33 - 7.32 (m, 2H), 7.20 - 7.16 (m, 2H), 5.21 - 5.14 (m, 1H), 4.58 (d, J = 8.2 Hz, 2H), 4.50 - 4.48 (m, 3H), 3.74 - 3.62 (m, 6H), 3.22 - 3.18 (m, 4H), 3.04 - 2.71 (m, 4H), 2.52 - 2.49 (m, 4H), 2.23 -2.16 (m, 4H). LCMS (ESI) calcd. for C29H33Cl2FN5O3+ [M+H]+: 588.19, found, 588.2.

[00246] Example 20: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04609)

[00247] With reference to the method of Scheme 1, the target compound (GT-04609) was obtained as a white solid (8 mg, yield 10%). 1H NMR (400 MHz, MeOD) 5 7.96 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.18 - 7.16 (m, 1H), 5.23 (dd, J = 13.2, 5.2 Hz, 1H), 4.68 (d, J = 17.4 Hz, 1H), 4.52 - 4.49 (m, 2H), 3.84 - 3.66 (m, 5H), 3.59 - 3.57 (m, 2H), 3.46 - 3.32 (m, 5H), 3.24 - 3.18 (m, 2H), 3.03 - 2.89 (m, 1H), 2.84 - 2.81 (m, 1H), 2.60 - 2.47 (m, 3H), 2.38 - 2.16 (m, 3H). LCMS (ESI) calcd. for C29H34Cl2N5O3+ [M+H]+: 570.20, found, 570.2.

[00248] Example 21: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04608)

[00249] With reference to the method of Scheme 1, the target compound (GT-04608) was obtained as a white solid (5 mg, yield 6%). 1H NMR (400 MHz, MeOD) 5 7.89 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.08 (dd, J = 6.4, 2.9 Hz, 1H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 4.47 (dd, J = 31.5, 17.7 Hz, 2H), 4.38 - 4.32 (m, 2H), 3.61 - 3.50 (m, 2H), 3.48 - 3.25 (m, 8H), 3.06 - 2.91 (m, 3H), 2.83 - 2.78 (m, 1H), 2.74 - 2.65 (m, 1H), 2.46 - 2.39 (m, 1H), 2.38 - 2.33 (m, 2H), 2.11 - 2.07 (m, 1H), 2.04 - 1.90 (m, 2H). LCMS (ESI) calcd. for C29H34Cl2N5O3+ [M+H]+: 570.20, found, 570.2.

[00250] Example 22: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-05212)

[00251] With reference to the method of Scheme 1, the target compound (GT-05212) was obtained as a white solid (23 mg, 25%). 1H NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.66 - 7.58 (m, 1H), 7.39 - 7.33 (m, 2H), 7.18 - 7.16 (m, 1H), 5.14 (dd, J = 13.1, 5.2 Hz, 1H), 4.90 (s, 1H), 4.51 (d, J = 17.2 Hz, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.27 - 4.06 (m, 2H), 3.35 - 3.08 (m, 10H), 3.00 - 2.84 (m, 2H), 2.82 - 2.65 (m, 1H), 2.61 (d, J = 16.9 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.33 - 2.30 (m, 1H), 2.25 - 2.09 (m, 1H), 2.08 - 1.95 (m, 1H). LCMS (ESI) calcd. for C29H32Cl2F2N5O3+ [M+H]+: 606.18, found, 606.2.

[00252] Example 23: Preparation of 3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1- yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04989)

[00253] With reference to the method of Scheme 1, the target compound (GT-04989) was obtained as a white solid (14 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 5 11.52 (s, 1H), 11.02 (s, 1H), 8.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.74 - 7.71 (m, 1H), 7.61 (dd, J = 9.1, 2.1 Hz, 1H), 7.28 -7.23 (m, 1H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.63 - 4.33 (m, 5H), 4.24 - 4.01 (m, 2H), 3.69 - 3.39 (m, 8H), 3.08 - 3.04 (m, 1H), 3.04 - 2.85 (m, 3H), 2.61 (d, J = 15.4 Hz, 1H), 2.47 - 2.41 (m, 1H), 2.39 - 2.32 (m, 2H), 2.28 - 2.09 (m, 2H), 2.03 - 1.98 (m, 1H). LCMS (ESI) calcd. for C30H34FN6O4+ [M+H]+: 561.26, found, 561.3.

[00254] Example 24: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04931)

[00255] With reference to the method of Scheme 1, the target compound (GT-04931) was obtained as a white solid (23 mg, 26%). 1H NMR (400 MHz, DMSO) 5 11.01 (s, 1H), 8.05 (dd, J = 8.9, 5.2 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.70 (dd, J = 16.6, 7.1 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.21 (td, J = 9.1, 2.1 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (d, J = 17.0 Hz, 1H), 4.37 (d, J = 17.2 Hz, 1H), 4.14 (dd, J = 48.4, 14.3 Hz, 1H), 3.83 - 3.57 (m, 6H), 3.36 - 2.99 (m, 6H), 2.99 - 2.84 (m, 2H), 2.61 (d, J = 16.6 Hz, 1H), 2.42 (dd, J = 13.3, 4.5 Hz, 2H), 2.25 - 1.93 (m, 3H). LCMS (ESI) calcd. for C30H32F3N6O4+ [M+H]+: 597.24, found, 597.3.

[00256] Example 25: Preparation of 3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04932)

[00257] With reference to the method of Scheme 1, the target compound (GT-04932) was obtained as a white solid (32 mg, 36%). 1H NMR (400 MHz, DMSO) 5 11.00 (s, 1H), 8.25 (s, 1H), 7.80 - 7.69 (m, 2H), 7.63 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.34 (td, J = 9.1, 2.1 Hz, 1H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.36 (d, J = 17.5 Hz, 1H), 4.21 - 4.04 (m, 1H), 3.99 - 3.90 (m, 4H), 3.64 - 3.50 (m, 3H), 3.48 - 3.35 (m, 3H), 3.22 - 3.10 (m, 1H), 3.00 - 2.85 (m, 1H), 2.85 - 2.67 (m, 1H), 2.61 (d, J = 16.8 Hz, 2H), 2.47 - 2.31 (m, 3H), 2.26 - 2.14 (m, 3H), 2.07 - 1.92 (m, 1H). LCMS (ESI) calcd. for C31H33F3N5O4+ [M+H]+: 596.25, found, 596.3.

[00258] Example 26: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-05105)

[00259] With reference to the method of Scheme 1, the target compound (GT-05105) was obtained as a white solid (12 mg, 10%). 1H NMR (400 MHz, DMSO-d6) 5 11.14 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.88 - 7.79 (m, 4H), 7.60 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.47 - 7.43 (m, 4H), 7.41 - 7.34 (m, 2H), 6.05 - 5.86 (m, 2H), 5.62 - 5.59 (m, 1H), 4.80 (d, J = 9.3 Hz, 1H), 4.70 (t, J = 10.3 Hz, 1H), 3.21 -3.08 (m, 6H), 3.08 - 2.89 (m, 8H), 2.65 (d, J = 17.9 Hz, 2H), 2.12 - 2.06 (m, 2H), 1.97 - 1.74 (m, 2H). LCMS (ESI) calcd. for C36H40F2N5O2S+ [M+H]+: 644.29, found, 644.3.

[00260] Example 27: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-05208)

[00261] With reference to the method of Scheme 1, the target compound (GT-05208) was obtained as a white solid (20 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 5 11.15 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 7.95 - 7.91 (m, 2H), 7.84 - 7.81 (m, 1H), 7.72 - 7.67 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H), 7.53 - 7.36 (m, 4H), 6.04 - 5.85 (m, 1H), 4.94 - 4.81 (m, 1H), 4.75 - 4.70 (m, 1H), 4.48 - 4.15 (m, 2H), 3.36 -3.19 (m, 5H), 3.11 - 3.03 (m, 8H), 2.98 - 2.80 (m, 2H), 2.68 - 2.63 (m, 1H), 2.18 - 1.88 (m, 3H), 1.32 (t, J = 6.5 Hz, 1H). LCMS (ESI) calcd. for C35H39F2N6O2S+ [M+H]+: 645.28, found, 645.3.

[00262] Example 28: Preparation of 3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-05042)

[00263] With reference to the method of Scheme 1, the target compound (GT-05042) was obtained as a white solid (11 mg, 9%). 1H NMR (400 MHz, DMSO-d6) 5 11.15 (s, 1H), 8.74 (d, J = 4.6 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.71 - 7.67 (m, 4H), 7.67 - 7.62 (m, 1H), 7.49 - 7.43 (m, 4H), 5.95 - 5.86 (m, 1H), 4.90 - 4.85 (m, 1H), 4.73 - 4.62 (m, 1H), 4.48 - 4.34 (m, 2H), 3.16 - 3.05 (m, 6H), 2.98 - 2.82 (m, 4H), 2.66 (d, J = 16.7 Hz, 2H), 2.15 - 1.96 (m, 5H), 1.34 - 1.31 (m, 4H). LCMS (ESI) calcd. for C35H39F2N6O2S+ [M+H]+: 645.28, found, 645.3.

[00264] Example 29: Preparation of 1-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-04941)

[00265] With reference to the method of Scheme 1, the target compound (GT-04941) was obtained as a white solid (15 mg, 18%). 1H NMR (400 MHz, DMSO) 5 10.69 (s, 1H), 7.91 - 7.82 (m, 2H), 7.75 (d, J = 7.4 Hz, 1H), 7.53 - 7.43 (m, 4H), 7.38 - 7.31 (m, 4H), 7.27 - 7.21 (m, 2H), 4.80 (d, J = 17.0 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.42 (brs, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.67 - 3.47 (m, 7H), 3.14 - 3.06 (m, 2H), 3.03 - 2.73 (m, 7H), 2.33 - 2.22 (m, 2H), 2.17 - 2.06 (m, 2H). LCMS (ESI) calcd. for C35H41N6O3+ [M+H]+: 593.32, found, 593.3.

[00266] Example 30: Preparation of 5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione (GT-05255)

[00267] With reference to the method of Scheme 1, the target compound (GT-05255) was obtained as a white solid (34 mg, 37%). 1H NMR (400 MHz, DMSO-d6) 5 10.93 (s, 1H), 8.15 - 8.10 (m, 1H), 7.65 - 7.44 (m, 4H), 7.40 - 7.31 (m, 5H), 7.31 - 7.14 (m, 3H), 4.52 - 4.41 (m, 2H), 3.82 (t, J = 6.7 Hz, 1H), 3.63 - 3.48 (m, 4H), 3.27 - 3.13 (m, 4H), 3.06 - 2.94 (m, 3H), 2.90 - 2.83 (m, 4H), 2.35 - 2.22 (m, 3H), 2.14 - 2.04 (m, 2H), 1.96 - 1.85 (m, 1H). LCMS (ESI) calcd. for C35H39N6O4+ [M+H]+: 607.30, found, 607.3.

[00268] Example 31: Preparation of 1-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-04942)

[00269] With reference to the method of Scheme 1, the target compound (GT-04942) was obtained as a white solid (22 mg, 24%). 1H NMR (400 MHz, DMSO) 5 10.67 (s, 1H), 7.92 - 7.76 (m, 5H), 7.74 -7.63 (m, 1H), 7.63 - 7.52 (m, 1H), 7.45 - 7.42 (m, 4H), 7.40 - 7.31 (m, 2H), 5.59 (d, J = 9.0 Hz, 1H), 4.77 (d, J = 16.4 Hz, 1H), 4.55 (d, J = 16.1 Hz, 1H), 3.80 - 3.76 (m, 3H), 3.28 - 3.19 (m, 4H), 3.14 -3.10 (m, 3H), 3.05 - 2.96 (m, 5H), 2.93 - 2.81 (m, 2H), 2.78 - 2.72 (m, 2H), 1.99 - 1.81 (m, 2H). LCMS (ESI) calcd. for C35H39F2N6O3+ [M+H]+: 629.30, found, 629.3.

[00270] Example 32: Preparation of 5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione (GT-05256)

[00271] With reference to the method of Scheme 1, the target compound (GT-05256) was obtained as a white solid (22 mg, 23%). 1H NMR (400 MHz, DMSO-d6) 5 10.91 (s, 1H), 8.08 - 8.00 (m, 2H), 7.98 - 7.95 (m, 1H), 7.90 - 7.79 (m, 4H), 7.44 (t, J = 7.4 Hz, 4H), 7.38 - 7.35 (m, 2H), 5.59 (brs, 1H), 4.20 - 4.04 (m, 2H), 3.65 - 3.61 (m, 4H), 3.27 - 3.17 (m, 4H), 3.18 - 3.08 (m, 4H), 3.06 - 2.98 (m, 5H), 2.02 - 1.78 (m, 2H). LCMS (ESI) calcd. for C35H37F2N6O4+ [M+H]+: 643.28, found, 643.3.

[00272] Example 33: Preparation of 1-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-05082)

[00273] With reference to the method of Scheme 1, the target compound (GT-05082) was obtained as a white solid (80 mg, 71%). 1H NMR (400 MHz, DMSO-d6) 5 10.69 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.85 - 7.80 (m, 2H), 7.76 - 7.61 (m, 4H), 7.44 - 7.40 (m, 4H), 5.87 (s, 1H), 4.80 (d, J = 16.7 Hz, 1H), 4.57 (d, J = 16.5 Hz, 1H), 4.31 (brs, 2H), 3.80 - 3.77 (m, 4H), 3.23 - 3.10 (m, 4H), 3.10 - 2.97 (m, 6H), 2.88 - 2.81 (m, 2H), 2.79 - 2.73 (m, 1H), 2.19 - 1.90 (m, 2H). LCMS (ESI) calcd. for C34H38F2N7O3+ [M+H]+: 630.30, found, 630.3.

[00274] Example 34:     Preparation of 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2- yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione (GT-05257)

[00275] With reference to the method of Scheme 1, the target compound (GT-05257) was obtained as a white solid (13 mg, 13%). 1H NMR (400 MHz, DMSO-d6) 5 10.92 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 8.06 (s, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.76 - 7.61 (m, 4H), 7.49 - 7.40 (m, 5H), 5.86 (s, 1H), 4.30 (s, 2H), 3.80 - 3.75 (m, 4H), 3.19 - 3.00 (m, 13H), 2.09 - 1.93 (m, 2H). LCMS (ESI) calcd. for C34H36F2N7O4+ [M+H]+: 644.28, found, 644.3.

[00276] Example 35: Preparation of 1-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-05335)

[00277] With reference to the method of Scheme 1, the target compound (GT-05335) was obtained as a white solid (25 mg, 23%). 1H NMR (400 MHz, DMSO-d6) 5 10.68 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.78 (d, J = 17.1 Hz, 1H), 4.56 (d, J = 16.9 Hz, 1H), 4.36 - 3.92 (m, 2H), 3.78 (t, J = 6.1 Hz, 3H), 3.25 - 3.17 (m, 7H), 3.07 - 2.95 (m, 2H), 2.94 - 2.82 (m, 2H), 2.79 - 2.73 (m, 2H), 2.44 - 2.33 (m, 3H), 2.18 - 2.00 (m, 1H), 1.96 - 1.89 (m, 2H), 1.83 - 1.72 (m, 2H), 1.50 - 1.34 (m, 2H), 1.00 (s, 3H), 0.97 (s, 3H). LCMS (ESI) calcd. for C37H44F2N6O4+ [M+H]+: 709.31, found, 709.3.

[00278] Example 36: Preparation of 5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione (GT-05271)

[00279] With reference to the method of Scheme 1, the target compound (GT-05271) was obtained as a white solid (20 mg, 19%). 1H NMR (400 MHz, DMSO-d6) 5 10.92 (s, 1H), 8.08 - 8.01 (m, 2H), 7.93 - 7.90 (m, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.12 - 3.96 (m, 3H), 3.33 - 3.13 (m, 9H), 3.12 - 2.96 (m, 4H), 2.69 - 2.57 (m, 2H), 2.42 - 2.37 (m, 3H), 2.19 - 2.04 (m, 1H), 1.90 (d, J = 16.6 Hz, 1H), 1.82 - 1.70 (m, 3H), 1.50 - 1.35 (m, 2H), 1.00 (s, 3H), 0.97 (s, 3H). LCMS (ESI) calcd. for C37H42ClF2N6O5+ [M+H]+: 723.29, found, 723.3.

[00280] Example 37: Preparation of 5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione (GT-05270)

[00281] With reference to the method of Scheme 1, the target compound (GT-05270) was obtained as a white solid (26 mg, 25%). 1H NMR (400 MHz, DMSO-d6) 5 10.92 (s, 1H), 8.04 - 8.00 (m, 2H), 7.98 - 7.90 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.99 (s, 1H), 3.82 (t, J = 6.7 Hz, 4H), 3.27 - 3.19 (m, 6H), 3.12 - 2.96 (m, 6H), 2.86 (t, J = 6.7 Hz, 4H), 2.70 - 2.57 (m, 3H), 2.29 (brs, 2H), 2.04 (brs, 2H), 1.47 (t, J = 6.8 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) calcd. for C37H44ClF2N6O4+ [M+H]+: 709.31, found, 709.3.

[00282] Example 38: Preparation of 5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione (GT-05258)

[00283] With reference to the method of Scheme 1, the target compound (GT-05258) was obtained as a white solid (16 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 5 10.92 (s, 1H), 8.02 (s, 2H), 7.94 - 7.92 (m, 1H), 7.36 - 7.32 (m, 2H), 7.20 - 7.17 (m, 1H), 4.99 (s, 1H), 4.11 - 3.91 (m, 2H), 3.36 - 3.17 (m, 13H), 3.13 - 3.01 (m, 3H), 2.28 -2.18 (m, 1H), 2.09 - 1.89 (m, 1H). LCMS (ESI) calcd. for C28H29Cl2F2N6O4+ [M+H]+: 621.16, found, 621.2.

[00284] Example 39: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-05333)

[00285] With reference to the method of Scheme 1, the target compound (GT-05333) was obtained as a white solid (26 mg, yield 24%). 1H NMR (400 MHz, DMSO) 5 11.01 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.6, 1.3 Hz, 1H), 5.75 (s, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 2H), 4.49 (d, J = 17.9 Hz, 2H), 4.37 (d, J = 17.9 Hz, 2H), 4.10 - 3.82 (m, 5H), 3.43 - 3.39 (m, 4H), 3.23 - 3.14 (m, 1H), 2.96 - 2.89 (m, 2H), 2.67 - 2.63 (m, 2H), 2.47 - 2.39 (m, 2H), 2.07 - 1.98 (m, 2H). LCMS (ESI) calcd. for C3oH3iChF2N4O3+ [M+H]+: 603.17, found, 603.2.

[00286] Example 40: Preparation of 3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09941)

[00287] With reference to the method of Scheme 1, the target compound (GT-09941) was obtained as a white solid (7 mg, yield 11%). 1H NMR (400 MHz, DMSO) 5 11.14 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.40 - 7.30 (m, 4H), 7.24 (brs, 2H), 5.95 (d, J = 8.9 Hz, 1H), 4.87 (d, J = 20.5 Hz, 1H), 4.77 (d, J = 20.4 Hz, 1H), 4.63 (s, 1H), 4.43 (s, 2H), 3.59 - 3.48 (m, 4H), 3.32 - 3.18 (m, 4H), 3.05 - 2.83 (m, 6H), 2.67 - 2.63 (m, 2H), 2.31 - 2.21 (m, 2H), 2.17 - 2.06 (m, 3H). LCMS (ESI) calcd. for C36H42N5O2S+ [M+H]+: 608.31, found, 608.3.

[00288] Example 41: Preparation of 3-(4-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09938)

[00289] With reference to the method of Scheme 1, the target compound (GT-09938) was obtained as a white solid (8 mg, yield 12%). 1H NMR (400 MHz, DMSO) 5 11.20 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.56 - 7.43 (m, 4H), 7.38 - 7.32 (m, 4H), 7.26 - 7.22 (m, 2H), 6.07 - 5.94 (m, 1H), 5.24 (d, J = 20.0 Hz, 1H), 4.88 (d, J = 20.6 Hz, 1H), 4.53 - 4.33 (m, 3H), 3.65 - 3.55 (m, 2H), 3.14 - 3.05 (m, 4H), 2.98 - 2.82 (m, 4H), 2.74 - 2.66 (m, 2H), 2.46 -2.38 (m, 2H), 2.32 - 2.22 (m, 3H), 2.20 - 2.06 (m, 4H). LCMS (ESI) calcd. for C36H42N5O2S+ [M+H]+: 608.31, found, 608.3.

[00290] Example 42: Preparation of 3-(6-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09862)

[00291] With reference to the method of Scheme 1, the target compound (GT-09862) was obtained as a white solid (8 mg, yield 12%). 1H NMR (400 MHz, DMSO) 5 11.14 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.51 - 7.44 (m, 4H), 7.37 - 7.31 (m, 4H), 7.25 - 7.21 (m, 2H), 6.01 - 5.86 (m, 1H), 4.88 (d, J = 20.7 Hz, 1H), 4.74 (d, J = 20.2 Hz, 1H), 4.46 (brs, 3H), 3.56 - 3.51 (m, 2H), 3.13 - 3.04 (m, 2H), 3.03 - 2.92 (m, 4H), 2.89 - 2.80 (m, 2H), 2.67 - 2.62 (m, 2H), 2.45 -2.42 (m, 3H), 2.34 - 2.26 (m, 2H), 2.14 - 1.98 (m, 4H). LCMS (ESI) calcd. for C36H42N5O2S+ [M+H]+: 608.31, found, 608.3.

[00292] Example 43: Preparation of 3-(4-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09617)

[00293] With reference to the method of Scheme 1, the target compound (GT-09617) was obtained as a white solid (12 mg, yield 16%). 1H NMR (400 MHz, DMSO) 5 11.12 (s, 1H), 7.91 - 7.77 (m, 5H), 7.67 - 7.52 (m, 2H), 7.48 - 7.43 (m, 4H), 7.37 - 7.35 (m, 2H), 5.97 (d, J = 10.5 Hz, 1H), 5.60 (d, J = 7.3 Hz, 1H), 4.86 (d, J = 19.2 Hz, 1H), 4.74 (d, J = 18.1 Hz, 1H), 3.89 - 3.67 (m, 1H), 3.26 - 3.09 (m, 6H), 3.08 - 2.94 (m, 7H), 2.65 (d, J = 16.8 Hz, 2H), 2.47 - 2.39 (m, 2H), 2.15 - 2.03 (m, 1H), 1.82 - 1.73 (m, 2H). LCMS (ESI) calcd. for C36H40F2N5O2S+ [M+H]+: 644.29, found, 644.3.

[00294] Example 44: Preparation of 3-(6-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09691)

[00295] With reference to the method of Scheme 1, the target compound (GT-09691) was obtained as a white solid (14 mg, yield 20%). 1H NMR (400 MHz, DMSO) 5 11.06 (s, 1H), 7.95 - 7.84 (m, 1H), 7.81 - 7.66 (m, 4H), 7.61 (s, 2H), 7.44 - 7.33 (m, 4H), 7.34 - 7.23 (m, 2H), 5.93 - 5.82 (m, 1H), 5.57 - 5.47 (m, 1H), 4.77 (d, J = 20.2 Hz, 1H), 4.63 (d, J = 19.9 Hz, 1H), 4.01 - 3.68 (m, 2H), 3.65 - 3.38 (m, 6H), 3.13 - 3.02 (m, 5H), 3.07 - 2.92 (m, 5H), 2.61 - 2.55 (m, 2H), 2.08 - 1.96 (m, 1H), 1.89 -1.70 (m, 1H). LCMS (ESI) calcd. for C36H40F2N5O2S+ [M+H]+: 644.29, found, 644.3.

[00296] Example 45: Preparation of 3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09618)

[00297] With reference to the method of Scheme 1, the target compound (GT-09618) was obtained as a white solid (15 mg, yield 20%). 1H NMR (400 MHz, DMSO) 5 11.15 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.68 (d, J = 7.0 Hz, 3H), 7.61 (dd, J = 13.9, 7.5 Hz, 2H), 7.51 - 7.37 (m, 4H), 5.98 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 5.01 (dd, J = 33.7, 18.0 Hz, 1H), 4.80 (d, J = 20.1 Hz, 1H), 4.29 - 3.92 (m, 2H), 3.27 - 2.90 (m, 13H), 2.66 (d, J = 14.1 Hz, 2H), 2.47 - 2.38 (m, 1H), 2.17 - 2.05 (m, 1H), 2.06 - 1.82 (m, 2H). LCMS (ESI) calcd. for C35H39F2N6O2S+ [M+H]+: 645.28, found, 645.3.

[00298] Example 46: Preparation of 3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09679)

[00299] With reference to the method of Scheme 1, the target compound (GT-09679) was obtained as a white solid (11 mg, yield 14%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.63 - 7.50 (m, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.03 - 5.90 (m, 1H), 4.84 (d, J = 19.7 Hz, 1H), 4.70 (d, J = 20.2 Hz, 1H), 3.17 - 3.08 (m, 4H), 3.02 - 2.93 (m, 4H), 2.71 - 2.61 (m, 2H), 2.42 - 2.33 (m, 6H), 2.15 - 2.00 (m, 4H), 1.96 - 1.85 (m, 2H), 1.74 -1.59 (m, 2H), 1.51 - 1.37 (m, 3H), 0.99 (s, 3H), 0.96 (s, 3H). LCMS (ESI) calcd. for C38H45ClF2N5O3S+ [M+H]+: 724.29, found, 724.3.

[00300] Example 47: Preparation of 3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09619)

[00301] With reference to the method of Scheme 1, the target compound (GT-09619) was obtained as a white solid (19 mg, yield 23%). 1H NMR (400 MHz, DMSO) 5 11.15 (d, J = 4.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.67 - 7.50 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.07 - 5.91 (m, 1H), 4.86 (d, J = 18.8 Hz, 1H), 4.75 (d, J = 21.0 Hz, 1H), 3.91 - 3.74 (m, 1H), 3.27 - 3.19 (m, 7H), 3.05 - 2.86 (m, 4H), 2.72 - 2.62 (m, 2H), 2.44 - 2.29 (m, 4H), 2.19 - 2.00 (m, 3H), 1.90 (d, J = 17.2 Hz, 1H), 1.80 - 1.57 (m, 2H), 1.52 - 1.36 (m, 2H), 0.98 (d, J = 13.3 Hz, 6H). LCMS (ESI) calcd. for C38H45ClF2N5O3S+ [M+H]+: 724.29, found, 724.3.

[00302] Example 48: Preparation of 3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09692)

[00303] With reference to the method of Scheme 1, the target compound (GT-09692) was obtained as a white solid (10 mg, yield 13%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 7.90 - 7.85 (m, 1H), 7.72 - 7.69 (m, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.98 - 5.92 (m, 1H), 4.84 (d, J = 20.9 Hz, 1H), 4.70 (d, J = 20.1 Hz, 1H), 3.31 - 3.17 (m, 6H), 3.15 - 3.02 (m, 3H), 3.03 - 2.90 (m, 3H), 2.68 - 2.62 (m, 2H), 2.43 - 2.33 (m, 4H), 2.14 - 2.04 (m, 3H), 1.90 (d, J = 15.5 Hz, 1H), 1.79 -1.60 (m, 3H), 1.47 - 1.38 (m, 2H), 0.98 (d, J = 12.9 Hz, 6H). LCMS (ESI) calcd. for C38H45ClF2N5O4+ [M+H]+: 708.31, found, 708.3.

[00304] Example 49: Preparation of 3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09680)

[00305] With reference to the method of Scheme 1, the target compound (GT-09680) was obtained as a white solid (21 mg, yield 27%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.65 - 7.51 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.01 - 5.90 (m, 1H), 4.83 (d, J = 18.0 Hz, 1H), 4.70 (d, J = 20.4 Hz, 1H), 3.57 - 3.53 (m, 2H), 3.24 - 3.19 (m, 4H), 3.03 - 2.96 (m, 3H), 2.89 - 2.81 (m, 4H), 2.65 - 2.58 (m, 4H), 2.30 - 2.24 (m, 4H), 2.03 (s, 4H), 1.80 - 1.67 (m, 2H), 1.47 - 1.45 (m, 2H), 0.96 (s, 6H). LCMS (ESI) calcd. for C38H47ClF2N5O2S+ [M+H]+: 710.31, found, 710.3.

[00306] Example 50: Preparation of 3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09576)

[00307] With reference to the method of Scheme 1, the target compound (GT-09576) was obtained as a white solid (23 mg, yield 28%). 1H NMR (400 MHz, DMSO) 5 11.15 (s, 1H), 7.86 (d, J = 6.5 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.60 - 7.55 (m, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 4.90 (d, J = 20.5 Hz, 1H), 4.78 (d, J = 20.1 Hz, 1H), 3.94 - 3.64 (m, 2H), 3.55 (brs, 2H), 3.39 - 3.31 (m, 4H), 3.25 - 3.18 (m, 3H), 3.07 - 2.97 (m, 4H), 2.94 - 2.79 (m, 3H), 2.67 - 2.60 (m, 3H), 2.33 - 2.25 (m, 3H), 2.17 - 2.07 (m, 1H), 2.04 (s, 2H), 1.85 - 1.72 (m, 2H), 1.46 (t, J = 6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) calcd. for C38H47ClF2N5O2S+ [M+H]+: 710.31, found, 710.3.

[00308] Example 51: Preparation of 3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09863)

[00309] With reference to the method of Scheme 1, the target compound (GT-09863) was obtained as a white solid (16 mg, yield 21%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 7.99 - 7.92 (m, 1H), 7.75 - 7.62 (m, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.98 - 5.94 (m, 1H), 4.84 (d, J = 20.2 Hz, 1H), 4.69 (d, J = 19.6 Hz, 1H), 3.54 (s, 2H), 3.25 - 3.17 (m, 4H), 3.07 - 2.96 (m, 4H), 2.93 - 2.75 (m, 4H), 2.71 - 2.53 (m, 6H), 2.33 - 2.25 (m, 3H), 2.15 - 2.07 (m, 1H), 2.03 (s, 3H), 1.92 -1.63 (m, 2H), 0.96 (s, 6H). LCMS (ESI) calcd. for C38H47ClF2N5O2S+ [M+H]+: 710.31, found, 710.3.

[00310] Example 52: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09934)

[00311] With reference to the method of Scheme 1, the target compound (GT-09934) was obtained as a white solid (8 mg, yield 12%). 1H NMR (400 MHz, DMSO) 5 11.15 (s, 1H), 8.03 - 7.94 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.81 - 7.69 (m, 1H), 7.42 - 7.34 (m, 2H), 7.20 (dd, J = 7.0, 2.3 Hz, 1H), 6.04 - 5.88 (m, 1H), 4.86 (d, J = 20.5 Hz, 1H), 4.76 (d, J = 20.2 Hz, 1H), 4.52 - 4.40 (m, 1H), 3.68 - 3.61 (m, 2H), 3.29 - 3.23 (m, 4H), 3.21 - 3.13 (m, 4H), 3.05 - 2.90 (m, 4H), 2.67 - 2.61 (m, 2H), 2.41 -2.36 (m, 2H), 2.18 - 2.03 (m, 4H).LCMS (ESI) calcd. for C29H34Cl2N5O2S+ [M+H]+: 586.18, found, 586.3.

[00312] Example 53: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09939)

[00313] With reference to the method of Scheme 1, the target compound (GT-09939) was obtained as a white solid (14 mg, yield 21%). 1H NMR (400 MHz, DMSO) 5 11.21 (s, 1H), 8.07 - 7.87 (m, 2H), 7.78 - 7.62 (m, 1H), 7.40 - 7.30 (m, 2H), 7.25 - 7.14 (m, 1H), 6.02 - 5.98 (m, 1H), 5.24 (d, J = 18.2 Hz, 1H), 4.89 (d, J = 18.3 Hz, 1H), 4.53 - 4.30 (m, 2H), 3.70 - 3.55 (m, 4H), 3.17 - 3.07 (m, 4H), 2.97 - 2.82 (m, 2H), 2.74 - 2.66 (m, 2H), 2.44 - 2.39 (m, 2H), 2.30 - 2.18 (m, 3H), 2.18 - 2.04 (m, 4H). LCMS (ESI) calcd. for C29H34Cl2N5O2S+ [M+H]+: 586.18, found, 586.3.

[00314] Example 54: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09935)

[00315] With reference to the method of Scheme 1, the target compound (GT-09935) was obtained as a white solid (8 mg, yield 12%). 1H NMR (400 MHz, DMSO) 5 11.14 (s, 1H), 8.14 - 8.10 (m, 1H), 7.93 - 7.86 (m, 1H), 7.82 - 7.74 (m, 1H), 7.42 - 7.35 (m, 2H), 7.22 - 7.18 (m, 1H), 5.96 (d, J = 10.3 Hz, 2H), 4.89 (d, J = 20.8 Hz, 1H), 4.75 (d, J = 20.4 Hz, 2H), 4.55 - 4.42 (m, 2H), 3.65 - 3.54 (m, 4H), 3.24 - 3.16 (m, 6H), 3.03 - 2.92 (m, 4H), 2.67 - 2.63 (m, 2H), 2.44 - 2.33 (m, 2H), 2.18 - 2.04 (m, 3H). LCMS (ESI) calcd. for C29H34Cl2N5O2S+ [M+H]+: 586.18, found, 586.3.

[00316] Example 55: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09687)

[00317] With reference to the method of Scheme 1, the target compound (GT-09687) was obtained as a white solid (13 mg, yield 19%). 1H NMR (400 MHz, DMSO) 5 11.07 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.14 - 7.05 (m, 1H), 5.89 (d, J = 11.3 Hz, 1H), 4.79 (d, J = 20.5 Hz, 1H), 4.65 (d, J = 20.6 Hz, 1H), 4.10 - 3.83 (m, 2H), 3.17 - 2.98 (m, 10H), 2.95 - 2.84 (m, 2H), 2.63 - 2.55 (m, 2H), 2.50 - 2.45 (m, 2H), 2.17 - 2.08 (m, 1H), 2.06 - 2.01 (m, 1H), 1.99 - 1.87 (m, 1H). LCMS (ESI) calcd. for C29H32C12F2N5O2S+ [M+H]+: 622.16, found, 622.2.

[00318] Example 56: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09575)

[00319] With reference to the method of Scheme 1, the target compound (GT-09575) was obtained as a white solid (31 mg, yield 43%). 1H NMR (400 MHz, DMSO) 5 11.15 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 5.3 Hz, 2H), 7.21 - 7.15 (m, 1H), 6.01 - 5.95 (m, 1H), 4.89 (d, J = 19.8 Hz, 1H), 4.77 (d, J = 20.9 Hz, 1H), 3.97 - 3.72 (m, 2H), 3.24 - 3.14 (m, 9H), 3.06 - 2.86 (m, 4H), 2.70 - 2.64 (m, 2H), 2.18 - 2.07 (m, 2H), 2.03 - 1.84 (m, 2H). LCMS (ESI) calcd. for C29H32Cl2F2N5O2S+ [M+H]+: 622.16, found, 622.2.

[00320] Example 57: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09693)

[00321] With reference to the method of Scheme 1, the target compound (GT-09693) was obtained as a white solid (11 mg, yield 16%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 8.06 - 7.95 (m, 1H), 7.78 - 7.68 (m, 2H), 7.33 (d, J = 4.7 Hz, 2H), 7.16 (t, J = 4.8 Hz, 1H), 6.01 - 5.90 (m, 1H), 4.86 (d, J = 20.7 Hz, 1H), 4.72 (d, J = 20.1 Hz, 1H), 4.30 - 3.84 (m, 2H), 3.18 - 3.05 (m, 11H), 2.70 - 2.62 (m, 2H), 2.22 - 1.93 (m, 6H). LCMS (ESI) calcd. for C29H32Cl2F2N5O2S+ [M+H]+: 622.16, found, 622.2.

[00322] Example 58: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09688)

[00323] With reference to the method of Scheme 1, the target compound (GT-09688) was obtained as a white solid (12 mg, yield 17%). 1H NMR (400 MHz, DMSO) 5 11.14 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.63 - 7.54 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 6.2 Hz, 1H), 6.02 - 5.88 (m, 1H), 5.75 (s, 1H), 4.85 (d, J = 20.1 Hz, 1H), 4.71 (d, J = 19.7 Hz, 1H), 3.98 - 3.84 (m, 2H), 3.31 - 3.21 (m, 6H), 3.17 - 3.06 (m, 3H), 3.01 - 2.92 (m, 2H), 2.70 - 2.61 (m, 4H), 2.14 - 2.06 (m, 1H), 2.04 - 1.94 (m, 1H). LCMS (ESI) calcd. for C30H31Cl2F2N4O2S+ [M+H]+: 619.15, found, 619.2.

[00324] Example 59: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09614)

[00325] With reference to the method of Scheme 1, the target compound (GT-09614) was obtained as a white solid (10 mg, yield 14%). 1H NMR (400 MHz, DMSO) 5 11.14 (s, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.68 - 7.54 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.6, 1.2 Hz, 1H), 6.00 (d, J = 11.0 Hz, 1H), 5.77 (s, 1H), 4.89 (d, J = 18.7 Hz, 1H), 4.76 (d, J = 20.2 Hz, 1H), 3.97 - 3.74 (m, 4H), 3.37 -3.19 (m, 9H), 3.08 - 2.92 (m, 2H), 2.71 - 2.65 (m, 2H), 2.17 - 2.09 (m, 1H), 2.02 - 1.93 (m, 1H). LCMS (ESI) calcd. for C30H31Cl2F2N4O2S+ [M+H]+: 619.15, found, 619.2.

[00326] Example 60: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09694)

[00327] With reference to the method of Scheme 1, the target compound (GT-09694) was obtained as a white solid (10 mg, yield 15%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 8.00 - 7.88 (m, 1H), 7.73 - 7.64 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.03 -5.89 (m, 1H), 5.74 (s, 1H), 4.85 (d, J = 20.6 Hz, 1H), 4.71 (d, J = 20.2 Hz, 1H), 4.07 - 3.84 (m, 2H), 3.65 - 3.52 (m, 2H), 3.37 - 3.31 (m, 6H), 3.32 - 3.05 (m, 4H), 2.99 - 2.92 (m, 1H), 2.69 - 2.63 (m, 2H), 2.14 - 1.99 (m, 3H). LCMS (ESI) calcd. for C30H31Cl2F2N4O2S+ [M+H]+: 619.15, found, 619.2.

[00328] Example 61: Preparation of 3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09861)

[00329] With reference to the method of Scheme 1, the target compound (GT-09861) was obtained as a white solid (13 mg, yield 21%). 1H NMR (400 MHz, DMSO) 5 11.15 (s, 1H), 8.09 (dd, J = 8.8, 5.2 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.77 (t, J = 6.8 Hz, 1H), 7.61 (dd, J = 8.9, 1.7 Hz, 1H), 7.26 (t, J = 8.5 Hz, 1H), 5.97 (d, J = 14.1 Hz, 1H), 4.88 (d, J = 20.4 Hz, 1H), 4.74 (d, J = 20.3 Hz, 1H), 4.45 (brs, 2H), 4.25 - 4.01 (m, 2H), 3.61 - 3.50 (m, 6H), 3.02 - 2.95 (m, 4H), 2.67 - 2.63 (m, 2H), 2.37 - 2.31 (m, 2H), 2.26 - 2.15 (m, 2H), 2.15 - 1.96 (m, 3H). LCMS (ESI) calcd. for C30H34FN6O3S+ [M+H]+: 577.24, found, 577.3.

[00330] Example 62: Preparation of 3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09940)

[00331] With reference to the method of Scheme 1, the target compound (GT-09940) was obtained as a white solid (10 mg, yield 15%). 1H NMR (400 MHz, DMSO) 5 11.21 (s, 1H), 8.12 - 8.08 (m, 1H), 8.04 - 7.90 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.61 (dd, J = 9.1, 2.0 Hz, 1H), 7.26 (td, J = 9.0, 2.1 Hz, 1H), 6.05 - 6.00 (m, 1H), 5.25 (d, J = 21.4 Hz, 1H), 4.88 (d, J = 20.4 Hz, 1H), 4.49 - 4.36 (m, 1H), 4.22 - 4.00 (m, 2H), 3.64 - 3.50 (m, 6H), 3.21 - 3.07 (m, 4H), 3.02 - 2.89 (m, 2H), 2.74 - 2.66 (m, 2H), 2.40 - 2.33 (m, 2H), 2.29 - 2.19 (m, 2H), 2.18 - 2.06 (m, 2H). LCMS (ESI) calcd. for C30H34FN6O3S+ [M+H]+: 577.24, found, 577.3.

[00332] Example 63: Preparation of 3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09864)

[00333] With reference to the method of Scheme 1, the target compound (GT-09864) was obtained as a white solid (11 mg, yield 16%). 1H NMR (400 MHz, DMSO) 5 11.14 (s, 1H), 8.14 - 8.05 (m, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.61 (dd, J = 9.0, 2.0 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H), 5.96 (d, J = 9.3 Hz, 1H), 4.89 (d, J = 20.5 Hz, 1H), 4.75 (d, J = 20.5 Hz, 1H), 4.49 (s, 2H), 4.22 - 4.03 (m, 2H), 3.61 - 3.49 (m, 6H), 3.04 - 2.89 (m, 4H), 2.72 - 2.67 (m, 2H), 2.41 - 2.32 (m, 3H), 2.22 - 2.04 (m, 4H). LCMS (ESI) calcd. for C30H34FN6O3S+ [M+H]+: 577.24, found, 577.3.

[00334] Example 64: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione (GT-09689)

[00335] With reference to the method of Scheme 1, the target compound (GT-09689) was obtained as a white solid (13 mg, yield 19%). 1H NMR (400 MHz, DMSO) 5 11.13 (s, 1H), 8.05 (dd, J = 8.9, 5.3 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.71 (brs, 1H), 7.62 (brs, 1H), 7.56 (dd, J = 9.1, 2.1 Hz, 1H), 7.21 (t, J = 9.0 Hz, 1H), 6.04 - ...

Claims

1. A compound of Formula (I),^a2^a3p          (Ra5)mRa1^—Z2^ / Z4 Z5—n' J -^R—X HN-Z3 zr^ / Formula (I)or salts, enantiomers, diastereoisomers, isotopically enriched analogs, solvates, or polymorphs thereof, whereinZ1 represents C(O), C(S), CH2, or CD2, and Z2, Z3, and Z4 each independently represent C(O) or C(S);Z5 represents CH or N;Ra1, Ra2, Ra3, and Ra4 each independently represent hydrogen, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy or halogenated C1-6 alkoxy;(Ra5)m indicates that the isoindoline ring to which it is attached is optionally substituted with m Ra5, with each Ra5 being identical or different and each independently representing deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, or C2-6 alkynyl;m represents an integer of 0, 1, 2, or 3;R represents C(O) or optionally substituted linear or branched C1-5 alkylene;X represents:44 A TV B 7 Rc \V c 7 / ( D )(^dl)nl (Rd2)n2       (^d3)n3   (^d4)n4wherein ring A represents nitrogen-containing heterocyclylene, and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterium, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0-20;ring B represents nitrogen-containing heterocyclylene, and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0-20;Rc represents C(O), CRc1Rc2, or a bond, wherein Rc1 and Rc2 each independently represent H,deuterium, halogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;ring C represents cycloalkylene, heterocyclylene, arylene, or heteroarylene, m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0-20; andring D represents heterocyclyl, cycloalkyl, aryl, or heteroaryl, and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0-20.

2. The compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof of claim 1, wherein(i) Ra1, Ra2, Ra3, and Ra4 each independently represent H; and / or(ii) R represents C(O) or optionally substituted linear or branched C1-3 alkylene; and / or(iii) X represents:(Rdl)n1 (Rd2)n2(Rd3)n3   (Rd4)n4wherein the ring A represents 4- to 30-membered nitrogen-containing heterocyclylene (including 4- to 20-membered nitrogen-containing heterocyclylene, and 4- to 15membered nitrogen-containing heterocyclylene), and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0-20;the ring B represents 4- to 30-membered nitrogen-containing heterocyclylene, and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 0-20;Rc represents C(O), CRc1Rc2, or a bond, wherein Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched C1-10 alkyl, optionallysubstituted C3-30 cycloalkyl, optionally substituted C5-30 aryl, optionally substituted 4-to 30-membered heterocyclyl, or optionally substituted 5- to 30-membered heteroaryl;the ring C represents 4- to 30-membered heterocyclylene, C3-30 cycloalkylene, C5-30 arylene, or 5- to 30-membered heteroarylene, m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0-20; and / orthe ring D represents C3-30 cycloalkyl, 4- to 30-membered heterocyclyl, C5-30 aryl, or 5- to 30-membered heteroaryl, and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, wherein each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 0-20.

3. The compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof of claim 1 or 2, wherein(i) the ring A represents 4- to 20-membered nitrogen-containing heterocyclylene (including 4- to 15-membered nitrogen-containing heterocyclylene), and (Rd1)n1 indicates that the ring A is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n1 represents an integer of 0-20; and / or(ii) the ring B represents 4- to 20-membered nitrogen-containing heterocyclylene (including 4-to 15-membered nitrogen-containing heterocyclylene), and (Rd2)n2 indicates that the ring B is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n2 represents an integer of 020; and / or(iii) the Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted linear or branched C1-6 alkyl, optionally substituted C3-20 cycloalkyl (including optionally substituted C3-15 cycloalkyl), optionally substituted C5-20 aryl (including optionally substituted C5-15 aryl), optionally substituted 4- to 20-membered heterocyclyl (including optionally substituted 4- to 15membered heterocyclyl), or optionally substituted 5- to 20-membered heteroaryl (including optionally substituted 5- to 15-membered heteroaryl) ; and / or(iv) the ring C represents 4- to 20-membered heterocyclylene (including 4- to 15-membered heterocyclylene), C3-20 cycloalkylene (including C3-15 cycloalkylene), C5-20 arylene (including C5-15arylene), or 5- to 20-membered heteroarylene (including 5- to 15-membered heteroarylene), m1 represents an integer of 0 or 1, and (Rd3)n3 indicates that the ring C is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n3 represents an integer of 0-20; and / or(v) the ring D represents C3-20 cycloalkyl (including C3-15 cycloalkyl), 4- to 20-membered heterocyclyl (including 4- to 15-membered heterocyclyl), C5-20 aryl (including C5-15 aryl), or 5- to 20membered heteroaryl (including 5- to 15-membered heteroaryl), and (Rd4)n4 indicates that the ring D is optionally substituted with n4 Rd4 groups, wherein each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, or C2-6 alkenyl, and n4 represents an integer of 020.

4. The compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof of any one of claims 1-3, wherein(i) R represents C(O) or optionally substituted methylene; and / or(ii) the ring A and the ring B each independently represent azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, piperidinylene, piperazinylene, azacycloheptanylene, diazacycloheptanylene, azacyclooctylene, diazacyclooctylene, azabicyclo[3.1.1]heptanylene, azabicyclo[2.2.1]heptanylene, azabicyclo[3.2.1]octanylene, azabicyclo[2.2.2]octanylene, diazabicyclo[3.1.1]heptanylene, diazabicyclo[2.2.1]heptanylene, diazabicyclo[3.2.1]octanylene, diazabicyclo[2.2.2]octanylene,      quinuclidinylene,      2,6-diazaspiro[3.3]heptanylene, 2,7-diazaspiro[3.5]nonanylene, 2,8-diazaspiro[4.5]decanylene, 3,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 7-azaspiro[3.5]nonanylene, 8-azaspiro[4.5]decanylene, or octahydropyrrolo[3,4-c]pyrrolylene, each optionally substituted with one or more (e.g., 1-10) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl; and / or(iii) Rc1 and Rc2 each independently represent:H, deuterium, halogen, or optionally substituted linear or branched C1-10 alkyl; or cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro-cycloalkyl (e.g., C5-C20 spiro-cycloalkyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, and spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g., C6-C20 bridged cycloalkyl, such as adamantanyl, noradamantanyl, bornyl, norbornyl, bicyclo[2.2.1]heptanyl, 2-oxobicyclo[2.2.1]heptyl, or bicyclo[2.2.1]heptenyl), each optionally substituted with one or more (e.g., 1-10) substituents selected from the group consisting ofdeuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl; orazetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxy-piperidinyl, difluoro-piperidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, azacyclooctyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptanyl, 4,5-diazacycloheptanyl, 1,3-diazacycloheptanyl), diazacyclooctyl, bridged heterocyclyl (e.g., 6- to 20-membered bridged heterocyclyl, such as 6-azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, and quinuclidinyl), and azaspirocycloalkyl (e.g., 5- to 20-membered azaspirocycloalkyl, such as 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, and 7-azaspiro[3.5]nonanyl), or octahydropyrrolo[3,4-c]pyrrolyl, each optionally substituted with one or more (e.g., 1-10) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl; orphenyl or naphthyl, each optionally substituted with one or more (e.g., 1-7) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, and C2-6 alkenyl; orfuranyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl,quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,           or          6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, each optionally substituted with one or more (e.g., 110) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, and C2-6 alkenyl; and / or(iv) the ring C represents:cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, spiro-cycloalkylene (e.g., C5-C20 spiro-cycloalkylene, such as spiro[3.3]heptylene,      spiro[2.5]octylene,      spiro[3.5]nonylene, spiro[4.4]nonylene,spiro[4.5]decylene, spiro[5.5]undecylene), p-menthanylene, m-menthanylene, or bridged cycloalkylene (e.g., C6-C20 bridged cycloalkylene, such as adamantanylene, noradamantanylene, bornylene, norbornylene, bicyclo[2.2.1]heptylene, 2-oxobicyclo[2.2.1]heptylene, or bicyclo[2.2.1]heptentylene), each optionally substituted with one or more (e.g., 1-20) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl; orazetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, tetrahydropyridinylene, dihydroxy-piperidinylene, difluoro-piperidinylene, morpholinylene, thiomorpholinylene, azacycloheptanylene, azacyclooctylene, dioxacyclohexylene, azacycloheptanylene,azacyclooctylene, diazacycloheptanylene (e.g.,     1,4-diazacycloheptanylene,    4,5-diazacycloheptanylene, 1,3-diazacycloheptanylene), diazacyclooctylene, bridged heterocyclylene (e.g., 6- to  20-membered bridged heterocyclylene,  such  as  6-azabicyclo[3.1.1]heptanylene,             2,5-diazabicyclo[2.2.1]heptanylene,             3,6-diazabicyclo[3.1.1]heptanylene,              3-azabicyclo[3.2.1]octanylene,              3,8-diazabicyclo[3.2.1]octanylene,             3,8-diazabicyclo[3.2.1]octanylene,             2,5-diazabicyclo[2.2.2]octanylene, and quinuclidinylene), azaspirocycloalkylene (e.g., 5- to 20membered azaspirocycloalkylene, such as 2,6-diazaspiro[3.3]heptanylene, 2,7-diazaspiro[3.5]nonanylene, 2,8-diazaspiro[4.5]decanylene, 3,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, and 7-azaspiro[3.5]nonanylene), or octahydropyrrolo[3,4-c]pyrrolylene, each optionally substituted with one or more (e.g., 1-20) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, aminosubstituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl,and C2-6 alkynyl; orphenylene or naphthylene, each optionally substituted with one or more (e.g., 1-6) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl; orfuranylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene,   pyridazinylene, pyrazinylene,   triazinylene, indolylene,isoindolylene,    indolinylene,   benzofuranylene,    chromanylene,    isobenzofuranylene,benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolylene, benzo[b][1,4]oxazinylene, 3,4-dihydro-2H-benzo[b][1,4]oxazinylene, quinolinylene, isoquinolinylene,    1,2,3,4-tetrahydroquinolinylene,    naphthyridinylene,cinnolinylene, quinazolinylene, quinoxalinylene, 1,2,3,4-tetrahydroquinoxalinylene, phthalazinylene, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinylene, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene,           5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinylene,thieno[2,3-d]pyrimidinylene, thieno[3,2-d]pyrimidinylene, isoxazolo[4,5-c]pyridinylene, isoxazolo[4,5-c]pyrimidinylene, isoxazolo[4,5-d]pyrimidinylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, pyrrolo[2,1-b]thiazolylene, imidazo[2,1-b]thiazolylene, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinylene,             or            6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinylene, each optionally substituted with one or more (e.g., 1-20) substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl; and / or (v) the ring D represents:cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro-cycloalkyl (e.g., C5-C20 spiro-cycloalkyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, and spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g., C6-C20 bridged cycloalkyl, such as adamantanyl, noradamantanyl, bornyl, norbornyl, bicyclo[2.2.1]heptanyl, 2-oxobicyclo[2.2.1]heptyl, or bicyclo[2.2.1]heptenyl), each optionally substituted with one or more (e.g., 1-20) substituents selected from the group consisting ofdeuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl; orazetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxy-piperidinyl, difluoro-piperidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, azacyclooctyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptanyl, 4,5-diazacycloheptanyl, 1,3-diazacycloheptanyl), diazacyclooctyl, bridged heterocyclyl (e.g., 6- to 20-membered bridged heterocyclyl, such as 6-azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, and quinuclidinyl), and azaspirocycloalkyl (e.g., 5- to 20-membered azaspirocycloalkyl, such as 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, and 7-azaspiro[3.5]nonanyl), or octahydropyrrolo[3,4-c]pyrrolyl, each optionally substituted with one or more (e.g., 1-20) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl; orphenyl or naphthyl, each optionally substituted with one or more (e.g., 1-7) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, and C2-6 alkenyl; orfuranyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl,quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,           or          6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, each optionally substituted with one or more (e.g., 120) substituents selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, and C2-6 alkenyl.

5. The compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof of any one of claims 1-4, wherein R represents:-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-;wherein the above groups are optionally substituted with a substituent selected from the group consisting of deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl, and C2-6 alkenyl.

6. The compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof of any one of claims 1-5, wherein X represents:

7. The compound of Formula (I) or salts, enantiomers, diastereoisomers, solvates, or polymorphs thereof of claim 1, which is selected from:3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione;2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione;3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-3-(6-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(2-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-benzhydrylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-3-(7-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione;2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione;3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-1-3-(6-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;3-(7-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;4-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;5-(3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidine]-1'-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;3-(4-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-3-(6-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-thioxoisoindolin-2-yl)piperidine-2,6-dione;1-(5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-benzhydrylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-benzhydrylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione;1-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione;5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione;1-(5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; and5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidin]-1'-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione.

8. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof of any one of claims 1-7, which is sulfate, hydrohalide (including hydrochloride, hydrobromide), maleate, sulfonate, citrate, lactate, lactobionate, L-tartrate, fumarate, L-malate, L-lactate, a-ketoglutarate, hippurate, D-glucuronate, D-gluconate, a-D-glucoheptonate, glycolate, mucate, L-ascorbate, orotate, picrate, glycinate, alaninate, arginate, cinnamate, laurate, pamoate, sebacate, besylate, methanesulfonate, ethanesulfonate, edisylate, formate, acetate, 2,2-dichloroacetate, trimethylacetate, propionate, valerate, palmitate, triphenylacetate, 2-ethyl-butane-1,4-dioate, iodate, nicotinate, L-pyroglutamate, L-prolinate, ferulate, 2-hydroxyethanesulfonate, nitrate, gentisate, cholate, salicylate, terephthalate, glutarate, adipate, stearate, oleate, undecylenate, camphorate, camsylate, dodecylsulfate, phosphate, thiocyanate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, carbonate, malonate, benzoate, mandelate, succinate, pyruvate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, 3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, 2-naphthalenesulfonate, glycolate, trifluoroacetate, terephthalate, or 4-methylbenzenesulfonate of the compound of Formula (I).

9. A pharmaceutical composition, comprising: the compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 1-8, and at least one pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition of claim 9, further comprising a second therapeutic agent, e.g., an anticancer agent.

11. The compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 18, for use in the prevention or treatment of a disease or disorder associated with cereblon protein.

12. The compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 18, for use in the prevention or treatment of a disease or disorder selected from the group consisting of: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratorydistress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

13. The compound of Formula (I) or pharmaceutically acceptable salts thereof of claim 11 or 12, wherein the disease or disorder is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplantation-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (including acute B-lymphoblastic leukemia, T-lymphoblastic leukemia, acute T-lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma cell leukemia, monocytic leukemia, and myelomonocytic leukemia); lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, immunoblastic T-Cell lymphoma, CD20 positive lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Burkitt’s lymphoma, marginal zone lymphoma (MZL), primary lymphoma, B-cell lymphoma, recurrent B-cell nonHodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma, recurrent mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, recurrent transformed nonHodgkin’s lymphoma, refractory B-cell non-Hodgkin’s lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin’s lymphoma; Burkitt’s lymphoma (Burkitt’s lymphoma); thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, and small cell lung cancer; inflammatory myofibroblastoma; colorectal cancer; intestinal cancer; brain glioma; astroblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer, ductal carcinoma of the breast, and patients with Cowden syndrome; pancreatic cancer; central nervous system tumor; neuroblastoma; glioma; peripheral neuroepithelioma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; metrocarcinoma; head and neck cancer; brain cancer; oral cancer; sarcoma, including rhabdomyosarcoma, various lipogenic tumors, Ewing’s sarcoma / primitive neuroectodermal tumors (Ewing / PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; Richter syndrome (RS); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren’s syndrome, atopic dermatitis, hidradenitis suppurativa, gout, type I diabetes, urticaria, inflammatory bowel disease(including Crohn's disease and ulcerative colitis); keratoconjunctivitis; inflammatory diseases, including Crohn’s disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, Acquired immunodeficiency syndrome (AIDS), COVID-19 novel coronavirus infection, gram-negative bacteria infection, gram-positive bacteria infection, tuberculosis, etc; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplantation rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; pediatric aplastic anemia; cardiovascular diseases (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ dysfunction caused by cachexia and septic shock; and acute liver failure.

14. Use of the compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 1-8, or the pharmaceutical composition of claim 9 or 10 for the manufacture of a medicament for the prevention or treatment of a disease or disorder associated with cereblon protein.

15. Use of the compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 1-8, or the pharmaceutical composition of claim 9 or 10 for the manufacture of a medicament for the prevention or treatment of a disease or disorder selected from the group consisting of: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

16. A method for treating or preventing a disease or disorder associated with cereblon protein in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 1-8, or the pharmaceutical composition of claim 9 or 10.

17. A method for treating or preventing a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula (I) or pharmaceutically acceptable salts thereof of any one of claims 1-8, or the pharmaceutical composition of claim 9 or 10, wherein the disease or disorder is selected from the group consisting of: tumor, infectious disease, inflammatory disease, autoimmune disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure, and diabetes.

18. The use of claim 14 or 15, or the method of claim 16 or 17, wherein the disease or disorder is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplantation-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocyticleukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, acute B-lymphoblastic leukemia, T-lymphoblastic leukemia, acute T-lymphoblastic leukemia, lymphoma cell leukemia, monocytic leukemia, myelomonocytic leukemia; lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, immunoblastic T-Cell lymphoma, CD20 positive lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Burkitt’s lymphoma, marginal zone lymphoma (MZL), primary lymphoma, B-cell lymphoma, recurrent B-cell non-Hodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma, recurrent mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, recurrent transformed non-Hodgkin’s lymphoma, refractory B-cell non-Hodgkin’s lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin’s lymphoma; Burkitt’s lymphoma (Burkitt’s lymphoma); thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, and small cell lung cancer; inflammatory myofibroblastoma; colorectal cancer; intestinal cancer; brain glioma; astroblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer, ductal carcinoma of the breast, and patients with Cowden syndrome; pancreatic cancer; central nervous system tumor; neuroblastoma; glioma; peripheral neuroepithelioma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; metrocarcinoma; head and neck cancer; brain cancer; oral cancer; sarcoma, including rhabdomyosarcoma, various lipogenic tumors, Ewing’s sarcoma / primitive neuroectodermal tumors (Ewing / PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; cholangiocarcinoma; bone cancer; cervical cancer; skin cancer; Richter syndrome (RS); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren’s syndrome, atopic dermatitis, hidradenitis suppurativa, gout, type I diabetes, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis; inflammatory diseases, including pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, Acquired immunodeficiency syndrome (AIDS), COVID-19 novel coronavirus infection, gramnegative bacteria infection, gram-positive bacteria infection, tuberculosis, etc; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplantation rejection; sarcoidosis; adult respiratory distress syndrome; anemia; pediatric aplastic anemia; cardiovascular diseases (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ dysfunctioncaused by cachexia and septic shock; and acute liver failure.

19. A method for preparing the compound of Formula (I) of claim 1, comprising reacting a compound of Formula (M1) with a compound of Formula (M2) to obtain the compound of Formula (I):Ra2 Ra3Ra1^_^Ra4z2Z4   Z5XHN-Z3   Zf(M1)(Ra5)mX LE       (Rdl)n1 (Rd2)n2       (Rd3)n3 (Rd4)n4(M2)Ra2 Ra3Ra1'^  VRa4z2Z4    Z5-Nhn-z3   Zf(I)rR—Xa(Ra5)mwherein Rai, Ra2, Ra3, Ra4, (Ra5)m, Zi, Z2, Z3, Z4, Z5, (Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in claim i;nitrogen-containing heterocycle A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably, a 4- to 20-membered nitrogen-containing heterocycle; more preferably, a 4-to i5-membered nitrogen-containing heterocycle);R represents optionally substituted linear or branched Ci-5 alkylene;LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, o-nitrobenzenesulfonyl, C(O)Cl, or COOH; andXa of the compound of Formula (I) correspondingly represents a structure represented by the following formula:(Rdl)n1 (Rd2)n2      (Rd3)n3   (Rd4)n4,wherein nitrogen-containing heterocyclylene A is a divalent group obtained by removing a hydrogen atom from the nitrogen atom of said nitrogen-containing heterocycle A, and said nitrogencontaining heterocyclylene A represents a 4- to 30-membered nitrogen-containing heterocyclylene (preferably a 4- to 20-membered nitrogen-containing heterocyclylene; more preferably a 4- to 15membered nitrogen-containing heterocyclylene), and(Rdi)ni, ring B, (Rd2)n2, Rc, ring C, mi, (Rd3)n3, ring D, and (Rd4)n4 are as defined in any one of claims 1-8.

20. The method of claim 19, wherein (1) when the group LE represents methanesulfonyloxy, the compound of Formula (M1) is prepared by reacting a compound of Formula (M3) with methanesulfonic anhydride or methanesulfonyl chloride:Ra2 Ra3 DRa1^Lj / Ra4Z4 z5-nhn-z3 zr(M3)(RasimR XOHwherein Rai, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, Z5, and R are as defined in claim 19; orwherein (2) when the group LE represents Cl, Br, or I, the compound of Formula (Mi) is prepared by subjecting the compound of Formula (M3) to a halogenation reaction with a hydrohalic acid.

21. The method of claim 20 or 21, wherein R represents CH2 in each of the compound of Formula (M1), the compound of Formula (I), and the compound of Formula (M3).

22. The method of claim 21, wherein the compound of Formula (M3) is prepared by subjecting a compound of Formula (M4) to a coupling reaction with (tributylstannyl)methanol in the presence of a palladium catalyst:Ra2 Ra3 DRa-| ^a4z4 Z5-N ‘HN-Z3 z(M4)(Ra5)rBrwherein Rai, Ra2, Ra3, Ra4, (Ra5)m, Z1, Z2, Z3, Z4, and Z5 are as defined in claim 19.

23. The method of claim 22, wherein when Z5 in the compound of Formula (M4) represents N, and Zi represents C(O), CH2, or CD2, and Z2, Z3, and Z4 each independently represent C(O), the compound of Formula (M4) is prepared by subjecting a compound of Formula (M5) and a compound of Formula (M6) to an amine-ester exchange reaction:Ra2 Ra3Ra- .   , Ra4O=(   N-NH2O (M5)Br+(Ra5)mO(M6)Ra2 Ra3   ORai O=BrO (M4)wherein Ra1, Ra2, Ra3, Ra4, and (Ra5)m are as defined in claim 19.

24. The method of claim 22, wherein when Z1 in the compound of Formula (M4) represents C(O), C(S), CH2, or CD2; Z2, Z3, and Z4 each independently represent C(O) or C(S); and at least one of Z1, Z2, Z3, and Z4 represents C(S), the compound of Formula (M4) is prepared by subjecting a compound of Formula (M7) to a thionation reaction with a thionating reagent:wherein Z6 in the compound of Formula (M7) represents C(O), CH2, or CD2; andRai, Ra2, Ra3, Ra4, and (Ra5)m are as defined in claim 19.

25. The method of claim 24, wherein the thionating reagent comprises carbon disulfide, hexamethyldisilathiane, sulfur, thiourea, hydrogen sulfide, phosphorus pentasulfide, Lawesson's reagent, Belleau's reagent, and Davy's reagent.

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