Novel substituted isoindolinone skeleton-based compounds, bifunctional protein degraders containing same, and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) and formula (II), or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, and the use thereof. The present disclosure also relates to a pharmaceutical composition comprising a compound of formula (I) or a compound of formula (II), or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof as an active ingredient, and uses thereof.

Description

[00262] As used herein, the term "alkenylene", used alone or in combination, refers to a linear or branched divalent 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 alkenylene groups include C2-8 alkenylene, C2-6 alkenylene, or C2-4 alkenylene, with representative but non-limiting examples including vinylene (e.g., -CH=CH-), 1-propenylene, allylidene, 1-butenylene, 2-butenylene, 3-butenylene, isobutenylene, pentenylene, n-pent-2,4-dienylene, 1-methyl-but-1-enylene, 2-methyl-but-1-enylene, 3-methyl-but-1-enylene, 1-methyl-but-2-enylene, 2-methyl-but-2-enylene, 3-methyl-but-2-enylene, 1-methyl-but-3-enylene, 2-methyl-but-3-enylene, 3-methyl-but-3-enylene, and hexenylene.

[00263] 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 C2-6 alkenyl group 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.

[00264] 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- JVv- trimethylbicyclo[2.2.1]heptan-5-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-6-yl,          , or .

[00265] 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.

[00266] 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.

[00267] 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.

[00268] As used herein, "noradamantane" has a definition known to those skilled in the art, and its structural formula is e.g., as follows:       or t^^. 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.

[00269] 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:

[00270] In the present disclosure, the term "leaving group" used alone or in combination is well known to those skilled in the art, which is a leaving molecular fragment (ion or neutral molecule) that carries a pair of electrons from a reactant in chemical reactions, as is a term used in nucleophilic substitution and elimination reactions. Common ionic leaving groups include Cl-, Br-, I- and sulfonate (such as p-toluenesulfonate, TsO-), and neutral molecular leaving groups include water, ammonia, and alcohol. In the present disclosure, those skilled in the art can select an appropriate leaving group as needed, such as but not limited to -N3, halogen, methanesulfonyloxy (MsO-), trifluoromethanesulfonyloxy (TfO-) or p-toluenesulfonyloxy (TsO), etc.

[00271] Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of Formula (I) or Formula (II) of the present disclosure are also encompassed within the scope of the present invention.

[00272] In all embodiments of the present disclosure, the salts or pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (II) refer to non-toxic inorganic or organic acid and / or base addition salts. Examples include: sulfates, hydrohalides (including hydrochlorides and hydrobromates), maleates, sulfonates, citrates, lactates, lactobionates, L-tartrates, fumarates, L-malates, L-lactates, a-Ketoglutarates, hippurates, D-glucuronates, D-gluconates, a-D-glucoheptonates, glycolates, mucates, L-ascorbates, orotates, picrates, glycinates, alaninates, argininates, cinnamates, laurates, pamoates, sebacates, benzenesulfonates, methanesulfonates, ethanesulfonates, edisylates, formates, acetates, 2,2-dichloroacetates, trimethylacetates, propionates, valerates, palmitates, triphenylacetates, 2-ethylsuccinates, iodates, niacinates, L-pyroglutamates, L-prolinates, ferulates, 2-hydroxyethanesulfonates, nitrates, gentisates, cholates, salicylates, terephthalates, glutarates, adipates, stearates, oleates, undecenoates, camphorates, camphorsulfonates, dodecyl sulfonates, phosphates, thiocyanates, dihydrophosphates, pyrophosphates, metaphosphates, oxalates, carbonates, malonates, benzoates, mandelates, succinates, pyruvates, para-chlorobenzenesulfonates, 1,5-naphthalenedisulfonates, 3-hydroxy-2-naphthoates, 1-hydroxy-2-naphthoates, 2-naphthalenesulfonates, glycolates, trifluoroacetates, terephthalates, or p-toluenesulfonates, etc.

[00273] "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 non-toxic compatible substances used in pharmaceutical formulations.

[00274] As used herein, the term "room temperature" refers to the ambient temperature, such as 20-30oC.

[00275] 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.

[00276] 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.

[00277] 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.

[00278] As used herein, the term "enantiomers" refers to two isomers of a compound that are non-superimposable mirror images.

[00279] 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.

[00280] As used herein, the term "prodrug" refers to a compound that can be converted in vivo, such as by hydrolysis in the blood, into its biologically active form. When a prodrug is administered to a patient, it releases the parent compound in the body. Prodrugs are generally prepared by modifying functional groups, and such modifications can be removed by conventional operations (e.g., acid / base hydrolysis) or by cleavage in vivo to release the parent drug. Prodrugs include, for example, forms in which the hydroxyl, amino, or mercapto groups of the compounds of the present invention are combined with any group that, when administered to a patient, can be cleaved to re-form the hydroxyl, amino, or mercapto groups. Accordingly, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, tert-butoxycarbonyl (Boc), and benzoate / amide derivatives of the hydroxyl, mercapto, and amino functional groups of the compounds of Formula (I) and Formula (II). In addition, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. These esters may themselves be active and / or may be hydrolyzed under physiological conditions in the human body. Suitable pharmaceutically acceptable, in vivo hydrolyzable ester groups include those that are readily cleaved in the human body to release the parent acid or a salt thereof. Description of the Drawings

[00281] Fig. 1 shows the Western blot assay results of the degradation of target substrate proteins by the compounds of the present disclosure in hPBMC, MDA-MB-231, LNcap, and H1975 cells. Examples

[00282] 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.

[00283] The following abbreviations are used throughout the specification and examples: ACN           acetonitrile AcOH         acetic acid potassium acetate MeCN        acetonitrile MeOH      Methanol AcOK MS mass spectrometry AIBN 2,2'-azobis(2-methylpropionitrile) MsO- Methanesulfonyloxy Bn Benzyl MsCl methanesulfonyl chloride Boc t-Butyloxy carbonyl NaHMDS Sodium bis(trimethylsilyl)amide Brettphos G3 Pd Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) NBS N-Bromosuccinimide Brettphos Dicyclohexyl[3,6-dimethoxy-2',4',6'-tris(1- methylethyl)[1,1'-biphenyl]-2-yl]phosphine NMI N-Methylimidazole BINAP 2,2’-Bis(diphenylphosphino)- 1,1’-binaphthalene 1H NMR Proton   nuclear   magnetic resonance BPO Dibenzoyl peroxide HFIP Hexafluoroisopropanol Cbz Carbobenzoxy MeO- Methoxy CNBr cyanogen bromide o / n Overnight Con. Concentration PCC Pyridinium chlorochromate DCE 1,2-Dichloroethane PE petroleum ether DCM dichloromethane Pin2B2 pinacolborane DEA Diethylamine PyBOP Benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate DIAD Diisopropyl azodicarboxylate Ruphos  Pd G3 Methanesulfonato(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (CAS No.: 1445085-77-7) DIEA, DIPEA or N, N-diisopropylethylamine rt room temperature DMA N,N-Dimethylacetamide tBu tert-butyl DMAP 4-Dimethylaminopyridine tBuONa Sodium tert-butoxide DME Dimethylether TBSCl tert Butyldimethylchlorosilane DMEDA N,N'-dimethylethylenediamine TCFH N,N,N',N'- Tetramethylchloroformamidi nium hexafluorophosphate DMF N,N-dimethylformamide TEA triethylamine DMSO dimethyl sulfoxide TFA trifluoroacetic acid EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride TfO- Trifluoromethanesulfonate ESI electrospray ionization Tf2O Triflic anhydride equiv equivalent THF Tetrahydrofuran EtOH ethanol THP tetrahydropyran EtOAc, or EA Ethyl acetate TLC thin layer chromatography HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate TMS tetramethylsilane HPLC high   performance   liquid chromatography TsCl p-toluenesulfonyl chloride HRMS high     resolution     mass spectrometry TsO- Tosyloxy IPA Isopropyl alcohol TsOH p-Toluenesulfonic acid LC-MS liquid chromatography-mass spectrometry ®T3P propylphosphonic anhydride LiHMDS Lithium hexamethyldisilazide TTIP titanium(IV) isopropoxide LRMS low     resolution     mass spectrometry Xantphos 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene LC Me liquid chromatography methyl Xphos 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl

[00284] 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, CDCI3 (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. Supercritical fluid chromatography (SFC) chiral resolution / separation was performed on a SHIMADZU LC-20AP instrument equipped with a Daicel CHIRALPAK®IE column. All reactions were carried out under ambient atmosphere unless otherwise specified. Reaction progress was monitored by TLC or LC-MS.

[00285] Solvents and reagents are processed as follows: the solvents used in the reactions such as DCM, DMF, NMP, anhydrous EtOH, and anhydrous MeOH were commercially available; preparative HPLC was performed using HPLC-grade CH3CN and deionized water; all other reactants, reagents and chemicals were commercially available, unless otherwise specified, or were synthesized using methods known in the art. 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.

[00286] General synthesis methods

[00287] 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) and Formula (II) of the present disclosure according to routine techniques in the art.

[00288] General synthesis method 1 for intermediate compounds: DIEA, DMF Scheme M-1

[00289] General synthesis method 2 for intermediate compounds: Scheme M-2

[00290] In Scheme M-2, ring D of the substrate amine used and Q1 of the substrate acid used are as defined in the structure of Formula (PBM-7) and its various embodiments. The Rca of the substrate acid used is a monovalent group corresponding to the divalent group Rc in the structure of Formula (PBM-7). For example, Rca represents -CHO, -OH, -NH(Rd), -C(O)NH2, -N(Rd)-Rf- NH(Re), -Rf-C(O)NH2, -Rf-C(O)OH, -C(O)OH, -Rf-H, -Rf-NH(Rd), -O-Rf-NH(Rd), , (RC2)m2             , (RC2)m2 wherein Rd, Re, Rf, Rg, Rc1, Rc2, ring W1, ring W2, t1, t2, m1, and m2 are as defined in the compound of Formula (I) and its various embodiments in the present disclosure. It should be understood that when the group Rca contains active hydrogen or reactive group that can participate in the reaction of Scheme M-2, the active hydrogen or reactive group can be protected by techniques and methods known to those skilled in the art, such as using protecting groups. For example, when Rca represents a piperidinyl or piperazinyl group, conventional protecting groups such as Boc can be used to protect the hydrogen on the N. For example, when Rca represents -CHO, conventional protecting groups can be used to protect the aldehyde group, such as by forming an acetal. The removal of the protecting group can be achieved by techniques and methods known to those skilled in the art. For instance, the removal of the Boc protecting group can be accomplished under acidic conditions such as hydrochloric acid or trifluoroacetic acid. As another example, the removal of the acetal protecting group can be achieved under acidic conditions, such as sulfuric acid, hydrochloric acid, or trifluoroacetic acid.

[00291] In Scheme M-2, to a solution of the substrate acid (1 equiv) and the substrate amine (1 equiv) in DMF were added HATU (1.5 equiv) and DIEA (5 equiv). The mixture was then reacted at room temperature for 30 minutes. After monitoring the reaction via LC-MS and confirming its completion, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and concentrated to give a crude product. The crude product was purified by column chromatography (eluent (v / v): DCM / MeOH = 100 / 1) to afford the target compound.

[00292] General synthesis method 3 for intermediate compounds: palladium-catalyzed / y—A A \y2-y3    Ihnw2>h o2n—^y, + v       X y4:y5          (R^lmz coupling reaction                                                                         . or                                                          T,s1 1A(1 \j__oni substitution reaction       Y2Y3 / s' W / /     \\    , reduction          Y? Y3 / S W u \\ vT / T ________02N^> 'M-N W2 W W1 H-Rn1 reacti°n r H.N-A  U-N W2 W W1 / )~Rn1 t1                      ,pr^Y4 Y5            '"~K 7t1                     Y4;Y5 \ ^--^2   T"7 t1 (   )m1                               <R )s1           (RC2)m2    (RC’)m1                                           (RC2)m2 (R'Arnl 1                        2 3                                               4 Scheme M-3

[00293] In Scheme M-3, (Rm1)s1 of compound 1 indicates that the 6-membered ring to which it is attached is optionally substituted with s1 Rm1 groups, with each Rm1 being identical or different and each independently representing halogen, hydroxy, C1-6 alkyl (e.g., methyl or ethyl), halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy (e.g., methoxy or isopropoxy), halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, NO2, NH2, or cyano, s1 represents an integer of 0, 1, 2, 3 or 4, Y1 represents halogen (e.g., fluorine, chlorine, or bromine), and Y2, Y3, Y4, and Y5 each independently represent N or CH, with the provision that Y2, Y3, Y4, and Y5 are not all N simultaneously. Ring W1, ring W2, t1, t2, (Rc1)m1, and (Rc2)m2 are as defined in the compound of Formula (I) of the present disclosure. Rn1 represents Boc, H or -NHRh, wherein Rh represents hydrogen or C1-6 alkyl (e.g., methyl or ethyl). It should be understood that when ring W1-Rn1 contains additional reactive groups (e.g., -NH- or -NH2) that can participate in the reaction of Scheme M-3, the reactive groups can be protected by techniques and methods known to those skilled in the art, such as using protecting groups.

[00294] Depending upon the target compound, the reaction substrate, reaction conditions (including reaction dosage, temperature, time, etc.), and work up, etc. in Scheme M-3 can be appropriately modified and adjusted using techniques and methods well known to those skilled in the art to obtain the desired target compound. In Scheme M-3, the substitution reaction or palladium-catalyzed coupling reaction of step 1 can be conventional techniques and methods known to those skilled in the art. When step 1 is a substitution reaction, Y1 represents fluorine, and compounds 1 and 2 react under basic conditions (such as K2CO3). When step 1 is a palladium-catalyzed coupling reaction, Y1 represents bromine, and the palladium catalyst and phosphine ligand used can be conventional ones suitable for coupling reactions. There are many types of conventional palladium catalysts for coupling reactions, such as palladium acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), diphenylphosphinoferrocene dichloropalladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium on carbon, etc. The phosphine ligand can be a conventional ligand such as Xantphos or BINAP. The reduction reaction of step 2 in Scheme M-3 can be conventional techniques and methods known to those skilled in the art, such as H2 / Pd / C or Fe / NH4Cl / MeOH.

[00295] General synthesis method 4 for intermediate compounds: Scheme M-4

[00296] General synthesis method 5 for intermediate compounds: or CAS No.: 761440-16-8 or CAS No.: 1197953-49-3 or F CAS No.: 1061358-71-1 or CAS No.: 1211443-61-6 I CAS No.: 2267331-23-5 Scheme M-5

[00297] In Scheme M-5, (Rm1)s1 of the compounds indicates that the 6-membered ring to which it is attached is optionally substituted with s1 Rm1 groups, with each Rm1 being identical or different and each independently representing halogen, hydroxy, C1-6 alkyl (e.g., methyl or ethyl), halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy (e.g., methoxy or isopropoxy), halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, NO2, NH2, or cyano. Y1 represents halogen (e.g., fluorine, chlorine, or bromine), and Y2, Y3, Y4, and Y5 each independently represent N or CH, with the provision that Y2, Y3, Y4, and Y5 are not all N simultaneously. Ring W1, ring W2, t1, t2, (Rc1)m1, and (Rc2)m2 are as defined in the compound of Formula (I) of the present disclosure. Rn1 represents    0^, Boc, H, or -NHRh, where Rh represents hydrogen or Ci-6 alkyl (e.g., methyl or ethyl). It should be understood that when ring W1-Rn1 contains additional reactive groups (such as -NH-, -NH2, or aldehyde group) that can participate in the reaction of Scheme M-5, the reactive groups can be protected by techniques and methods known to those skilled in the art, such as using protecting groups. The removal of protecting groups can be achieved through techniques and methods known to those skilled in the art. For example, the removal of the Boc protecting group can be achieved under acidic conditions such as hydrochloric acid or trifluoroacetic acid. As another example, the removal of the acetal protecting group can be achieved under acidic conditions, such as sulfuric acid, hydrochloric acid, or trifluoroacetic acid.

[00298] Depending upon the target compound, the reaction substrate, reaction conditions (including reaction dosage, temperature, time, etc.), and work up, etc. in Scheme M-5 can be appropriately modified and adjusted using techniques and methods well known to those skilled in the art to obtain the desired target compound. In Scheme M-5, the substitution reaction or coupling reaction can be conventional techniques and methods known to those skilled in the art. For example, substitution reactions can be carried out under heating conditions in the presence of triethylamine / isopropanol, p-toluenesulfonic acid / n-butanol, DIEA / ethanol, NaHMDS, or NaI / DIEA / DMF; coupling reactions can be performed under heating conditions in the presence of Brettphos Pd G3 / Brettphos ligand / Cs2CO3.

[00299] General synthesis method 6 for intermediate compounds: Scheme M-6

[00300] General synthesis method 7 for intermediate compounds: NC Scheme M-7

[00301] The removal of protecting groups can be achieved through techniques and methods known to those skilled in the art. For example, the removal of the Boc protecting group can be achieved under acidic conditions such as concentrated sulfuric acid.

[00302] General synthesis method 8 for intermediate compounds: Scheme M-8

[00303] Depending upon the target compound, the reaction substrate, reaction conditions (including reaction dosage, temperature, time, etc.), and work up, etc. in Scheme M-8 can be appropriately modified and adjusted using techniques and methods well known to those skilled in the art to obtain the desired target compound. In Scheme M-8, the amide condensation reaction can be conventional techniques and methods known to those skilled in the art. For example, the amide condensation reaction can be carried out at room temperature in the presence of HATU / DIEA / DMF or HOAt / EDCI / TEA / DCM.

[00304] General synthesis method 9 for intermediate compounds: Scheme M-9

[00305] General synthesis method 10 for intermediate compounds: Scheme M-10

[00306] General synthesis method 11 for intermediate compounds: Scheme M-11

[00307] General synthesis method 12 for intermediate compounds: Pd2dba3, xantphos Cs2CO3, 1,4-dioxane 1. IPA, 80°C, 3h 2. (n-Bu)3P, rt.-80°C, o / n Scheme M-12

[00308] In Scheme M-12, Z5 represents CH or N.

[00309] General synthesis method 13 for intermediate compounds: Scheme M-13

[00310] General synthesis method 1 for compounds of Formula (I): PBM—CHO + reductive amination Scheme I-1

[00311] In Scheme I-1, the PBM aldehyde or ketone substrate is a compound whose PBM moiety corresponds to the PBM moiety of the compound of Formula (I) herein. In the PBM substrate aldehyde or ketone, and in the other amine substrate, Ra1, Ra2, Ra3, Ra4, Z, and (Ra5)m are as defined in the compound of Formula (I) herein. In Scheme I-1, (i) RL1 represents NH, and RL2 and RL3, together with the nitrogen atom to which they are attached, form (Rdi)m , wherein ring Y1 and (Rdi)ni are as defined in the compound of Formula (I) herein; or (ii) Rli and Rl2 together form     (R«dni , wherein ring Y1 and (Rdi)ni are as defined in the compound of Formula (I) herein, and RL3 represents H; or (iii) RL1 represents NH, RL2 represents a bond, and RL3 represents H; or * * * *        S (iv) Rli represents         02   , wherein the symbol **** indicates the point of (Rd3)n3 ### 4-n y3 M- attachment to RL2, RL2 represents             , wherein the symbol ### indicates the point of attachment to N, and ring Y3 and (Rd3)n3 are as defined in the compound of Formula (I) herein, and RL3 represents H.

[00312] The reductive amination reaction in Scheme I-1 can be carried out by conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction can be carried out in the presence of sodium triacetoxyborohydride and 1,2-dichloroethane (or N,N-dimethylformamide) at a temperature ranging from room temperature to 80 oC. Alternatively, the reductive amination reaction can be carried out in the presence of sodium borohydride and 1,4-dioxane at a temperature ranging from room temperature to 80 oC.

[00313] For example, the procedure of Scheme I-1 can be as follows: To a solution of the corresponding PBM aldehyde or ketone substrate compound (1.0 equiv) and amine substrate (1.2 equiv) in N,N-dimethylformamide was added sodium acetate (0.9 equiv), and the mixture was stirred at room temperature for 1 h. Then acetic acid (0.9 equiv) and sodium cyanoborohydride (2.8 equiv) were added, and the reaction was carried out at room temperature. After the completion of the reaction was confirmed by LC-MS, the final target compound was obtained by purification via C18 reversed-phase column chromatography.

[00314] General synthesis method 2 for compounds of Formula (I): Urea Formation (Triphosgene) 1-2-1 I-2-2 I-2-3 Scheme I-2

[00315] In Scheme I-2, PBM, Z, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Rw, ring Y1, (Rd1)n1, ring Y2, and (Rd2)n2 are as defined in the compound of Formula (I) and its various sub-embodiments of the present disclosure.

[00316] The specific procedure of Scheme I-2 can be as follows:

[00317] To a solution of compound I-2-1 (40 mg, 0.095 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (36.84 mg, 0.285 mmol), followed by the addition of triphosgene (0.006 mL, 0.038 mmol) under stirring, and the mixture was stirred at room temperature for 0.5 h. Then a solution of compound I-2-2 (37.35 mg, 0.105 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction was carried out at room temperature for 1 h. After the completion of the reaction was confirmed by LC-MS, the reaction mixture was filtered, and the filtrate was purified by reversed-phase column chromatography to afford the target product.

[00318] General synthesis method 3 for compounds of Formula (I): Scheme I-3

[00319] In Scheme I-3, PBM, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z, Ra6, Rw1, ring A1, ring A2, ring A3, y1, y2, (Ry1)a1, (Ry2)a2, and (Ry3)a3 are as defined in the compound of Formula (I) and its various subembodiments of the present disclosure.

[00320] The reductive amination reaction in Scheme I-3 can be carried out by conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction can be carried out in the presence of sodium triacetoxyborohydride and 1,2-dichloroethane (or dichloromethane) at a temperature ranging from room temperature to 80 oC.

[00321] For example, to a solution of the corresponding PBM aldehyde or ketone substrate (1.0 equiv) and amine substrate (1.0 equiv) in dichloromethane was added an appropriate amount of acetic acid. The mixture was reacted at room temperature for 30 minutes, then sodium cyanoborohydride (3.0 equiv) was added, and the reaction was continued at room temperature. After the completion of the reaction was confirmed by LC-MS, the final target compound was obtained by purification via C18 reversed-phase column chromatography.

[00322] General synthesis method 4 for compounds of Formula (I):

[00323] In Scheme I-4, PBM, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z, Rw2, ring A1, ring A2, ring A3, y1, y2, y3, (Ry1)a1, (Ry2)a2, and (Ry3)a3 are as defined in the compound of Formula (I) and its various subembodiments of the present disclosure. In Scheme I-4, RL1, RL2, and RL3 are as defined in Scheme I-1. -Rw3-CH2- is a non-limiting example of Rw1 of the compound of Formula (I) herein, wherein Rw3 represents a bond or an optionally substituted linear or branched C1-19 alkylene, wherein any one or more methylene groups in the main carbon chain skeleton of the linear or branched C1-19 alkylene are optionally replaced by one or more groups selected from: Ra, Rb, and any combination thereof; wherein each Ra is independently selected from the group consisting of: O, C(O), OC(O), S, S(O), S(O)2, S(O)2N(Ra7), N(Ra7)S(O)2, C(O)N(Ra7), N(Ra7)C(O), N(Ra7), and N(Ra7)C(O)N(Ra7), where each Ra7 independently represents H or C1-3 alkyl, and when any two or more methylene in the main carbon chain skeleton of the linear or branched C1-19 alkylene are replaced by two or more Ra groups, the Ra groups are not directly connected to each other; and wherein each Rb is independently selected from the group consisting of: optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, alkynylene, alkenylene, and any combination thereof; and wherein one or more hydrogens of said linear or branched C1-19 alkylene are optionally replaced by a substituent selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10membered heterocyclyl, and any combination thereof.

[00324] The reductive amination reaction in Scheme I-4 can be carried out by conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction can be carried out in the presence of sodium triacetoxyborohydride and 1,2-dichloroethane (or dichloromethane) at a temperature ranging from room temperature to 80 oC.

[00325] For example, to a solution of the corresponding PBM aldehyde or ketone substrate (1.0 equiv) and amine substrate (1.0 equiv) in dichloromethane was added an appropriate amount of acetic acid. The mixture was reacted at room temperature for 30 minutes, then sodium cyanoborohydride (3.0 equiv) was added, and the reaction was continued at room temperature. After the completion of the reaction was confirmed by LC-MS, the final target compound was obtained by purification via C18 reversed-phase column chromatography.

[00326] General synthesis method 5 for compounds of Formula (I): amide condensation Scheme I-5

[00327] In Scheme I-5, PBM, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z, Rw2, ring A1, ring A2, ring A3, y1, y2, y3, (Ry1)a1, (Ry2)a2, and (Ry3)a3 are as defined in the compound of Formula (I) and its various subembodiments herein. RL1, RL2, and RL3 in Scheme I-5 are as defined in Scheme I-1. Rw3 in Scheme I-5 is as defined in Scheme I-4.

[00328] The amide condensation reaction in Scheme I-5 can be carried out by conventional techniques and methods well known to those skilled in the art. For example, the amide condensation reaction can be carried out in the presence of HATU / DIEA / DMF, or HOAt / EDCI / TEA / DCM at room temperature.

[00329] The specific procedure of Scheme I-5 can be as follows:

[00330] To a solution of carboxylic acid substrate 1 (1.1 eq.) and amine substrate 2 (1.0 eq.) in anhydrous DMF (2 mL) were added triethylamine (3.0 eq.) and HATU (1.3 eq.). The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction was confirmed by LC-MS, the reaction mixture was filtered, and the filtrate was purified by high performance liquid chromatography (HPLC) to afford the target compound.

[00331] General synthesis method 1 for compounds of Formula (II): 0 0       (°a5)m (Rdi)n1 A-1-1 palladium-catalyzed coupling reaction A-1-2 A-1-3 Scheme II-1

[00332] In Scheme II-1, Z, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Rw, ring Y1, and (Rd1)n1 are as defined in the compound of Formula (II) and its various sub-embodiments of the present disclosure.

[00333] The palladium-catalyzed coupling reaction and deprotection in Scheme II-1 can be carried out by conventional techniques and methods well known to those skilled in the art.

[00334] The specific procedure of Scheme II-1 can be as follows:

[00335] Step 1: At room temperature, to a 100 mL round-bottom flask were sequentially added compound A-1 (1.0 eq.), compound A-1-1 (1.2 eq.), cesium carbonate (2.0 eq.), palladium catalyst (0.025 eq.), and N,N-dimethylformamide. Under a nitrogen atmosphere, the reaction mixture was heated to 80 oC and stirred for 16 hours. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate three times. The organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound A-1-2 (gray solid, yield 73%).

[00336] Step 2: At room temperature, to a solution of compound A-1-2 in dichloromethane in a 100 mL round-bottom flask was added trifluoroacetic acid. The reaction mixture was stirred for 1 hour, and the completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting residue was lyophilized to afford compound A-1-3.

[00337] General synthesis method 2 for compounds of Formula (II): HN Y1 N-Ns Boc (Rdl)n1 A-2-1 palladium-catalyzed coupling reaction A-2-2 A-2-3 Scheme II-2

[00338] In Scheme II-2, Z, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Rw, ring Y1, and (Rd1)n1 are as defined in the compound of Formula (II) and its various sub-embodiments of the present disclosure.

[00339] The palladium-catalyzed coupling reaction and deprotection in Scheme II-2 can be carried out by conventional techniques and methods well known to those skilled in the art.

[00340] The specific procedure of Scheme II-1 can be as follows:

[00341] Step 1: At room temperature, to a 100 mL round-bottom flask were sequentially added compound A-1 (1.0 eq.), compound A-2-1 (1.2 eq.), cesium carbonate (2.0 eq.), palladium catalyst (0.025 eq.), and N,N-dimethylformamide. Under a nitrogen atmosphere, the reaction mixture was heated to 80 oC and stirred for 16 hours. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate three times. The organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound A-2-2 (gray solid, yield 73%).

[00342] Step 2: At room temperature, to a solution of compound A-2-2 in dichloromethane in a 100 mL round-bottom flask was added trifluoroacetic acid. The reaction mixture was stirred for 1 hour, and the completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting residue was lyophilized to afford compound A-2-3.

[00343] General synthesis method 3 for compounds of Formula (II): 0 0 X B-1 (Rdl)n1 substitution reaction B-1-1 B-1-2 Scheme II-3 B-1-3

[00344] In Scheme II-3, Ra1, Ra2, Ra3, Ra4, Rw, ring Y1, and (Rd1)n1 are as defined in the compound of Formula (II) and its various sub-embodiments of the present disclosure. X represents H or F.

[00345] The substitution reaction and deprotection in Scheme II-3 can be carried out by conventional techniques and methods well known to those skilled in the art.

[00346] The specific procedure of Scheme II-3 can be as follows:

[00347] Step 1: At room temperature, to a 100 mL round-bottom flask were sequentially added compound B-1 (1.0 eq.), compound B-1-1 (1.2 eq.), N,N-diisopropylethylamine (5.0 eq.), and dimethyl sulfoxide. Under a nitrogen atmosphere, the reaction mixture was heated to 130 °C and stirred for 16 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate three times. The organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound B-1-2 (gray solid, yield 62%).

[00348] Step 2: At room temperature, to a solution of compound B-1-2 in dichloromethane in a 100 mL round-bottom flask was added trifluoroacetic acid. The reaction mixture was stirred for 1 hour, and the completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting residue was lyophilized to afford compound B-1-3.

[00349] General synthesis method 4 for compounds of Formula (II): B-1                      B-2-1                                       B-2-2                                                  B-2-3 Scheme II-4

[00350] In Scheme II-4, Ra1, Ra2, Ra3, Ra4, Rw, ring Y1, and (Rd1)n1 are as defined in the compound of Formula (II) and its various sub-embodiments of the present disclosure. X represents H or F.

[00351] The substitution reaction and deprotection in Scheme II-4 can be carried out by conventional techniques and methods well known to those skilled in the art.

[00352] The specific procedure of Scheme II-4 can be as follows:

[00353] Step 1: At room temperature, to a 100 mL round-bottom flask were sequentially added compound B-1 (1.0 eq.), compound B-2-1 (1.2 eq.), N,N-diisopropylethylamine (5.0 eq.), and dimethyl sulfoxide. Under a nitrogen atmosphere, the reaction mixture was heated to 130 oC and stirred for 16 hours. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate three times. The organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound B-2-2 (gray solid, yield 62%).

[00354] Step 2: At room temperature, to a solution of compound B-2-2 in dichloromethane in a 100 mL round-bottom flask was added trifluoroacetic acid. The reaction mixture was stirred for 1 hour, and the completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting residue was lyophilized to afford compound B-2-3.

[00355] General synthesis method 5 for compounds of Formula (II): Scheme II-5

[00356] In Scheme II-5, Ra1, Ra2, Ra3, Ra4, Z, (Ra5)m, ring Y3, and (Rd3)n3 are as defined in the compound of Formula (I) and its various sub-embodiments of the present disclosure.

[00357] 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.

[00358] It should be understood that, in each of the above synthetic schemes, when a group contains an active hydrogen or a reactive group that is not intended to participate in the scheme reaction, such active hydrogen or reactive group can be protected by techniques and methods well known to those skilled in the art, for example, using protecting groups. For example, when the reactive group is piperidinyl or piperazinyl, conventional protecting groups such as Boc and the like can be used to protect the hydrogen on the nitrogen. For example, when the reactive group is -CHO, conventional protecting groups can be used to protect the aldehyde group, such as by forming an acetal. The deprotection of the protecting groups can be achieved by techniques and methods well known to those skilled in the art. For example, the removal of the Boc protecting group can be achieved under acidic conditions, such as hydrochloric acid or trifluoroacetic acid. As another example, the removal of the acetal protecting group can be achieved under acidic conditions, such as sulfuric acid, hydrochloric acid, or trifluoroacetic acid. Examples

[00359] Intermediate Example 1: Preparation of compound GT-04304

[00360] With reference to the method of Scheme II-1, the target compound (GT-04304) was obtained (gray solid, 6.5 g, yield 97 %). 1H NMR (400 MHz, MeOD) 8 7.57 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 6.95 (dd, J = 8.4, 1.8 Hz, 1H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 4.44 - 4.31 (m, 2H), 3.38 (t, J = 5.1 Hz, 4H), 3.03 (s, 4H), 2.86 (dd, J = 13.3, 5.3 Hz, 1H), 2.81 - 2.72 (m, 1H), 2.45 (dd, J = 13.1, 4.7 Hz, 1H), 2.17 - 2.09 (m, 1H). LCMS (ESI) calcd. for C17H22N5O3+ [M+H]+: 344.17, found, 344.2.

[00361] Example 1 of compound of Formula (II): Preparation of compound GT-06985

[00362] With reference to the method of Scheme II-1, the target compound (GT-06985) was obtained (gray solid, 11.7 g, yield 99 %). 1H NMR (400 MHz, MeOD) 8 7.49 (d, J = 8.3 Hz, 1H), 7.45 - 7.36 (m, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (q, J = 16.7 Hz, 2H), 3.44 - 3.36 (m, 4H), 3.09 (d, J = 4.6 Hz, 4H), 2.95 - 2.85 (m, 1H), 2.81 - 2.75 (m, 1H), 2.48 (qd, J = 13.2, 4.7 Hz, 1H), 2.19 - 2.10 (m, 1H). LCMS (ESI) calcd. for C17H21FN5O3+ [M+H]+: 362.16, found, 362.2.

[00363] Example 2 of compound of Formula (II): Preparation of compound GT-06988

[00364] With reference to the method of Scheme II-1, the target compound (GT-06988) was obtained (gray solid, 7.9 g, yield 97 %). 1H NMR (400 MHz, DMSO-d6) 8 10.96 (s, 1H), 8.74 (s, 2H), 7.73 (s, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 5.05 (dd, J = 13.3, 5.0 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 4.20 (d, J = 16.9 Hz, 1H), 3.25 (s, 4H), 2.98 (s, 4H), 2.92 - 2.82 (m, 1H), 2.59 (d, J = 17.2 Hz, 1H), 2.36 (dd, J = 13.2, 4.4 Hz, 1H), 2.04 - 1.91 (m, 1H). LCMS (ESI) calcd. for C17H21FN5O3+ [M+H]+: 362.16, found, 362.2.

[00365] Example 3 of compound of Formula (II): Preparation of compound GT-06989

[00366] With reference to the method of Scheme II-1, the target compound (GT-06989) was obtained (gray solid, 5.4 g, yield 87 %). 1H NMR (400 MHz, MeOD) § 6.77 (s, 1H), 6.65 (d, J = 12.1 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 (q, J = 17.0 Hz, 2H), 3.38 (t, J = 4.8 Hz, 4H), 3.02 (s, 4H), 2.85 (dd, J = 13.3, 5.2 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.42 (dd, J = 13.1, 4.7 Hz, 1H), 2.17 - 2.07 (m, 1H). LCMS (ESI) calcd. for C17H21FN5O3+ [M+H]+: 362.16, found, 362.2.

[00367] Example 4 of compound of Formula (II): Preparation of compound GT-07368

[00368] With reference to the method of Scheme II-1, the target compound (GT-07368) was obtained (gray solid, 5.4 g, yield 98 %). 1H NMR (400 MHz, DMSO-d6) 8 10.98 (s, 1H), 8.78 (s, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.08 (dd, J = 7.6, 4.4 Hz, 2H), 5.09 (dd, J = 13.2, 5.2 Hz, 1H), 4.36 (d, J = 17.6 Hz, 1H), 4.24 (d, J = 17.6 Hz, 1H), 3.24 (s, 4H), 2.93 (s, 4H), 2.89 (d, J = 5.2 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.40 (qd, J = 13.2, 4.4 Hz, 1H), 2.07 - 1.97 (m, 1H). LCMS (ESI) calcd. for C17H22N5O3+ [M+H]+: 344.17, found, 344.1.

[00369] Example 5 of compound of Formula (II): Preparation of compound GT-05579

[00370] With reference to the method of Scheme II-1, the target compound (GT-05579) was obtained (gray solid, 4.1 g, yield 97 %). 1H NMR (400 MHz, DMSO-D6) 8 11.07 (s, 1H), 8.85 (s, 2H), 8.35 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 5.05 (dd, J = 12.9, 5.3 Hz, 1H), 3.68 (d, J = 4.3 Hz, 1H), 3.31 (d, J = 18.6 Hz, 4H), 2.88 (td, J = 14.6, 5.2 Hz, 4H), 2.56 (dd, J = 20.1, 10.7 Hz, 2H), 2.01 (dd, J = 9.9, 4.8 Hz, 1H). LCMS (ESI) calcd. for C17H20N5O4+ [M+H]+: 358.15, found, 358.1.

[00371] Example 6 of compound of Formula (II): Preparation of compound GT-04310

[00372] With reference to the method of Scheme II-3, the target compound (GT-04310) was obtained (pale yellow solid, 1.5 g, yield 96 %). 1H NMR (400 MHz, DMSO-D6) 8 11.09 (s, 1H), 8.84 (s, 1H), 8.42 (s, 1H), 7.65 (d, J = 10.3 Hz, 1H), 7.57 (d, J = 7.0 Hz, 1H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 3.30 (s, 4H), 2.97 (d, J = 33.3 Hz, 4H), 2.93 - 2.83 (m, 1H), 2.56 (dd, J = 22.6, 11.2 Hz, 2H), 2.05 - 1.97 (m, 1H). LCMS (ESI) calcd. for C17H19FN5O4+ [M+H]+: 376.14, found, 376.2.

[00373] Example 7 of compound of Formula (II): Preparation of compound GT-07007

[00374] With reference to the method of Scheme II-4, the target compound (GT-07007) was obtained (gray solid, 3.6 g, yield 92 %). 1H NMR (400 MHz, DMSO-d6) 5 11.09 (s, 1H), 9.48 (s, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz, 1H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 3.58 (s, 4H), 3.02 (s, 4H), 2.92 - 2.83 (m, 1H), 2.57 (dd, J = 19.3, 10.3 Hz, 2H), 2.08 - 1.99 (m, 1H). LCMS (ESI) calcd. for Ci7H2oNs04+ [M+H]+: 358.15, found, 358.2.

[00375] Example 8 of compound of Formula (II): Preparation of compound GT-07051

[00376] With reference to the method of Scheme II-4, the target compound (GT-07051) was obtained (gray solid, 1.6 g, yield 97 %). 1H NMR (400 MHz, DMSO-d6) 5 10.95 (s, 1H), 9.65 (s, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.13 - 7.06 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.34 (d, J = 17.0 Hz, 1H), 4.23 (t, J = 17.0 Hz, 1H), 3.46 - 3.30 (m, 4H), 3.11 (brs, 4H), 2.94 - 2.84 (m, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.43 - 2.31 (m, 1H), 1.98 - 1.90 (m, 1H). LCMS (ESI) calcd. for C17H22N5O3+ [M+H]+: 344.17, found, 344.2.

[00377] Example 9 of compound of Formula (II): Preparation of compound GT-07008

[00378] The target compound GT-07008 was prepared by referring to the method of Scheme II-5.

[00379] Step 1: In a 100 mL round-bottom flask, to a solution of (1-aminopiperidin-4-yl)methanol (1.0 eq.) in 1,4-dioxane were sequentially added (Boc)2O (1.2 eq.) and triethylamine (3.0 eq.). The reaction mixture was stirred at room temperature for 16 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure. The resulting concentrate was washed with water, and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate=0-50%) to afford tert-butyl (4-(hydroxymethyl)piperidin-1-yl)carbamate as a white solid (yield 80%).

[00380] Step 2: In a 100 mL round-bottom flask, to a solution of tert-butyl (4-(hydroxymethyl)piperidin-1-yl)carbamate (1.0 eq.) in dichloromethane were sequentially added MsCl (1.2 eq.) and triethylamine (3.0 eq.). The reaction mixture was stirred at room temperature for 1 hour. The completion of the reaction was confirmed by TLC. The reaction mixture was washed with water, and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 0-40%) to afford (1-((tert-butoxycarbonyl)amino)piperidin-4-yl)methyl methanesulfonate as a white solid (yield 85%).

[00381] Step 3: In a 100 mL round-bottom flask, to a solution of (1-((tert-butoxycarbonyl)amino)piperidin-4-yl)methyl methanesulfonate (1.3 eq.) and 3-(5-mercapto-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 eq.) in dimethyl sulfoxide was added triethylamine (3.0 eq.). The reaction mixture was stirred at room temperature for 16 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was washed with water, and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 0-50%) to afford tert-butyl (4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)thio)methyl)piperidin-1-yl)carbamate as a white solid (yield 50%).

[00382] Step 4: At room temperature, to a solution of tert-butyl (4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)thio)methyl)piperidin-1-yl)carbamate in dichloromethane in a 100 mL round-bottom flask was added trifluoroacetic acid. The reaction mixture was stirred for 1 hour, and the completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the resulting residue was lyophilized to afford the target compound GT-07008 (gray solid, 0.6 g, yield 93 %). 1H NMR (400 MHz, MeOD) 6 11.80 (s, 1H), 10.03 (s, 1H), 8.48 - 8.43 (m, 1H), 8.38 (s, 1H), 8.25 (d, J = 7.1 Hz, 1H), 5.91 (dd, J = 13.3, 5.1 Hz, 1H), 5.17 (dd, J = 50.0, 17.4 Hz, 2H), 4.26 (s, 4H), 3.86 (d, J = 6.1 Hz, 2H), 3.77 -3.68 (m, 1H), 3.42 (d, J = 17.0 Hz, 1H), 3.30 - 3.12 (m, 2H), 2.89 - 2.68 (m, 3H), 2.27 - 2.16 (m, 2H). LCMS (ESI) calcd. for C19H25N4O3S+ [M+H]+: 389.16, found, 389.2.

[0001] Example 10 of compound of Formula (II): Preparation of compound GT-07966

[0002] With reference to the method of Scheme II-1, the target compound (GT-07966) was obtained (yellow solid, 1.56 g, yield 94 %). 1H NMR (400 MHz, DMSO-d6) 6 10.93 (s, 1H), 8.99 (s, 2H), 7.56 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.94(s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.2 Hz, 1H), 4.31 (d, J = 16.8 Hz, 1H), 4.18 (d, J =16.8 Hz, 1H), 4.08 - 4.01 (m, 2H), 2.99 - 2.82 (m, 5H), 2.58 (d,J = 16.8 Hz, 1H), 2.33 (dd, J = 13.2, 4.4 Hz, 1H), 2.15 (d, J = 8.8 Hz, 2H), 1.98 - 1.89 (m, 3H). LCMS (ESI) calcd. for C19H24N5O3+: 370.19; found, 370.1.

[0003] Example 11 of compound of Formula (II): Preparation of compound GT-08008

[0004] With reference to the method of Scheme II-1, the target compound (GT-08008) was obtained (yellow solid, 1.7 g, yield 83 %). 1H NMR (400 MHz, DMSO-d6) 6 10.93 (s, 1H), 9.49 (s, 1H), 7.98 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.03(s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.2 Hz, 1H), 4.30 (dd, J = 11.2, 5.6 Hz, 3H), 4.18 (d, J = 16.8 Hz, 1H), 3.46 (d, J = 10.4 Hz, 2H), 3.34 (d, J = 11.2 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.75 - 2.64 (m,1H), 2.58 (d, J = 16.8 Hz, 1H), 2.35 (ddd, J = 26.0, 13.2, 4.4 Hz, 2H), 1.98 - 1.91 (m, 1H). LCMS (ESI) calcd. for C18H22N5O3+: 356.16; found, 356.1.

[0005] Example 12 of compound of Formula (II): Preparation of compound GT-08009

[0006] With reference to the method of Scheme II-1, the target compound (GT-08009) was obtained (yellow solid, 1.2 g, yield 75 %). 1H NMR (400 MHz, DMSO-d6) 8 10.93 (s, 1H), 9.03 (s, 1H), 8.77 (s, 1H), 7.72 (s, 1H), 7.45 (d, J = 8.4Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.2 Hz, 1H), 4.30 (d, J = 16.4 Hz, 2H),4.17 (d, J = 16.8 Hz, 1H), 3.63 (s, 1H), 3.15 (s, 2H), 3.07 - 2.77 (m, 2H), 2.58 (d, J = 16.8 Hz, 1H), 2.39 -2.14 (m, 2H), 1.95 (dd, J = 9.2, 3.6 Hz, 1H), 1.75 (d, J = 10.8 Hz, 1H), 0.83 (dd, J = 9.6, 6.8 Hz, 1H). LCMS (ESI) calcd. for C18H22N5O3+: 356.17; found, 356.1.

[0007] Example 13 of compound of Formula (II): Preparation of compound GT-08007

[0008] With reference to the method of Scheme II-1, the target compound () was obtained GT-08007 (brown solid, 1.1 g, yield 99 %). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 8.91 (s, 2H), 7.73 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.2 Hz, 1H), 4.31 (d, J = 16.8 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 3.26 (d, J = 4.8 Hz, 4H), 3.12 (s, 2H), 2.91 (ddd, J = 18.4, 13.6, 6.4 Hz, 3H), 2.59 (d, J = 16.8 Hz, 1H), 2.35 (qd, J = 13.2, 4.4 Hz, 1H), 2.04 - 1.82 (m, 3H). LCMS (ESI) calcd. for C18H24N5O3+ [M+H]+: 358.18; found, 358.2.

[0009] Example 14 of compound of Formula (II): Preparation of compound GT-08006

[0010] With reference to the method of Scheme II-1, the target compound (GT-08006) was obtained (brown solid, 980 mg, yield 95%). 1H NMR (400 MHz, DMSO-D6) 8 10.99 (s, 1H), 9.02 (s, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 16.8 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.35 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.80 (t, J = 6.0 Hz, 4H), 3.01 - 2.90 (m, 1H), 2.64 (d, J = 16.8 Hz, 5H), 2.39 (ddd, J = 26.0, 13.2, 4.4 Hz, 1H), 1.99 (dd, J = 17.6, 10.4 Hz, 5H). LCMS (ESI) calcd. for C20H26N5O3+ [M+H]+: 384.20; found, 384.3.

[0011] Example 15 of compound of Formula (II): Preparation of compound GT-07965

[0012] With reference to the method of Scheme II-1, the target compound (GT-07965) was obtained (off-white solid, 1.1 g, yield 99 %). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 8.93 (s, 1H), 8.76 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 6.95 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.03 (dd, J = 13.2, 4.8 Hz, 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.19 (s, 1H), 3.47 (s, 2H), 3.10 -2.82 (m, 7H), 2.68 (s, 2H), 2.59 (d, J = 17.6 Hz, 1H), 2.34 (dt, J = 22.4, 11.2 Hz, 1H), 2.02 - 1.90 (m, 1H). LCMS (ESI) calcd. for C19H24N5O3+ [M+H]+: 370.18; found, 370.1.

[0013] Example 16 of compound of Formula (II): Preparation of compound GT-09916

[0014] With reference to the method of Scheme II-1, the target compound (GT-09916) was obtained (off-white solid, 503 mg, yield 95 %). 1H NMR (400 MHz, DMSO-D6) 5 11.10 (s, 1H), 8.75 (s, 2H), 8.41 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.53 - 7.44 (m, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 3.29 (d, J = 20.1 Hz, 4H), 2.96 (d, J = 26.0 Hz, 4H), 2.91 - 2.85 (m, 1H), 2.63 - 2.55 (m, 1H), 2.49 (d, J = 4.9 Hz, 1H), 2.07 - 1.97 (m, 1H). LCMS (ESI) calcd. for C17H19FN5O4+ [M+H]+: 376.14, found, 376.2.

[0015] Example 17 of compound of Formula (II): Preparation of compound GT-09995

[0016] With reference to the method of Scheme II-1, the target compound (GT-09995) was obtained (off-white solid, 2110 mg, yield 91 %). 1H NMR (400 MHz, DMSO-d6) 5 11.09 (s, 1H), 8.87 (s, 2H), 8.75 (s, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.45 - 3.22 (m, 4H), 3.15 - 2.67 (m, 5H), 2.58 (d, J = 19.9 Hz, 1H), 2.50 - 2.43 (m, 1H), 2.01 (dd, J = 9.1, 3.7 Hz, 1H). LCMS (ESI) calcd. for C17H19FN5O4+ [M+H]+: 376.14, found, 376.2.

[0017] Example 18 of compound of Formula (II): Preparation of compound GT-08195

[0018] With reference to the method of Scheme II-1, the target compound (GT-08195) was obtained (gray solid, 480 mg, yield 99%). 1H NMR (400 MHz, DMSO-d6) 5 10.94 (s, 1H), 9.26 (s, 1H), 8.56 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.09 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 4.31 (d, J = 16.8 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 3.39 (s, 2H), 3.30 (s, 2H), 3.12 (d, J = 32.4 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.59 (d, J = 17.2 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.20 (s, 2H), 1.94 (t, J = 12.8 Hz, 3H). LCMS (ESI) calcd. for C19H24N5O3+ [M+H]+: 370.19, found, 370.2.

[00383] Example 1 of compound of Formula (I): Preparation of compound GT-07089

[00384] With reference to the method of Scheme I-1, the target compound (GT-07089) was obtained (white solid, 28 mg, yield 40.95%). 1H NMR (400 MHz, DMSO-d6) 5 11.62 (s, 1H), 11.09 (s, 1H), 10.95 (s, 1H), 9.02 (s, 1H), 8.21 (dd, J = 9.5, 2.4 Hz, 1H), 8.04 (s, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.84 (s, 1H), 5.04 (dd, J = 13.2, 5.0 Hz, 1H), 4.87 - 4.73 (m, 1H), 4.31 (d, J = 16.9 Hz, 2H), 3.69 (s, 3H), 3.55 (s, 2H), 3.25 (d, J = 6.9 Hz, 4H), 3.07 (s, 9H), 2.88 (t, J = 12.5 Hz, 3H), 2.59 (d, J = 16.6 Hz, 1H), 2.35 (dd, J = 19.9, 7.2 Hz, 3H), 2.19 - 1.93 (m, 8H), 1.74 - 1.58 (m, 2H), 1.46 (d, J = 10.5 Hz, 2H). LCMS (ESI) calcd. for C42H53N12O4+ [M+H]+: 789.43, found, 789.5.

[00385] Example 2 of compound of Formula (I): Preparation of compound GT-07090

[00386] With reference to the method of Scheme I-1, the target compound (GT-07090) was obtained (white solid, 32 mg, yield 47.07%). 1H NMR (400 MHz, DMSO-d6) 8 10.93 (s, 1H), 10.84 (s, 1H), 8.61 (d, J = 8.1 Hz, 1H), 7.87 (dd, J = 11.3, 9.2 Hz, 2H), 7.51 (d, J = 9.7 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.52 (dd, J = 23.0, 12.0 Hz, 3H), 4.36 -4.16 (m, 2H), 3.55 (d, J = 8.5 Hz, 2H), 3.11 (ddd, J = 26.2, 20.2, 8.8 Hz, 10H), 2.95 - 2.83 (m, 1H), 2.58 (d, J = 16.6 Hz, 1H), 2.33 (ddd, J = 40.3, 20.3, 15.8 Hz, 2H), 2.10 (d, J = 9.9 Hz, 2H), 2.04 - 1.84 (m, 5H), 1.70 - 1.47 (m, 4H), 1.35 - 1.23 (m, 2H). LCMS (ESI) calcd. for C41H48ClN10O5+ [M+H]+: 795.35, found, 795.3.

[00387] Example 3 of compound of Formula (I): Preparation of compound GT-06941

[00388] With reference to the method of Scheme I-1, the target compound (GT-06941) was obtained (white solid, 30 mg, yield 44.80%). 1H NMR (400 MHz, DMSO-d6) 8 10.94 (s, 1H), 10.42 (s, 1H), 9.51 (d, J = 6.3 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 3.7 Hz, 1H), 8.27 (t, J = 7.1 Hz, 1H), 7.77 (s, 1H), 7.45 (t, J = 10.2 Hz, 1H), 7.32 - 6.93 (m, 2H), 6.91 - 6.38 (m, 2H), 5.39 - 4.97 (m, 2H), 4.76 (d, J = 18.5 Hz, 1H), 4.37 - 4.15 (m, 3H), 3.87 - 3.71 (m, 2H), 3.66 -3.53 (m, 4H), 3.32 - 2.98 (m, 8H), 2.90 (s, 1H), 2.64 - 2.54 (m, 1H), 2.35 (dd, J = 13.2, 4.3 Hz, 1H), 2.12 - 1.87 (m, 8H), 1.80 (d, J = 11.7 Hz, 2H), 1.22 (d, J = 12.4 Hz, 2H). LCMS (ESI) calcd. for C40H47F2N12O5+ [M+H]+: 813.38, found, 813.4.

[00389] Example 4 of compound of Formula (I): Preparation of compound GT-07091

[00390] With reference to the method of Scheme I-1, the target compound (GT-07091) was obtained (white solid, 35 mg, yield 52.67%). 1H NMR (400 MHz, DMSO-d6) 8 10.94 (s, 1H), 10.67 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 13.1 Hz, 2H), 4.37 - 4.15 (m, 3H), 4.07 (d, J = 9.1 Hz, 1H), 3.53 - 3.43 (m, 3H), 3.24 - 3.00 (m, 10H), 2.96 -2.82 (m, 1H), 2.62 - 2.53 (m, 1H), 2.35 (dd, J = 13.0, 4.3 Hz, 1H), 2.23 (s, 1H), 1.96 (dd, J = 16.8, 8.9 Hz, 3H), 1.43 - 1.25 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H53ClN9O5+ [M+H]+: 822.39, found, 822.5

[00391] Example 5 of compound of Formula (I): Preparation of compound GT-06948

[00392] With reference to the method of Scheme I-1, the target compound (GT-06948) was obtained (white solid, 28 mg, yield 39.36%). 1H NMR (400 MHz, DMSO-d6) 8 11.60 (s, 1H), 11.09 (s, 1H), 10.98 (s, 1H), 9.01 (s, 1H), 8.55 (s, 1H), 8.19 (dd, J = 9.6, 2.4 Hz, 1H), 8.02 (d, J = 13.1 Hz, 1H), 7.64 (dd, J = 9.8, 4.9 Hz, 2H), 7.56 (d, J = 6.9 Hz, 1H), 6.83 (s, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.80 (dd, J = 17.4, 8.7 Hz, 1H), 3.59 - 3.48 (m, 5H), 3.33 (d, J = 9.1 Hz, 4H), 3.05 (d, J = 7.9 Hz, 10H), 2.89 - 2.77 (m, 3H), 2.58 (d, J = 18.3 Hz, 1H), 2.30 (s, 2H), 2.14 - 1.92 (m, 8H), 1.64 (d, J = 5.8 Hz, 2H), 1.44 (d, J = 10.6 Hz, 2H). LCMS (ESI) calcd. for C42H50FN12O5+ [M+H]+: 821.40, found, 821.5.

[00393] Example 6 of compound of Formula (I): Preparation of compound GT-06949

[00394] With reference to the method of Scheme I-1, the target compound (GT-06949) was obtained (white solid, 29 mg, yield 42.00%). 1H NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 10.59 (s, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.52 (s, 1H), 8.35 - 7.86 (m, 3H), 7.69 - 7.54 (m, 2H), 7.20 (t, J = 5.3 Hz, 2H), 7.01 (dd, J = 8.8, 2.3 Hz, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.46 (d, J = 12.8 Hz, 2H), 4.35 (s, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.28 (d, J = 8.7 Hz, 4H), 3.16 - 3.00 (m, 6H), 2.85 (ddd, J = 36.7, 29.5, 11.0 Hz, 3H), 2.56 (dd, J = 19.8, 10.2 Hz, 2H), 2.23 (s, 1H), 2.00 (dd, J = 19.0, 9.5 Hz, 3H), 1.39 - 1.25 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H50ClFN9O6+ [M+H]+: 854.36, found, 854.5.

[00395] Example 7 of compound of Formula (I): Preparation of compound GT-06950

[00396] With reference to the method of Scheme I-1, the target compound (GT-06950) was obtained (white solid, 34 mg, yield 48.08%). 1H NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 10.51 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.51 (s, 1H), 7.91 - 7.82 (m, 2H), 7.65 (d, J = 10.2 Hz, 1H), 7.57 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 9.7 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.52 (dd, J = 21.2, 11.4 Hz, 3H), 3.85 (dd, J = 11.4, 7.7 Hz, 1H), 3.41 - 3.22 (m, 4H), 3.19 - 3.00 (m, 6H), 2.98 - 2.77 (m, 2H), 2.64 - 2.52 (m, 2H), 2.22 (s, 1H), 2.00 (ddd, J = 45.5, 34.0, 14.0 Hz, 7H), 1.72 - 1.20 (m, 7H), 0.93 (t, J = 7.3 Hz, 1H). LCMS (ESI) calcd. for C41H45ClFN10O6+ [M+H]+: 827.32, found, 827.3.

[00397] Example 8 of compound of Formula (I): Preparation of compound GT-06951

[00398] With reference to the method of Scheme I-1, the target compound (GT-06951) was obtained (white solid, 27 mg, yield 38.79%). 1H NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 10.02 (s, 1H), 9.51 (d, J = 6.4 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.48 (s, 1H), 8.40 (d, J = 3.7 Hz, 1H), 8.25 (d, J = 5.3 Hz, 1H), 7.65 (d, J = 10.2 Hz, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.11 (dd, J = 55.2, 52.2 Hz, 1H), 6.66 (dd, J = 165.7, 7.8 Hz, 1H), 5.13 (dd, J = 48.6, 40.4 Hz, 2H), 4.77 (d, J = 19.5 Hz, 1H), 4.24 (s, 1H), 3.87 - 3.72 (m, 2H), 3.67 - 3.43 (m, 4H), 3.33 - 3.28 (m, 3H), 3.20 (t, J = 11.3 Hz, 2H), 3.14 - 3.00 (m, 4H), 2.91 (dd, J = 32.3, 15.2 Hz, 2H), 2.64 - 2.51 (m, 2H), 2.13 - 1.76 (m, 10H), 1.22 (d, J = 11.6 Hz, 2H). LCMS (ESI) calcd. for C4oH44FsN12O6+ [M+H]+: 845.35, found, 845.3.

[00399] Example 9 of compound of Formula (I): Preparation of compound GT-07095

[00400] With reference to the method of Scheme I-1, the target compound (GT-o7o95) was obtained (white solid, 23 mg, yield 32.89%). 1H NMR (400 MHz, DMSO-d6) 6 11.59 (s, 1H), 1o.97 (s, 1H), 1o.87 (s, 1H), 9.o2 (d, J = 2.5 Hz, 1H), 8.19 (d, J = 9.7 Hz, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.38 - 7.27 (m, 1H), 6.84 (s, 1H), 5.05 (dd, J = 13.2, 5.0 Hz, 1H), 4.81 (dd, J = 17.4, 8.7 Hz, 1H), 4.38 (dd, J = 71.9, 16.7 Hz, 2H), 3.71 (s, 2H), 3.51 - 3.42 (m, 3H), 3.29 (dd, J = 18.7, 7.2 Hz, 4H), 3.06 (d, J = 7.7 Hz, 9H), 2.86 (dd, J = 25.0, 14.1 Hz, 3H), 2.60 (d, J = 16.8 Hz, 1H), 2.46 - 2.23 (m, 3H), 2.01 (dd, J = 16.0, 9.6 Hz, 8H), 1.66 (d, J = 5.9 Hz, 2H), 1.44 (d, J = 10.8 Hz, 2H). LCMS (ESI) calcd. for C42H52FN12O4+ [M+H]+: 807.42, found, 807.5.

[00401] Example 10 of compound of Formula (I): Preparation of compound GT-07096

[00402] With reference to the method of Scheme I-1, the target compound (GT-07096) was obtained (white solid, 26 mg, yield 37.18%). 1H NMR (400 MHz, DMSO-d6) 6 11.53 (d, J = 20.2 Hz, 1H), 10.96 (s, 1H), 10.80 (s, 1H), 9.00 (d, J = 3.8 Hz, 1H), 8.16 (d, J = 9.5 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 10.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 2.8 Hz, 1H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.92 - 4.66 (m, 1H), 4.26 (dd, J = 50.4, 16.9 Hz, 2H), 3.69 (s, 2H), 3.57 (s, 3H), 3.25 (s, 3H), 3.06 (s, 9H), 2.87 (ddd, J = 30.6, 20.9, 8.3 Hz, 3H), 2.59 (d, J = 16.4 Hz, 1H), 2.44 - 2.23 (m, 3H), 2.13 - 1.77 (m, 8H), 1.72 - 1.56 (m, 2H), 1.50 - 1.28 (m, 2H). LCMS (ESI) calcd. for C42H52FN12O4+ [M+H]+: 807.42, found, 807.5.

[00403] Example 11 of compound of Formula (I): Preparation of compound GT-07097

[00404] With reference to the method of Scheme I-1, the target compound (GT-07097) was obtained (white solid, 33 mg, yield 47.19%). 1H NMR (400 MHz, DMSO-d6) 6 11.59 (s, 1H), 11.06 (s, 1H), 10.96 (s, 1H), 9.02 (s, 1H), 8.19 (dd, J = 9.7, 2.6 Hz, 2H), 7.99 (s, 1H), 7.63 (d, J = 9.5 Hz, 1H), 6.84 (s, 1H), 6.73 (s, 1H), 6.65 (d, J = 12.0 Hz, 1H), 5.09 - 4.93 (m, 1H), 4.82 (s, 1H), 4.25 (dd, J = 56.5, 17.3 Hz, 2H), 3.72 (s, 5H), 3.24 (s, 4H), 3.07 (s, 9H), 2.85 (d, J = 12.3 Hz, 3H), 2.59 (d, J = 16.1 Hz, 1H), 2.32 (dd, J = 12.4, 8.3 Hz, 3H), 2.02 (dd, J = 22.5, 10.9 Hz, 8H), 1.71 - 1.59 (m, 2H), 1.43 (d, J = 11.3 Hz, 2H). LCMS (ESI) calcd. for C42H52FN12O4+ [M+H]+: 807.42, found, 807.5.

[00405] Example 12 of compound of Formula (I): Preparation of compound GT-07195

[00406] With reference to the method of Scheme I-1, the target compound (GT-07195) was obtained (white solid, 24 mg, yield 34.78%). 1H NMR (400 MHz, DMSO-d6) 5 10.96 (s, 1H), 10.50 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 7.91 - 7.82 (m, 2H), 7.74 (d, J = 35.5 Hz, 1H), 7.48 -7.40 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 - 4.23 (m, 4H), 3.95 - 3.84 (m, 1H), 3.55 (s, 2H), 3.31 -3.02 (m, 10H), 2.96 - 2.84 (m, 1H), 2.59 (d, J = 17.1 Hz, 1H), 2.45 - 2.31 (m, 1H), 2.22 (s, 1H), 2.10 (d, J = 9.2 Hz, 2H), 2.02 - 1.83 (m, 5H), 1.73 - 1.22 (m, 7H). LCMS (ESI) calcd. for C41H47ClFN10O5+ [M+H]+: 813.34, found, 813.3.

[00407] Example 13 of compound of Formula (I): Preparation of compound GT-07196

[00408] With reference to the method of Scheme I-1, the target compound (GT-07196) was obtained (white solid, 20 mg, yield 28.77%). 1H NMR (400 MHz, DMSO-D6) 5 10.95 (s, 1H), 10.61 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 9.2, 3.6 Hz, 2H), 7.79 (s, 1H), 7.47 (d, J = 9.7 Hz, 1H), 7.37 (dd, J = 10.0, 6.5 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 - 4.15 (m, 5H), 3.55 (s, 2H), 3.27 - 3.01 (m, 10H), 2.96 - 2.84 (m, 1H), 2.59 (d, J = 16.6 Hz, 1H), 2.36 (dd, J = 13.1, 4.5 Hz, 1H), 2.23 (s, 1H), 2.10 (d, J = 9.7 Hz, 2H), 2.00 - 1.82 (m, 5H), 1.48 (ddt, J = 29.3, 22.0, 12.4 Hz, 7H). LCMS (ESI) calcd. for C41H47ClFN10O5+ [M+H]+: 813.34, found, 813.3.

[00409] Example 14 of compound of Formula (I): Preparation of compound GT-07100

[00410] With reference to the method of Scheme I-1, the target compound (GT-07100) was obtained (white solid, 35 mg, yield 50.35%). 1H NMR (400 MHz, DMSO-d6) 5 10.95 (s, 1H), 10.73 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 62.8 Hz, 1H), 7.86 (dd, J = 9.2, 4.3 Hz, 2H), 7.48 (d, J = 9.7 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 6.71 (s, 1H), 6.63 (d, J = 12.1 Hz, 1H), 4.99 (dd, J = 13.2, 5.0 Hz, 1H), 4.59 - 4.45 (m, 3H), 4.24 (dd, J = 55.8, 17.3 Hz, 2H), 3.93 - 3.83 (m, 1H), 3.56 (s, 2H), 3.25 - 3.02 (m, 9H), 2.95 - 2.80 (m, 1H), 2.63 -2.54 (m, 1H), 2.34 (td, J = 12.9, 4.2 Hz, 1H), 2.29 - 2.17 (m, 1H), 2.10 (d, J = 9.9 Hz, 2H), 2.02 - 1.83 (m, 5H), 1.66 - 1.21 (m, 7H). LCMS (ESI) calcd. for C41H47ClFN10O5+ [M+H]+: 813.34, found, 813.3.

[00411] Example 15 of compound of Formula (I): Preparation of compound GT-07103

[00412] With reference to the method of Scheme I-1, the target compound (GT-07103) was obtained (white solid, 10 mg, yield 14.61%). 1H NMR (400 MHz, DMSO-d6) 5 10.97 (s, 1H), 10.00 (s, 1H), 9.51 (d, J = 6.5 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.76 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.28 - 6.96 (m, 1H), 6.66 (dd, J = 165.7, 7.8 Hz, 1H), 5.34 - 5.01 (m, 2H), 4.77 (d, J = 20.4 Hz, 1H), 4.35 (dt, J = 25.8, 12.9 Hz, 3H), 3.87 - 3.71 (m, 2H), 3.67 - 3.43 (m, 4H), 3.25 - 2.84 (m, 9H), 2.59 (d, J = 17.2 Hz, 1H), 2.47 - 2.34 (m, 1H), 2.12 - 1.75 (m, 10H), 1.22 (q, J = 11.5 Hz, 2H). LCMS (ESI) calcd. for C40H46F3N12O5+ [M+H]+: 831.37, found, 831.4.

[00413] Example 16 of compound of Formula (I): Preparation of compound GT-07104

[00414] With reference to the method of Scheme I-1, the target compound (GT-07104) was obtained (white solid, 16 mg, yield 23.37%). 1H NMR (400 MHz, DMSO-d6) 8 10.96 (s, 1H), 10.15 (s, 1H), 9.51 (d, J = 6.5 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.37 (d, J = 10.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.11 (td, J = 53.7, 3.6 Hz, 1H), 6.66 (dd, J = 166.1, 7.8 Hz, 1H), 5.32 - 4.98 (m, 2H), 4.77 (d, J = 19.5 Hz, 1H), 4.26 (dd, J = 49.9, 16.9 Hz, 3H), 3.86 - 3.69 (m, 2H), 3.60 (dd, J = 24.7, 13.4 Hz, 3H), 3.46 (s, 1H), 3.28 - 2.99 (m, 8H), 2.96 - 2.82 (m, 1H), 2.59 (d, J = 16.7 Hz, 1H), 2.43 - 2.30 (m, 1H), 2.00 (td, J = 25.8, 12.1 Hz, 8H), 1.80 (dd, J = 23.5, 11.6 Hz, 2H), 1.22 (dd, J = 24.0, 11.6 Hz, 2H). LCMS (ESI) calcd. for C40H46F3N12O5+ [M+H]+: 831.37, found, 831.4.

[00415] Example 17 of compound of Formula (I): Preparation of compound GT-07105

[00416] With reference to the method of Scheme I-1, the target compound (GT-07105) was obtained (white solid, 35 mg, yield 51.13%). 1H NMR (400 MHz, DMSO-d6) 8 10.95 (s, 1H), 10.29 (s, 1H), 9.51 (d, J = 6.5 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 4.0 Hz, 1H), 8.27 (t, J = 7.3 Hz, 1H), 8.10 (s, 1H), 7.11 (td, J = 53.8, 3.7 Hz, 1H), 6.90 - 6.39 (m, 3H), 5.18 (d, J = 80.3 Hz, 1H), 4.99 (dd, J = 13.3, 5.0 Hz, 1H), 4.77 (d, J = 18.9 Hz, 1H), 4.36 - 4.14 (m, 3H), 3.85 - 3.71 (m, 2H), 3.68 - 3.41 (m, 5H), 3.11 (t, J = 44.1 Hz, 7H), 2.95 - 2.79 (m, 1H), 2.58 (d, J = 16.3 Hz, 1H), 2.32 (qd, J = 13.1, 4.4 Hz, 1H), 2.00 (ddd, J = 24.8, 18.9, 11.3 Hz, 8H), 1.80 (dd, J = 23.2, 11.5 Hz, 2H), 1.22 (q, J = 11.5 Hz, 2H). LCMS (ESI) calcd. for C40H46F3N12O5+ [M+H]+: 831.37, found, 831.4.

[00417] Example 18 of compound of Formula (I): Preparation of compound GT-07106

[00418] With reference to the method of Scheme I-1, the target compound (GT-07106) was obtained (white solid, 36 mg, yield 53.01%). 1H NMR (400 MHz, DMSO-d6) 8 10.96 (s, 1H), 10.53 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.24 - 7.88 (m, 3H), 7.78 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.19 (dd, J = 11.3, 5.6 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.05 (dd, J = 13.3, 5.0 Hz, 1H), 4.46 (d, J = 16.5 Hz, 3H), 4.35 (s, 1H), 4.28 (d, J = 16.7 Hz, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.29 - 3.00 (m, 12H), 2.93 - 2.85 (m, 1H), 2.59 (d, J = 16.5 Hz, 1H), 2.40 (dt, J = 13.4, 8.9 Hz, 1H), 2.22 (s, 1H), 2.04 - 1.84 (m, 3H), 1.37 - 1.25 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H52ClFN9O5+ [M+H]+: 840.38, found, 840.5.

[00419] Example 19 of compound of Formula (I): Preparation of compound GT-07107

[00420] With reference to the method of Scheme I-1, the target compound (GT-07107) was obtained (white solid, 36 mg, yield 53.01%). 1H NMR (400 MHz, DMSO-d6) 5 10.95 (s, 1H), 10.48 (s, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.36 (d, J = 10.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 5.5 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 13.1 Hz, 2H), 4.35 (s, 1H), 4.32 - 4.17 (m, 2H), 4.07 (d, J = 9.2 Hz, 1H), 3.27 - 2.98 (m, 12H), 2.95 - 2.85 (m, 1H), 2.59 (d, J = 16.8 Hz, 1H), 2.36 (qd, J = 13.1, 4.5 Hz, 1H), 2.22 (s, 1H), 2.05 - 1.87 (m, 3H), 1.37 - 1.25 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H52ClFN9O5+ [M+H]+: 840.38, found, 840.5.

[00421] Example 20 of compound of Formula (I): Preparation of compound GT-07108

[00422] With reference to the method of Scheme I-1, the target compound (GT-07108) was obtained (white solid, 31 mg, yield 45.65%). 1H NMR (400 MHz, DMSO-d6) 5 10.95 (s, 1H), 10.74 (s, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 86.9, 8.8 Hz, 3H), 7.90 (d, J = 8.7 Hz, 1H), 7.22 (t, J = 8.3 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.71 (s, 1H), 6.63 (d, J = 12.1 Hz, 1H), 4.99 (dd, J = 13.2, 5.0 Hz, 1H), 4.46 (d, J = 13.1 Hz, 2H), 4.37 - 4.14 (m, 4H), 4.07 (d, J = 9.2 Hz, 1H), 3.25 - 3.01 (m, 10H), 2.95 - 2.73 (m, 2H), 2.62 - 2.53 (m, 1H), 2.34 (td, J = 13.0, 4.4 Hz, 1H), 2.23 (s, 1H), 1.96 (dd, J = 22.1, 8.8 Hz, 3H), 1.38 - 1.26 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H52ClFN9O5+ [M+H]+: 840.38, found, 840.5.

[00423] Example 21 of compound of Formula (I): Preparation of compound GT-05207

[00424] With reference to the method of Scheme I-1, the target compound (GT-05207) was obtained (white solid, 41 mg, yield 45.2%). 1H NMR (400 MHz, DMSO-D6) 5 11.50 (s, 1H), 11.09 (s, 1H), 10.75 (s, 1H), 9.00 (s, 1H), 8.53 (s, 1H), 8.15 (dd, J = 9.6, 2.7 Hz, 1H), 7.92 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 9.6 Hz, 1H), 7.26 (s, 1H), 7.17 - 7.00 (m, 1H), 6.83 (s, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.86 - 4.71 (m, 1H), 3.71 (d, J = 12.0 Hz, 2H), 3.60 - 3.54 (m, 3H), 3.13 - 3.09 (m, 3H), 3.06 (s, 8H), 2.93 - 2.87 (m, 1H), 2.80 (t, J = 11.2 Hz, 2H), 2.59 (d, J = 17.7 Hz, 3H), 2.33 - 2.26 (m, 2H), 2.08 - 1.94 (m, 9H), 1.68 - 1.59 (m, 2H), 1.44 - 1.34 (m, 2H). LCMS (ESI) calcd. for C42H51N12O5 + [M+H]+: 803.41, found, 803.5.

[00425] Example 22 of compound of Formula (I): Preparation of compound GT-05234

[00426] With reference to the method of Scheme I-1, the target compound (GT-05234) was obtained (yellow solid, 24 mg, yield 26.5%). 1H NMR (400 MHz, DMSO-d6) 3 11.08 (s, 1H), 10.34 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.48 (s, 1H), 7.85 (t, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.43 -7.34 (m, 2H), 7.26 (s, 1H), 7.14 (dd, J = 8.8, 2.3 Hz, 1H), 7.10 - 6.98 (m, 1H), 5.06 (dd, J = 13.0, 5.4 Hz, 1H), 4.59 - 4.47 (m, 3H), 3.86 (d, J = 7.8 Hz, 1H), 3.59 - 3.56 (m, 1H), 3.29 (s, 2H), 3.18 - 3.05 (m, 8H), 2.95 - 2.85 (m, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.22 (s, 1H), 2.11 (d, J = 10.0 Hz, 2H), 1.98 - 1.88 (m, 4H), 1.67 - 1.60 (m, 2H), 1.56 - 1.50 (m, 2H), 1.34 - 1.24 (m, 3H), 0.94 (t, J = 7.3 Hz, 2H). LCMS (ESI) calcd. for C41H46ClN10O6 + [M+H]+: 809.33, found, 809.3.

[00427] Example 23 of compound of Formula (I): Preparation of compound GT-05300

[00428] With reference to the method of Scheme I-1, the target compound (GT-05300) was obtained (yellow solid, 22 mg, yield 19.7%). 1H NMR (400 MHz, DMSO-D6) 3 11.09 (s, 1H), 10.08 (s, 1H), 9.51 (d, J = 6.5 Hz, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 7.14 - 7.05 (m, 1H), 5.10 - 5.03 (m, 1H), 4.77 (d, J = 19.8 Hz, 1H), 4.30 - 4.17 (m, 1H), 3.84 - 3.80 (m, 1H), 3.67 - 3.55 (m, 3H), 3.46 (s, 2H), 3.28 (s, 3H), 3.18 - 2.98 (m, 6H), 2.94 - 2.81 (m, 1H), 2.62 - 2.54 (m, 1H), 2.11 - 2.05 (m, 2H), 2.04 - 1.86 (m, 6H), 1.85 - 1.71 (m, 2H), 1.22 (dd, J = 23.8, 11.9 Hz, 2H). LCMS (ESI) C40H45F2N12O6+ [M+H]+: calcd. for 827.35, found, 827.4.

[00429] Example 24 of compound of Formula (I): Preparation of compound GT-05348

[00430] With reference to the method of Scheme I-1, the target compound (GT-05348) was obtained (yellow solid, 38 mg, yield 43%). 1H NMR (400 MHz, DMSO-D6) 3 11.07 (s, 1H), 10.31 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.78 (d, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.12 - 6.97 (m, 3H), 5.06 (dd, J = 13.0, 5.2 Hz, 1H), 4.44 (d, J = 12.5 Hz, 2H), 4.33 (s, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.59 (s, 2H), 3.33 - 3.28 (m, 2H), 3.09 (d, J = 27.5 Hz, 8H), 2.87 (t, J = 12.4 Hz, 1H), 2.70 - 2.55 (m, 2H), 2.19 (s, 1H), 2.06 - 1.98 (m, 1H), 1.94 (d, J = 11.9 Hz, 2H), 1.33 - 1.27 (m, 1H), 1.23 (s, 7H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H51ClN9O6+ [M+H]+: 836.36, found, 836.3.

[00431] Example 25 of compound of Formula (I): Preparation of compound GT-07241

[00432] With reference to the method of Scheme I-1, the target compound (GT-07241) was obtained (white solid, 18 mg, yield 25.87%). 1H NMR (400 MHz, DMSO-d6) 8 11.54 (s, 1H), 11.09 (s, 2H), 9.00 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 9.6, 2.5 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J = 9.0 Hz, 1H), 6.82 (s, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.86 - 4.71 (m, 1H), 3.70 (d, J = 11.6 Hz, 5H), 3.36 - 3.22 (m, 4H), 3.08 (d, J = 18.7 Hz, 9H), 2.85 (dt, J = 26.6, 12.9 Hz, 3H), 2.57 (dd, J = 18.6, 9.9 Hz, 2H), 2.32 (d, J = 11.3 Hz, 2H), 2.14 - 1.83 (m, 8H), 1.69 - 1.55 (m, 2H), 1.43 (d, J = 9.7 Hz, 2H). LCMS (ESI) calcd. for C42H51N12O5+ [M+H]+: 803.41, found, 803.5.

[00433] Example 26 of compound of Formula (I): Preparation of compound GT-07109

[00434] With reference to the method of Scheme I-1, the target compound (GT-07109) was obtained (white solid, 10 mg, yield 14.63%). 1H NMR (400 MHz, DMSO-d6) 8 11.62 (s, 1H), 10.96 (s, 2H), 9.02 (s, 1H), 8.22 (d, J = 9.6 Hz, 1H), 8.07 (s, 1H), 7.65 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.20 - 7.06 (m, 2H), 6.85 (s, 1H), 5.06 (dd, J = 13.3, 5.0 Hz, 1H), 4.85 - 4.79 (m, 1H), 4.21 (s, 2H), 3.70 (d, J = 11.7 Hz, 2H), 3.34 (dd, J = 49.3, 43.5 Hz, 7H), 3.16 - 2.99 (m, 9H), 2.90 (dd, J = 19.7, 11.0 Hz, 3H), 2.64 - 2.54 (m, 1H), 2.36 (dd, J = 19.5, 14.7 Hz, 3H), 2.04 (dd, J = 39.1, 27.8 Hz, 8H), 1.65 (d, J = 5.8 Hz, 2H), 1.49 (d, J = 10.7 Hz, 2H). LCMS (ESI) calcd. for C42H53N12O4+ [M+H]+: 789.43, found, 789.5.

[00435] Example 27 of compound of Formula (I): Preparation of compound GT-07099

[00436] With reference to the method of Scheme I-1, the target compound (GT-07099) was obtained (white solid, 16 mg, yield 25.16%). 1H NMR (400 MHz, DMSO-d6) 8 11.55 (s, 1H), 11.06 (d, J = 15.7 Hz, 2H), 9.02 - 8.93 (m, 1H), 8.18 (dd, J = 9.4, 3.0 Hz, 1H), 7.97 (s, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 7.41 (d, J = 4.4 Hz, 1H), 7.30 - 7.20 (m, 1H), 6.83 (s, 1H), 5.14 - 5.00 (m, 1H), 4.80 (dd, J = 17.4, 8.8 Hz, 1H), 3.76 (s, 3H), 3.06 (s, 6H), 2.87 (ddd, J = 27.9, 21.2, 10.1 Hz, 4H), 2.56 (dd, J = 19.8, 11.0 Hz, 2H), 2.30 (s, 2H), 2.12 - 1.82 (m, 8H), 1.72 - 1.55 (m, 3H), 1.42 (s, 1H). LCMS (ESI) calcd. for C38H44N11O5+ [M+H]+: 734.35, found, 734.4.

[00437] Example 28 of compound of Formula (I): Preparation of compound GT-07194

[00438] With reference to the method of Scheme I-1, the target compound (GT-07194) was obtained (white solid, 19 mg, yield 26.29%). 1H NMR (400 MHz, DMSO-d6) 8 11.59 (s, 1H), 10.99 (s, 1H), 9.02 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.06 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.82 (d, J = 15.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.83 (dd, J = 17.3, 8.7 Hz, 1H), 4.43 (d, J = 17.5 Hz, 2H), 3.68 (d, J = 12.0 Hz, 2H), 3.54 (s, 2H), 3.06 (s, 9H), 2.98 (d, J = 13.5 Hz, 2H), 2.93 - 2.80 (m, 4H), 2.60 (d, J = 16.3 Hz, 1H), 2.43 - 2.26 (m, 3H), 2.09 - 1.88 (m, 10H), 1.70 (dd, J = 36.2, 30.6 Hz, 6H), 1.42 (d, J = 10.2 Hz, 2H). LCMS (ESI) calcd. for C44H56N11O4S+ [M+H]+: 834.42, found, 834.5.

[00439] Example 29 of compound of Formula (I): Preparation of compound GT-07101

[00440] With reference to the method of Scheme I-1, the target compound (GT-07101) was obtained (white solid, 15 mg, yield 21.68%). 1H NMR (400 MHz, DMSO-d6) 6 11.08 (s, 1H), 10.79 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.71 (dd, J = 13.2, 5.9 Hz, 1H), 7.51 - 7.40 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.64 - 4.34 (m, 3H), 3.86 (d, J = 8.1 Hz, 1H), 3.53 - 3.39 (m, 2H), 3.17 (ddd, J = 47.1, 30.4, 8.6 Hz, 8H), 2.95 - 2.82 (m, 1H), 2.57 (dd, J = 18.1, 9.7 Hz, 2H), 2.26 - 1.99 (m, 4H), 1.90 (d, J = 9.8 Hz, 4H), 1.48 (ddt, J = 22.0, 14.6, 9.3 Hz, 8H). LCMS (ESI) calcd. for C41H46ClN10O6+ [M+H]+: 809.33, found, 809.3.

[00441] Example 30 of compound of Formula (I): Preparation of compound GT-07110

[00442] With reference to the method of Scheme I-1, the target compound (GT-07110) was obtained (white solid, 22 mg, yield 32.36%). 1H NMR (400 MHz, DMSO-d6) 6 10.95 (s, 2H), 8.61 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.57 (t, J = 9.2 Hz, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.19 - 7.07 (m, 3H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (dd, J = 19.7, 9.1 Hz, 3H), 4.37 (s, 2H), 3.90 - 3.81 (m, 1H), 3.37 (d, J = 69.5 Hz, 8H), 3.10 (dd, J = 27.8, 9.1 Hz, 4H), 2.97 - 2.83 (m, 1H), 2.58 (d, J = 16.6 Hz, 1H), 2.44 - 2.29 (m, 1H), 2.13 (t, J = 20.3 Hz, 3H), 2.02 - 1.83 (m, 5H), 1.67 - 1.44 (m, 4H), 1.32 (dd, J = 21.5, 10.7 Hz, 2H). LCMS (ESI) calcd. for C41H48ClN10O5+ [M+H]+: 795.35, found,795.4.

[00443] Example 31 of compound of Formula (I): Preparation of compound GT-07098

[00444] With reference to the method of Scheme I-1, the target compound (GT-07098) was obtained (white solid, 25 mg, yield 39.51%). 1H NMR (400 MHz, DMSO-d6) 6 10.08 (d, J = 6.0 Hz, 1H), 9.93 (s, 1H), 7.60 (dd, J = 8.0, 5.5 Hz, 1H), 6.91 - 6.83 (m, 2H), 6.70 (dd, J = 24.0, 8.2 Hz, 1H), 6.52 (t, J = 9.1 Hz, 1H), 6.44 - 6.34 (m, 2H), 6.31 - 6.18 (m, 1H), 6.13 (dd, J = 8.8, 2.3 Hz, 1H), 4.13 - 3.99 (m, 1H), 3.62 - 3.45 (m, 3H), 2.23 (t, J = 11.5 Hz, 1H), 2.08 (t, J = 11.7 Hz, 1H), 1.90 (dd, J = 29.7, 17.8 Hz, 2H), 1.71 (d, J = 4.1 Hz, 1H), 1.56 (dd, J = 15.6, 12.7 Hz, 2H), 1.15 - 0.86 (m, 8H), 0.71 - 0.44 (m, 6H), 0.29 (d, J = 9.2 Hz, 1H). LCMS (ESI) calcd. for C37H39ClN9O6+ [M+H]+: 740.27, found, 740.3.

[00445] Example 32 of compound of Formula (I): Preparation of compound GT-07102

[00446] With reference to the method of Scheme I-1, the target compound (GT-07102) was obtained (white solid, 10 mg, yield 4 13.92%). 1H NMR (400 MHz, DMSO-d6) 8 10.98 (s, 1H), 8.67 - 8.44 (m, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.49 - 7.40 (m, 2H), 7.38 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 5.09 (dd, J = 13.2, 4.9 Hz, 1H), 4.66 - 4.26 (m, 5H), 3.86 (s, 1H), 3.12 (ddd, J = 25.1, 19.4, 9.4 Hz, 8H), 2.96 - 2.85 (m, 2H), 2.62 (s, 1H), 2.44 - 2.36 (m, 1H), 2.10 - 1.81 (m, 9H), 1.57 (ddd, J = 32.5, 23.2, 10.2 Hz, 9H), 1.30 (dd, J = 14.7, 7.3 Hz, 2H). LCMS (ESI) calcd. for C43H51ClN9O5S+ [M+H]+: 840.34, found, 840.3.

[00447] Example 33 of compound of Formula (I): Preparation of compound GT-07394

[00448] With reference to the method of Scheme I-1, the target compound (GT-07394) was obtained (white solid, 22 mg, yield 32.29%). 1H NMR (500 MHz, DMSO-D6) 8 11.09 (s, 1H), 10.67 (s, 1H), 9.50 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 6.9 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.42 (d, J = 10.4 Hz, 1H), 7.30 (dd, J = 18.6, 5.4 Hz, 1H), 7.11 (td, J = 53.8, 4.4 Hz, 1H), 6.66 (dd, J = 207.5, 7.8 Hz, 1H), 5.29 - 5.02 (m, 2H), 4.77 (d, J = 21.7 Hz, 1H), 4.22 (dd, J = 11.5, 8.7 Hz, 1H), 3.79 (t, J = 21.1 Hz, 2H), 3.67 - 3.49 (m, 7H), 3.19 (d, J = 23.8 Hz, 3H), 3.06 (s, 2H), 2.94 - 2.84 (m, 1H), 2.57 (dt, J = 13.3, 5.9 Hz, 2H), 2.14 -1.72 (m, 10H), 1.44 - 1.15 (m, 2H). LCMS (ESI) calcd. for C40H45F2N12O6+ [M+H]+: 827.36, found, 827.3.

[00449] Example 34 of compound of Formula (I): Preparation of compound GT-07111

[00450] With reference to the method of Scheme I-1, the target compound (GT-07111) was obtained (white solid, 20 mg, yield 29.86%). 1H NMR (400 MHz, DMSO-d6) 8 10.96 (s, 1H), 10.73 (s, 1H), 9.51 (d, J = 5.8 Hz, 1H), 8.80 (t, J = 8.0 Hz, 1H), 8.42 (d, J = 4.3 Hz, 1H), 8.27 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 9.5 Hz, 1H), 7.26 - 6.96 (m, 3H), 6.93 - 6.42 (m, 1H), 5.32 - 5.02 (m, 2H), 4.77 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.2 Hz, 4H), 3.73 (dt, J = 42.2, 10.3 Hz, 4H), 3.45 (d, J = 9.9 Hz, 4H), 3.27 (s, 4H), 3.05 (d, J = 5.7 Hz, 2H), 2.98 - 2.85 (m, 1H), 2.59 (d, J = 16.7 Hz, 1H), 2.38 (dt, J = 13.6, 9.1 Hz, 1H), 2.15 - 1.70 (m, 11H), 1.23 (dd, J = 23.4, 11.8 Hz, 2H). LCMS (ESI) calcd. for C40H47F2N12O5+ [M+H]+: 813.38, found,813.3.

[00451] Example 35 of compound of Formula (I): Preparation of compound GT-07395

[00452] With reference to the method of Scheme I-1, the target compound (GT-07395) was obtained (white solid, 45 mg, yield 72.08%). 1H NMR (500 MHz, DMSO-D6) 8 11.17 - 11.01 (m, 1H), 9.51 (t, J = 6.8 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.45 - 8.38 (m, 1H), 8.26 (dt, J = 9.3, 4.7 Hz, 1H), 7.80 - 7.65 (m, 1H), 7.48 - 7.27 (m, 2H), 7.26 - 6.99 (m, 2H), 6.90 - 6.44 (m, 1H), 5.33 - 5.05 (m, 2H), 4.77 (d, J = 20.9 Hz, 1H), 4.33 - 4.21 (m, 1H), 3.85 - 3.81 (m, 2H), 3.45 (d, J = 10.0 Hz, 1H), 2.98 - 2.81 (m, 2H), 2.64 - 2.53 (m, 2H), 1.93 (dddd, J = 47.0, 34.3, 33.1, 16.6 Hz, 12H), 1.36 (ddd, J = 35.7, 23.2, 11.2 Hz, 2H). LCMS (ESI) calcd. for C36H38F2N11O6+ [M+H]+: 758.30, found,758.3

[00453] Example 36 of compound of Formula (I): Preparation of compound GT-07396

[00454] With reference to the method of Scheme I-1, the target compound (GT-07396) was obtained (white solid, 16 mg, yield 22.63%). 1H NMR (500 MHz, DMSO-D6) 5 10.99 (s, 1H), 9.50 (d, J = 7.4 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.39 (t, J = 6.6 Hz, 1H), 8.26 (t, J = 9.2 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.57 (d, J = 6.7 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.11 (td, J = 53.7, 4.3 Hz, 1H), 6.66 (dd, J = 207.5, 7.8 Hz, 1H), 5.31 - 5.02 (m, 2H), 4.76 (d, J = 22.5 Hz, 1H), 4.52 - 4.29 (m, 2H), 4.25 - 4.12 (m, 1H), 3.79 (t, J = 21.3 Hz, 2H), 3.65 - 3.58 (m, 2H), 3.44 - 3.27 (m, 6H), 3.09 - 3.02 (m, 2H), 2.95 - 2.87 (m, 2H), 2.60 (d, J = 16.9 Hz, 1H), 2.43 - 2.34 (m, 1H), 2.00 (ddd, J = 37.8, 23.9, 9.5 Hz, 10H), 1.81 - 1.69 (m, 3H), 1.48 - 1.37 (m, 1H), 1.22 - 0.99 (m, 2H). LCMS (ESI) calcd. for C42H50F2N11O5S+ [M+H]+: 858.37, found,858.3

[00455] Example 37 of compound of Formula (I): Preparation of compound GT-07179

[00456] With reference to the method of Scheme I-1, the target compound (GT-07179) was obtained (white solid, 32 mg, yield 47.35%). 1H NMR (400 MHz, DMSO-d6) 5 11.09 (s, 1H), 10.91 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.71 (t, J = 8.9 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.43 (t, J = 14.8 Hz, 2H), 4.35 (s, 1H), 4.08 (s, 1H), 3.59 (s, 4H), 3.31 - 3.06 (m, 8H), 2.90 (dd, J = 22.3, 8.4 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.22 (s, 1H), 2.08 - 1.84 (m, 3H), 1.43 (dd, J = 76.8, 10.8 Hz, 2H), 1.23 (s, 6H), 1.12 (s, 6H). LCMS (ESI) calcd. for C44H51ClN9O6+ [M+H]+: 836.37, found, 836.4.

[00457] Example 38 of compound of Formula (I): Preparation of compound GT-07112

[00458] With reference to the method of Scheme I-1, the target compound (GT-07112) was obtained (white solid, 25 mg, yield 37.59%). 1H NMR (400 MHz, DMSO-D6) 5 10.95 (s, 1H), 10.82 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 2H), 7.12 (d, J = 12.2 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 13.3 Hz, 2H), 4.29 (dt, J = 49.8, 13.9 Hz, 4H), 4.07 (d, J = 9.1 Hz, 1H), 3.43 (s, 3H), 3.26 - 3.03 (m, 8H), 2.96 - 2.85 (m, 1H), 2.59 (d, J = 16.8 Hz, 1H), 2.45 - 2.33 (m, 1H), 2.19 (s, 1H), 2.02 - 1.89 (m, 3H), 1.41 - 1.26 (m, 2H), 1.23 (s, 6H), 1.12 (s, 6H). LCMS (ESI) calcd. for C44H53ClN9O5+ [M+H]+: 822.39, found, 822.5.

[00459] Example 39 of compound of Formula (I): Preparation of compound GT-07180

[00460] With reference to the method of Scheme I-1, the target compound (GT-07180) was obtained (white solid, 33 mg, yield 53.23%). 1H NMR (400 MHz, DMSO-d6) 5 11.08 (d, J = 5.3 Hz, 1H), 10.99 (s, 1H), 8.59 - 8.43 (m, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 18.7, 8.3 Hz, 1H), 7.44 - 7.19 (m, 4H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.12 - 5.01 (m, 1H), 4.44 (d, J = 11.0 Hz, 2H), 4.35 (s, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.26 (dt, J = 55.9, 11.8 Hz, 3H), 3.02 - 2.85 (m, 2H), 2.75 - 2.52 (m, 2H), 2.22 - 1.82 (m, 4H), 1.60 (d, J = 11.3 Hz, 1H), 1.42 - 1.27 (m, 1H), 1.23 (s, 6H), 1.12 (s, 6H). LCMS (ESI) calcd. for C40H44ClN8O6+ [M+H]+: 767.31, found, 767.3.

[00461] Example 40 of compound of Formula (I): Preparation of compound GT-07181

[00462] With reference to the method of Scheme I-1, the target compound (GT-07181) was obtained (white solid, 25 mg, yield 35.66%). 1H NMR (400 MHz, DMSO-d6) 5 10.98 (s, 1H), 8.56 (t, J = 3.7 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H), 4.51 -4.25 (m, 6H), 4.07 (d, J = 9.1 Hz, 1H), 3.22 - 2.75 (m, 10H), 2.60 (d, J = 16.6 Hz, 1H), 2.38 (ddd, J = 26.4, 13.3, 4.5 Hz, 1H), 2.07 - 1.82 (m, 6H), 1.79 - 1.47 (m, 3H), 1.25 (d, J = 18.7 Hz, 8H), 1.12 (s, 6H). LCMS (ESI) calcd. for C46H56ClN8O5S+ [M+H]+: 867.38, found, 867.3.

[00463] Example 41 of compound of Formula (I): Preparation of compound GT-07126

[00464] With reference to the method of Scheme I-2, the target compound (GT-07126) was obtained (white solid, 31 mg, yield 40.49%). 1H NMR (500 MHz, DMSO-D6) 5 11.08 (s, 1H), 10.51 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 8.26 -8.19 (m, 1H), 8.14 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 17.0 Hz, 1H), 7.16 (s, 1H), 7.05 (s, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.73 - 4.55 (m, 1H), 3.98 (s, 3H), 3.75 (d, J = 13.1 Hz, 2H), 3.62 (s, 6H), 3.00 (t, J = 11.4 Hz, 3H), 2.93 - 2.83 (m, 2H), 2.60 - 2.52 (m, 2H), 2.13 - 1.97 (m, 5H). LCMS (ESI) calcd. for C38H38F3N10O7+ [M+H]+: 803.29, found, 803.3.

[00465] Example 42 of compound of Formula (I): Preparation of compound GT-06944

[00466] With reference to the method of Scheme I-2, the target compound (GT-06944) was obtained (white solid, 17 mg, yield 21.72%). 1H NMR (500 MHz, DMSO-D6) S 11.10 (s, 1H), 10.50 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 7.7 Hz, 1H), 8.39 (q, J = 7.4 Hz, 2H), 8.22 (dd, J = 7.8, 0.8 Hz, 1H), 8.18 (s, 1H), 7.63 (d, J = 10.3 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.63 (ddd, J = 15.4, 10.9, 4.2 Hz, 1H), 3.98 (s, 3H), 3.70 (t, J = 32.1 Hz, 4H), 3.19 - 2.63 (m, 9H), 2.62 - 2.55 (m, 1H), 2.52 (d, J = 9.1 Hz, 1H), 2.14 - 1.95 (m, 5H). LCMS (ESI) calcd. for C38H37F4N10O7+ [M+H]+: 821.28, found, 821.3.

[00467] Example 43 of compound of Formula (I): Preparation of compound GT-06943

[00468] With reference to the method of Scheme I-2, the target compound (GT-06943) was obtained (white solid, 23 mg, yield 24.46%). 1H NMR (500 MHz, DMSO-D6) S 10.95 (s, 1H), 10.51 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.43 - 8.37 (m, 2H), 8.22 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 6.94 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.70 - 4.53 (m, 1H), 4.24 (dd, J = 69.3, 17.0 Hz, 2H), 3.98 (s, 3H), 3.75 (d, J = 12.9 Hz, 2H), 3.29 (s, 5H), 3.00 (t, J = 11.7 Hz, 2H), 2.94 - 2.84 (m, 2H), 2.75 (d, J = 21.1 Hz, 2H), 2.58 (d, J = 16.4 Hz, 1H), 2.34 (dt, J = 13.2, 10.7 Hz, 1H), 2.05 (dt, J = 11.2, 9.8 Hz, 4H), 1.99 - 1.89 (m, 1H). LCMS (ESI) calcd. for C38H40F3N10O6+ [M+H]+: 789.31, found, 789.4.

[00469] Example 44 of compound of Formula (I): Preparation of compound GT-06945

[00470] With reference to the method of Scheme I-2, the target compound (GT-06945) was obtained (white solid, 15 mg, yield 19.50%). 1H NMR (500 MHz, DMSO-D6) S 10.98 (s, 1H), 10.51 (s, 1H), 8.70 (s, 1H), 8.46 (d, J = 7.7 Hz, 1H), 8.41 (dd, J = 9.6, 5.8 Hz, 2H), 8.22 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 10.7 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.17 (s, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (s, 1H), 4.27 (dd, J = 67.9, 17.0 Hz, 2H), 3.99 (s, 3H), 3.75 (d, J = 12.9 Hz, 2H), 3.49 - 3.17 (m, 3H), 2.91 (ddd, J = 49.7, 33.7, 13.6 Hz, 8H), 2.61 (s, 1H), 2.35 (qd, J = 13.2, 4.5 Hz, 1H), 2.06 (dt, J = 38.2, 22.3 Hz, 5H). LCMS (ESI) calcd. for C38H39F4N10O6+ [M+H]+: 807.30, found, 807.3.

[00471] Example 45 of compound of Formula (I): Preparation of compound GT-06946

[00472] With reference to the method of Scheme I-2, the target compound (GT-06946) was obtained (white solid, 12 mg, yield 15.60%). 1H NMR (500 MHz, DMSO-D6) S 10.98 (s, 1H), 10.52 (s, 1H), 8.70 (s, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.44 - 8.39 (m, 2H), 8.23 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.17 (s, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.71 - 4.60 (m, 1H), 4.37 (dd, J = 90.0, 16.8 Hz, 2H), 3.99 (s, 3H), 3.75 (d, J = 12.9 Hz, 2H), 3.43 - 3.09 (m, 5H), 3.01 (t, J = 11.6 Hz, 2H), 2.96 - 2.87 (m, 1H), 2.79 (d, J = 8.8 Hz, 3H), 2.59 (d, J = 16.9 Hz, 1H), 2.40 (qd, J = 13.1, 4.5 Hz, 1H), 2.16 - 1.91 (m, 5H). LCMS (ESI) calcd. for C38H39F4N10O6+ [M+H]+: 807.30, found, 807.3.

[00473] Example 46 of compound of Formula (I): Preparation of compound GT-06947

[00474] With reference to the method of Scheme I-2, the target compound (GT-06947) was obtained (white solid, 27 mg, yield 35.09%). 1H NMR (500 MHz, DMSO-D6) S 10.96 (s, 1H), 10.51 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 7.7 Hz, 1H), 8.43 - 8.37 (m, 2H), 8.22 (dd, J = 7.7, 0.8 Hz, 1H), 7.72 (s, 1H), 7.16 (s, 1H), 6.70 (s, 1H), 6.57 (d, J = 10.6 Hz, 1H), 4.99 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (dt, J = 15.3, 5.5 Hz, 1H), 4.36 - 4.11 (m, 2H), 3.99 (d, J = 15.6 Hz, 3H), 3.74 (d, J = 12.9 Hz, 2H), 3.46 (s, 3H), 3.38 - 3.22 (m, 2H), 3.17 - 2.79 (m, 6H), 2.57 (d, J = 16.8 Hz, 1H), 2.31 (qd, J = 13.4, 4.7 Hz, 1H), 2.15 - 1.91 (m, 5H). LCMS (ESI) calcd. for C38H39F4N10O6+ [M+H]+: 807.30, found, 807.3.

[00475] Example 47 of compound of Formula (I): Preparation of compound GT-09603

[00476] With reference to the method of Scheme I-1, the target compound (GT-09603) was obtained (white solid, 50 mg, yield 94.22 %). 1H NMR (400 MHz, DMSO-D6) S 9.51 (d, J = 6.5 Hz, 2H), 8.79 (d, J = 7.7 Hz, 1H), 8.49 - 8.37 (m, 2H), 8.26 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 10.1 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.12 (dd, J = 55.8, 52.3 Hz, 1H), 6.67 (dd, J = 164.5, 8.0 Hz, 1H), 5.31 - 5.04 (m, 2H), 4.77 (d, J = 22.3 Hz, 1H), 4.24 (s, 1H), 3.82 (d, J = 10.7 Hz, 2H), 3.67 - 3.55 (m, 4H), 3.45 (d, J = 10.7 Hz, 2H), 3.14 (s, 4H), 3.06 (s, 2H), 3.01 (s, 3H), 2.93 (d, J = 12.7 Hz, 1H), 2.76 (d, J = 16.3 Hz, 1H), 2.57 (s, 1H), 2.01 (dd, J = 34.7, 14.1 Hz, 8H), 1.81 (d, J = 11.6 Hz, 2H). LCMS (ESI) calcd. for C41H46F3N12O6+ [M+H]+: 859.36, found, 859.4.

[00477] Example 48 of compound of Formula (I): Preparation of compounds GT-09548 and GT-09549

[00478] The enantiomeric mixture product GT-06951 obtained from Example 8 of compound of Formula (I) was resolved and separated by supercritical fluid chromatography (SFC) to afford target compound GT-09548 and target compound GT-09549, respectively. The SFC preparation method and conditions are as follows.

[00479] The SFC preparation method is as follows: System: K-Prep LAB100G Column name: DAICELCHIRALCEL®IE Column dimensions: 250*40 mm 10 pm Mobile phase A: ethanol Mobile phase B: acetonitrile Mobile phase A: Mobile phase B 75:25 Wavelength: 254 nm Flow rate: 60ml / min Column temperature: room temperature Injection volume: 3 mL Cycle time: 11min Solvents: acetonitrile (redistilled grade) ethanol (redistilled grade) Sample solution preparation: The sample was dissolved in approximately 40 mL of ethanol.

[00480] The obtained target compound GT-09548 (white solid, 32 mg, yield 40%): 1H NMR (400 MHz, DMSO-d6) 5 11.08 (s, 1H), 9.50 (d, J = 6.1 Hz, 1H), 8.79 (d, J = 7.8 Hz, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.69 - 7.52 (m, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.11 (t, J = 53.7 Hz, 1H), 6.91 - 6.44 (m, 1H), 5.30 - 5.04 (m, 2H), 4.77 (d, J = 17.9 Hz, 1H), 4.21 (d, J = 13.0 Hz, 1H), 3.87 - 3.58 (m, 4H), 3.45 (d, J = 9.5 Hz, 1H), 2.86 (d, J = 17.6 Hz, 5H), 2.58 (d, J = 18.4 Hz, 2H), 2.18 (d, J = 7.0 Hz, 2H), 2.11 - 1.88 (m, 9H), 1.75 (d, J = 10.3 Hz, 2H), 1.59 (s, 1H), 1.30 (s, 1H), 1.14 - 1.00 (m, 2H). LCMS (ESI) calcd. for [M+H]+: 845.35, found, 845.3.

[00481] The obtained target compound GT-09549 (white solid, 36 mg, yield 42%): 1H NMR (400 MHz, DMSO-d6) 5 11.08 (s, 1H), 9.50 (d, J = 6.1 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.60 (t, J = 10.7 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.26 - 6.91 (m, 1H), 6.89 - 6.38 (m, 1H), 5.30 - 4.99 (m, 2H), 4.77 (d, J = 17.9 Hz, 1H), 4.21 (d, J = 13.8 Hz, 1H), 3.89 - 3.46 (m, 4H), 3.02 - 2.75 (m, 5H), 2.63 - 2.52 (m, 2H), 2.23 -1.89 (m, 11H), 1.74 (dd, J = 14.8, 8.5 Hz, 2H), 1.62 (s, 2H), 1.36 (d, J = 12.6 Hz, 1H), 1.06 (d, J = 12.4 Hz, 2H). LCMS (ESI) calcd. for C40H44F3N12O6+ [M+H]+: 845.35, found, 845.3.

[00482] Example 49 of compound of Formula (I): Preparation of compound GT-10020

[00483] With reference to the method of Scheme I-1, the target compound (GT-10020) was obtained (white solid, 26 mg, yield 48.73%). 1H NMR (400 MHz, DMSO-D6) S 11.47 (s, 1H), 11.10 (s, 1H), 10.54 (s, 1H), 9.00 (s, 1H), 8.49 (s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.92 (s, 1H), 7.60 (dd, J = 8.8, 4.3 Hz, 2H), 7.54 - 7.45 (m, 1H), 6.83 (s, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.88 - 4.76 (m, 1H), 3.71 (d, J = 12.3 Hz, 2H), 3.58 (s, 2H), 3.26 (s, 4H), 3.06 (s, 10H), 2.84 (dd, J = 24.2, 12.5 Hz, 3H), 2.61 (s, 2H), 2.33 (d, J = 1.8 Hz, 2H), 1.99 (d, J = 13.1 Hz, 8H), 1.66 (d, J = 5.9 Hz, 2H), 1.40 (d, J = 11.3 Hz, 2H). LCMS (ESI) calcd. for C42H50FN12O5+ [M+H]+: 821.40, found, 821.4.

[00484] Example 50 of compound of Formula (I): Preparation of compound GT-10032

[00485] With reference to the method of Scheme I-1, the target compound (GT-10032) was obtained (white solid, 41 mg, yield 76.84%). 1H NMR (400 MHz, DMSO-D6) S 11.54 (s, 1H), 11.09 (s, 1H), 10.86 (s, 1H), 9.01 (s, 1H), 8.97 (s, 1H), 8.16 (dd, J = 9.7, 2.5 Hz, 1H), 7.93 (s, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.82 (p, J = 8.6 Hz, 1H), 3.72 (s, 2H), 3.59 (s, 2H), 3.29 - 3.22 (m, 4H), 3.09 (d, J = 19.4 Hz, 10H), 2.91 - 2.77 (m, 3H), 2.61 (s, 2H), 2.32 (d, J = 10.2 Hz, 2H), 2.01 (dd, J = 15.0, 10.3 Hz, 8H), 1.72 -1.61 (m, 2H), 1.41 (d, J = 10.6 Hz, 2H). LCMS (ESI) calcd. for C42H50FN12O5+ [M+H]+: 821.40, found, 821.4.

[00486] Example 51 of compound of Formula (I): Preparation of compound GT-08188

[00487] With reference to the method of Scheme I-1, the target compound (GT-08188) was obtained (white solid, 44 mg, yield 64.70%). 1H NMR (400 MHz, DMSO-d6) S 11.61 (s, 1H), 11.14 (s, 1H), 11.01 (s, 1H), 9.02 (s, 1H), 8.20 (dd, J = 9.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.84 (s, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.82 (p, J = 8.6 Hz, 1H), 4.33 (d, J = 35.0 Hz, 2H), 3.70 (d, J = 12.0 Hz, 2H), 3.54 (s, 2H), 3.28 (d, J = 24.8 Hz, 4H), 3.06 (s, 10H), 2.96 - 2.80 (m, 3H), 2.63 (d, J = 16.7 Hz, 1H), 2.42 - 2.24 (m, 3H), 2.14 - 1.93 (m, 8H), 1.71 - 1.61 (m, 2H), 1.45 (d, J = 10.9 Hz, 2H). LCMS (ESI) calcd. for C42H52N12O4+ [M+H]+: 788.42, found, 788.4.

[00488] Example 52 of compound of Formula (I): Preparation of compound GT-10033

[00489] With reference to the method of Scheme I-1, the target compound (GT-10033) was obtained (white solid, 37 mg, yield 69.85%). 1H NMR (400 MHz, DMSO-D6) S 11.56 (s, 1H), 10.94 (s, 1H), 10.74 (s, 1H), 8.91 (d, J = 80.0 Hz, 1H), 8.24 - 8.07 (m, 1H), 7.95 (s, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.02 - 6.90 (m, 2H), 6.84 (s, 1H), 5.04 (dd, J = 13.2, 5.0 Hz, 1H), 4.82 (p, J = 8.6 Hz, 1H), 4.25 (d, J = 34.1 Hz, 2H), 3.89 (s, 2H), 3.72 (d, J = 11.8 Hz, 2H), 3.21 (s, 2H), 3.06 (s, 8H), 2.98 (d, J = 9.1 Hz, 3H), 2.82 (t, J = 11.0 Hz, 4H), 2.62 (t, J = 21.2 Hz, 3H), 2.32 (d, J = 4.7 Hz, 3H), 2.09 - 1.93 (m, 8H), 1.66 (d, J = 5.8 Hz, 2H), 1.40 (d, J = 11.7 Hz, 2H). LCMS (ESI) calcd. for C44H55N12O4+ [M+H]+: 815.45, found, 815.4.

[00490] Example 53 of compound of Formula (I): Preparation of compound GT-10034

[00491] With reference to the method of Scheme I-1, the target compound (GT-10034) was obtained (white solid, 32 mg, yield 60.41%). 1H NMR (400 MHz, DMSO-D6) S 11.57 (s, 1H), 10.93 (d, J = 12.2 Hz, 2H), 9.01 (s, 1H), 8.18 (dd, J = 9.6, 2.8 Hz, 1H), 7.98 (s, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.88 - 4.73 (m, 1H), 4.38 - 4.18 (m, 2H), 4.08 (s, 2H), 3.72 (d, J = 12.3 Hz, 3H), 3.46 (s, 2H), 3.34 (d, J = 12.1 Hz, 1H), 3.06 (s, 6H), 2.99 - 2.77 (m, 7H), 2.59 (d, J = 16.8 Hz, 1H), 2.34 (dd, J = 12.8, 4.6 Hz, 3H), 2.22 (s, 3H), 1.99 (dd, J = 17.7, 10.5 Hz, 7H), 1.72 - 1.61 (m, 2H), 1.46 (d, J = 10.5 Hz, 2H). LCMS (ESI) calcd. for C44H55N12O4+ [M+H]+: 815.45, found, 815.4.

[00492] Example 54 of compound of Formula (I): Preparation of compound GT-10035

[00493] With reference to the method of Scheme I-1, the target compound (GT-10035) was obtained (white solid, 32 mg, yield 59.39%). 1H NMR (400 MHz, DMSO-D6) S 11.55 (s, 1H), 11.30 (s, 1H), 10.94 (s, 1H), 9.01 (s, 1H), 8.16 (dd, J = 9.7, 2.7 Hz, 1H), 7.94 (s, 1H), 7.59 (d, J = 9.6 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 6.99 - 6.85 (m, 2H), 6.83 (s, 1H), 5.03 (d, J = 8.2 Hz, 1H), 4.82 (s, 1H), 4.36 - 4.16 (m, 2H), 4.03 (s, 2H), 3.86 (s, 2H), 3.70 (s, 6H), 3.17 (s, 2H), 3.06 (s, 6H), 2.95 - 2.86 (m, 1H), 2.77 (t, J = 11.6 Hz, 2H), 2.59 (d, J = 16.2 Hz, 2H), 2.35 - 2.26 (m, 3H), 1.96 (t, J = 21.6 Hz, 11H), 1.72 - 1.61 (m, 2H), 1.39 (s, 2H). LCMS (ESI) calcd. for C45H57N12O4+ [M+H]+: 829.46, found, 829.4.

[00494] Example 55 of compound of Formula (I): Preparation of compound GT-10036

[00495] With reference to the method of Scheme I-1, the target compound (GT-10036) was obtained (white solid, 32 mg, yield 61.31%). 1H NMR (400 MHz, DMSO-D6) S 11.61 (s, 1H), 11.02 (s, 1H), 10.94 (s, 1H), 9.02 (s, 1H), 8.20 (dd, J = 9.6, 2.5 Hz, 1H), 8.03 (s, 1H), 7.63 (d, J = 9.5 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.82 (p, J = 8.7 Hz, 1H), 4.31 (d, J = 16.6 Hz, 2H), 3.71 (d, J = 11.8 Hz, 2H), 3.58 (d, J = 9.5 Hz, 3H), 3.39 - 3.28 (m, 2H), 3.17 - 3.01 (m, 10H), 2.93 - 2.80 (m, 3H), 2.59 (d, J = 17.1 Hz, 1H), 2.38 - 2.27 (m, 3H), 2.24 - 1.84 (m, 11H), 1.74 - 1.59 (m, 2H), 1.43 (d, J = 10.6 Hz, 2H). LCMS (ESI) calcd. for C43H55N12O4+ [M+H]+: 803.45, found, 803.4.

[00496] Example 56 of compound of Formula (I): Preparation of compound GT-10037

[00497] With reference to the method of Scheme I-1, the target compound (GT-10037) was obtained (white solid, 22 mg, yield 42.26%). 1H NMR (400 MHz, DMSO-D6) 8 11.49 (s, 1H), 11.05 (s, 1H), 10.94 (s, 1H), 9.00 (s, 1H), 8.14 (d, J = 9.4 Hz, 2H), 7.93 (s, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.07 - 6.85 (m, 2H), 6.82 (s, 1H), 5.04 (dd, J = 12.9, 5.1 Hz, 1H), 4.82 (t, J = 8.6 Hz, 1H), 4.47 - 4.16 (m, 4H), 3.71 (d, J = 11.3 Hz, 2H), 3.62 (s, 4H), 3.09 (d, J = 26.9 Hz, 8H), 2.94 (dd, J = 15.9, 10.8 Hz, 2H), 2.77 (t, J = 10.8 Hz, 2H), 2.59 (d, J = 17.7 Hz, 1H), 2.38 - 2.28 (m, 3H), 2.10 - 1.89 (m, 9H), 1.65 (d, J = 5.8 Hz, 2H), 1.43 (d, J = 11.7 Hz, 2H). LCMS (ESI) calcd. for C43H53N12O4+ [M+H]+: 801.43, found, 801.4.

[00498] Example 57 of compound of Formula (I): Preparation of compound GT-10038

[00499] With reference to the method of Scheme I-1, the target compound (GT-10038) was obtained (white solid, 28 mg, yield 53.78%). 1H NMR (400 MHz, DMSO-D6) 8 11.60 (s, 1H), 10.94 (s, 1H), 9.02 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.1, 6.6 Hz, 1H), 7.05 - 6.86 (m, 2H), 6.84 (s, 1H), 5.03 (dd, J = 13.1, 4.9 Hz, 1H), 4.87 - 4.76 (m, 1H), 4.42 - 4.19 (m, 3H), 3.91 (s, 2H), 3.64 - 3.54 (m, 4H), 3.28 - 3.14 (m, 2H), 3.06 (s, 7H), 2.98 - 2.74 (m, 4H), 2.59 (d, J = 16.5 Hz, 1H), 2.33 (dd, J = 12.3, 8.3 Hz, 4H), 2.03 (dd, J = 35.3, 23.9 Hz, 8H), 1.65 (d, J = 5.6 Hz, 2H), 1.44 (d, J = 10.7 Hz, 2H). LCMS (ESI) calcd. for C43H53N12O4+ [M+H]+: 801.43, found, 801.4.

[00500] Example 58 of compound of Formula (I): Preparation of compound GT-10021

[00501] With reference to the method of Scheme I-1, the target compound (GT-10021) was obtained (white solid, 28 mg, yield 52.79%). 1H NMR (400 MHz, DMSO-D6) 8 11.10 (s, 1H), 10.25 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 8.47 (s, 1H), 7.85 (dd, J = 9.2, 4.3 Hz, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.42 (d, J = 9.7 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.53 (dd, J = 20.5, 11.2 Hz, 3H), 3.98 - 3.83 (m, 1H), 3.58 (s, 2H), 3.30 - 3.18 (m, 4H), 3.09 (dd, J = 26.1, 14.6 Hz, 6H), 2.94 - 2.83 (m, 1H), 2.59 (d, J = 20.2 Hz, 2H), 2.22 (s, 1H), 2.11 (d, J = 10.4 Hz, 2H), 2.06 - 1.98 (m, 1H), 1.92 (t, J = 12.5 Hz, 4H), 1.70 - 1.49 (m, 4H), 1.35 - 1.23 (m, 2H). LCMS (ESI) calcd. for C41H45ClFN10O6+ [M+H]+: 827.32, found, 827.3.

[00502] Example 59 of compound of Formula (I): Preparation of compound GT-10039

[00503] With reference to the method of Scheme I-1, the target compound (GT-10039) was obtained (white solid, 28 mg, yield 52.79%). 1H NMR (400 MHz, DMSO-D6) S 11.09 (s, 1H), 10.52 (s, 1H), 8.91 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 7.84 (dd, J = 14.8, 6.6 Hz, 2H), 7.40 (dd, J = 10.5, 6.1 Hz, 2H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (s, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.53 (dd, J = 20.5, 11.1 Hz, 3H), 3.86 (d, J = 7.7 Hz, 1H), 3.57 (s, 2H), 3.19 - 3.01 (m, 8H), 2.94 - 2.81 (m, 1H), 2.60 (s, 2H), 2.28 - 2.06 (m, 3H), 1.95 (dd, J = 30.9, 16.4 Hz, 4H), 1.58 (td, J = 27.1, 12.5 Hz, 6H), 1.29 (dd, J = 18.0, 10.7 Hz, 3H). LCMS (ESI) calcd. for C41H45ClFN10O6+ [M+H]+: 827.32, found, 827.3.

[00504] Example 60 of compound of Formula (I): Preparation of compound GT-08179

[00505] With reference to the method of Scheme I-1, the target compound (GT-08179) was obtained (white solid, 16 mg, yield 23.53%). 1H NMR (400 MHz, DMSO-d6) S 11.00 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.77 (s, 1H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H), 4.51 (dd, J = 23.9, 8.9 Hz, 3H), 4.30 (dd, J = 38.4, 17.4 Hz, 2H), 3.86 (d, J = 8.4 Hz, 1H), 3.06 - 2.86 (m, 4H), 2.75 (s, 3H), 2.64 (s, 1H), 2.35 (d, J = 18.0 Hz, 2H), 2.23 - 2.01 (m, 6H), 1.86 (dd, J = 32.9, 10.9 Hz, 6H), 1.68 - 1.59 (m, 2H), 1.57 - 1.48 (m, 2H), 1.12 (s, 2H). LCMS (ESI) calcd. for C41H48ClN10O5+ [M+H]+: 795.35, found, 795.4.

[00506] Example 61 of compound of Formula (I): Preparation of compound GT-10040

[00507] With reference to the method of Scheme I-1, the target compound (GT-10040) was obtained (white solid, 28 mg, yield 53.17%). 1H NMR (400 MHz, DMSO-D6) S 10.94 (s, 1H), 10.57 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.51 - 7.42 (m, 2H), 7.39 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 5.04 (dd, J = 13.1, 5.1 Hz, 1H), 4.61 - 4.46 (m, 3H), 4.24 (dd, J = 50.0, 16.7 Hz, 2H), 3.88 (s, 3H), 3.43 (s, 1H), 3.18 (d, J = 5.2 Hz, 3H), 3.08 (t, J = 11.8 Hz, 3H), 2.98 (d, J = 8.7 Hz, 3H), 2.85 (dd, J = 18.1, 6.2 Hz, 2H), 2.59 (d, J = 17.6 Hz, 2H), 2.33 (s, 1H), 2.11 (d, J = 9.3 Hz, 3H), 2.03 - 1.87 (m, 5H), 1.70 - 1.47 (m, 6H), 1.31 (dd, J = 14.7, 7.4 Hz, 3H). LCMS (ESI) calcd. for C43H50ClN10O5+ [M+H]+: 821.37, found, 821.3.

[00508] Example 62 of compound of Formula (I): Preparation of compound GT-10041

[00509] With reference to the method of Scheme I-1, the target compound (GT-10041) was obtained (white solid, 30 mg, yield 56.97%). 1H NMR (400 MHz, DMSO-D6) S 10.94 (s, 1H), 10.48 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 9.2, 3.6 Hz, 2H), 7.60 (s, 1H), 7.51 - 7.36 (m, 3H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 - 4.47 (m, 3H), 4.25 (dd, J = 53.5, 17.0 Hz, 2H), 4.07 (s, 2H), 3.92 - 3.81 (m, 1H), 3.37 (d, J = 11.5 Hz, 2H), 3.20 - 3.13 (m, 2H), 3.07 (t, J = 11.6 Hz, 2H), 2.94 (d, J = 14.8 Hz, 4H), 2.59 (d, J = 16.3 Hz, 1H), 2.21 (s, 4H), 2.11 (d, J = 9.4 Hz, 2H), 1.94 (dd, J = 20.2, 12.8 Hz, 4H), 1.67 - 1.49 (m, 5H), 1.31 (dd, J = 14.5, 7.4 Hz, 3H). LCMS (ESI) calcd. for C43H50ClN10O5+ [M+H]+: 821.37, found, 821.3.

[00510] Example 63 of compound of Formula (I): Preparation of compound GT-10042

[00511] With reference to the method of Scheme I-1, the target compound (GT-10042) was obtained (white solid, 30 mg, yield 56.01%). 1H NMR (400 MHz, DMSO-D6) 5 11.18 (s, 1H), 10.94 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 9.2, 4.5 Hz, 2H), 7.52 - 7.44 (m, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (d, J = 30.7 Hz, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.57 - 4.44 (m, 3H), 4.34 - 4.16 (m, 2H), 4.03 (s, 6H), 3.22 - 3.01 (m, 6H), 2.89 (d, J = 13.1 Hz, 1H), 2.59 (d, J = 17.0 Hz, 1H), 2.36 (dd, J = 13.2, 8.8 Hz, 1H), 2.15 - 1.84 (m, 11H), 1.67 - 1.49 (m, 5H), 1.35 - 1.22 (m, 3H). LCMS (ESI) calcd. for C44H52ClN10O5+ [M+H]+: 835.38, found, 835.4.

[00512] Example 64 of compound of Formula (I): Preparation of compound GT-10043

[00513] With reference to the method of Scheme I-1, the target compound (GT-10043) was obtained (white solid, 33 mg, yield 63.60%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 10.63 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.46 (dd, J = 9.1, 4.0 Hz, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 - 4.46 (m, 3H), 4.24 (dd, J = 53.0, 16.8 Hz, 2H), 3.86 (d, J = 7.9 Hz, 2H), 3.62 - 3.51 (m, 2H), 3.32 (d, J = 13.3 Hz, 2H), 3.12 (dt, J = 24.2, 10.4 Hz, 7H), 2.92 (d, J = 13.4 Hz, 1H), 2.59 (d, J = 17.1 Hz, 1H), 2.39 - 2.31 (m, 1H), 2.23 - 1.87 (m, 10H), 1.67 -1.49 (m, 5H), 1.30 (dt, J = 21.8, 10.9 Hz, 3H). LCMS (ESI) calcd. for C42H50ClN10O5+ [M+H]+: 809.37, found, 809.4.

[00514] Example 65 of compound of Formula (I): Preparation of compound GT-10044

[00515] With reference to the method of Scheme I-1, the target compound (GT-10044) was obtained (white solid, 15 mg, yield 28.98%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 10.79 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.00 (s, 1H), 7.90 - 7.81 (m, 2H), 7.48 (dt, J = 8.4, 2.9 Hz, 1H), 7.40 (dd, J = 10.9, 6.0 Hz, 2H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 7.06 - 6.83 (m, 2H), 5.03 (dd, J = 13.3, 5.0 Hz, 1H), 4.54 - 4.42 (m, 3H), 4.27 (t, J = 25.3 Hz, 2H), 3.92 - 3.80 (m, 1H), 3.60 (s, 2H), 3.20 - 3.13 (m, 3H), 3.04 (t, J = 11.6 Hz, 3H), 2.97 - 2.85 (m, 2H), 2.59 (d, J = 16.7 Hz, 1H), 2.41 - 2.30 (m, 1H), 2.11 (d, J = 8.9 Hz, 3H), 2.00 - 1.86 (m, 5H), 1.68 - 1.52 (m, 6H), 1.33 - 1.28 (m, 3H). LCMS (ESI) calcd. for C42H48ClN10O5+ [M+H]+: 807.35, found, 807.4.

[00516] Example 66 of compound of Formula (I): Preparation of compound GT-10045

[00517] With reference to the method of Scheme I-1, the target compound (GT-10045) was obtained (white solid, 19 mg, yield 36.71%). 1H NMR (400 MHz, DMSO-D6) S 10.94 (s, 2H), 8.61 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.50 - 7.43 (m, 2H), 7.39 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.98 (d, J = 11.9 Hz, 1H), 6.90 (dd, J = 16.9, 8.2 Hz, 1H), 5.03 (dd, J = 13.4, 4.9 Hz, 1H), 4.50 (dd, J = 29.8, 23.7 Hz, 4H), 4.25 (ddd, J = 21.5, 12.1, 4.1 Hz, 3H), 3.93 - 3.84 (m, 1H), 3.25 - 3.14 (m, 3H), 3.07 (t, J = 12.2 Hz, 3H), 2.91 (dd, J = 22.0, 8.8 Hz, 1H), 2.59 (d, J = 16.6 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.23 (s, 2H), 2.11 (d, J = 11.7 Hz, 3H), 1.93 (dd, J = 21.9, 9.5 Hz, 4H), 1.69 - 1.48 (m, 6H), 1.31 (td, J = 14.6, 7.3 Hz, 3H). LCMS (ESI) calcd. for C42H48ClN10O5+ [M+H]+: 807.35, found, 807.4.

[00518] Example 67 of compound of Formula (I): Preparation of compound GT-10022

[00519] With reference to the method of Scheme I-1, the target compound (GT-10022) was obtained (white solid, 26 mg, yield 49.80%). 1H NMR (400 MHz, DMSO-D6) S 11.10 (s, 1H), 9.97 (s, 1H), 9.51 (d, J = 6.7 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J = 4.2 Hz, 1H), 8.26 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 3.8 Hz, 1H), 6.66 (dd, J = 164.3, 7.8 Hz, 1H), 5.34 - 5.02 (m, 2H), 4.77 (d, J = 19.7 Hz, 1H), 4.24 (s, 1H), 3.91 - 3.71 (m, 2H), 3.66 - 3.55 (m, 3H), 3.44 (d, J = 10.0 Hz, 2H), 3.27 - 3.14 (m, 4H), 3.12 - 2.99 (m, 4H), 2.88 (s, 1H), 2.58 (d, J = 20.0 Hz, 1H), 2.01 (ddd, J = 35.0, 24.6, 11.4 Hz, 8H), 1.81 (d, J = 12.4 Hz, 2H), 1.22 (d, J = 11.9 Hz, 2H). LCMS (ESI) calcd. for C40H44F3N12O6+ [M+H]+: 845.35, found, 845.3.

[00520] Example 68 of compound of Formula (I): Preparation of compound GT-10046

[00521] With reference to the method of Scheme I-1, the target compound (GT-10046) was obtained (white solid, 23 mg, yield 44.05%). 1H NMR (400 MHz, DMSO-d6) S 11.09 (s, 1H), 10.04 (s, 1H), 9.51 (d, J = 6.5 Hz, 1H), 8.87 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 4.1 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.32 - 6.97 (m, 2H), 6.67 (dd, J = 165.1, 7.8 Hz, 2H), 5.35 - 4.97 (m, 2H), 4.77 (d, J = 19.9 Hz, 1H), 4.25 (s, 1H), 3.87 - 3.71 (m, 2H), 3.69 - 3.56 (m, 3H), 3.45 (d, J = 10.2 Hz, 2H), 3.31 - 3.20 (m, 2H), 3.08 (d, J = 33.6 Hz, 5H), 2.93 - 2.83 (m, 1H), 2.58 (d, J = 21.1 Hz, 2H), 2.16 - 1.88 (m, 8H), 1.81 (dd, J = 23.5, 12.0 Hz, 2H), 1.22 (q, J = 11.6 Hz, 2H). LCMS (ESI) calcd. for C40H44F3N12O6+ [M+H]+: 845.35, found, 845.3.

[00522] Example 69 of compound of Formula (I): Preparation of compound GT-08180

[00523] With reference to the method of Scheme I-1, the target compound (GT-08180) was obtained (white solid, 27 mg, yield 40.32%). 1H NMR (400 MHz, DMSO-d6) 6 11.01 (s, 1H), 9.47 (t, J = 23.5 Hz, 1H), 8.79 (d, J = 7.5 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.35 -6.94 (m, 4H), 6.91 - 6.46 (m, 2H), 5.32 - 5.06 (m, 2H), 4.77 (d, J = 19.0 Hz, 1H), 4.44 - 4.13 (m, 3H), 3.80 (t, J = 17.1 Hz, 2H), 3.66 - 3.56 (m, 2H), 3.45 (d, J = 10.2 Hz, 4H), 3.31 - 3.26 (m, 2H), 3.21 - 2.92 (m, 4H), 2.66 (dd, J = 33.0, 18.4 Hz, 3H), 2.45 - 2.34 (m, 1H), 2.00 (dd, J = 32.3, 12.2 Hz, 8H), 1.79 (s, 2H), 1.07 (s, 1H). LCMS (ESI) calcd. for C40H47F2N12O5+ [M+H]+: 813.38, found, 813.4.

[00524] Example 70 of compound of Formula (I): Preparation of compound GT-10047

[00525] With reference to the method of Scheme I-1, the target compound (GT-10047) was obtained (white solid, 25 mg, yield 48.23%). 1H NMR (400 MHz, DMSO-d6) 6 10.94 (s, 1H), 10.25 (s, 1H), 9.51 (d, J = 6.2 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 66.9, 7.9 Hz, 3H), 6.67 (dd, J = 165.7, 7.8 Hz, 1H), 5.37 - 4.98 (m, 2H), 4.77 (d, J = 18.9 Hz, 1H), 4.37 - 4.11 (m, 3H), 3.91 - 3.76 (m, 3H), 3.64 (d, J = 10.2 Hz, 2H), 3.45 (d, J = 10.2 Hz, 2H), 3.16 (s, 2H), 2.95 (dd, J = 20.4, 11.0 Hz, 4H), 2.88 - 2.75 (m, 2H), 2.59 (d, J = 17.0 Hz, 3H), 2.33 (s, 1H), 1.95 (ddd, J = 62.7, 25.9, 12.3 Hz, 10H), 1.20 (d, J = 13.1 Hz, 2H). LCMS (ESI) calcd. for C42H49F2N12O5+ [M+H]+: 839.39, found, 839.4.

[00526] Example 71 of compound of Formula (I): Preparation of compound GT-10048

[00527] With reference to the method of Scheme I-1, the target compound (GT-10048) was obtained (white solid, 20 mg, yield 38.58%). 1H NMR (400 MHz, DMSO-d6) 6 10.94 (s, 1H), 10.12 (s, 1H), 9.51 (d, J = 6.5 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.00 (s, 2H), 6.70 (d, J = 185.8 Hz, 2H), 5.33 - 4.96 (m, 2H), 4.77 (d, J = 19.7 Hz, 1H), 4.26 (d, J = 36.3 Hz, 3H), 4.07 (s, 2H), 3.81 (s, 2H), 3.60 (s, 2H), 3.29 (d, J = 11.7 Hz, 3H), 2.93 (dd, J = 16.5, 8.3 Hz, 4H), 2.64 - 2.54 (m, 1H), 2.40 - 2.31 (m, 1H), 2.22 (s, 4H), 2.13 - 1.91 (m, 8H), 1.81 (dd, J = 23.8, 11.6 Hz, 2H), 1.25 (dd, J = 23.1, 10.8 Hz, 2H). LCMS (ESI) calcd. for C42H49F2N12O5+ [M+H]+: 839.39, found, 839.4.

[00528] Example 72 of compound of Formula (I): Preparation of compound GT-10049

[00529] With reference to the method of Scheme I-1, the target compound (GT-10049) was obtained (white solid, 26 mg, yield 49.33%). 1H NMR (400 MHz, DMSO-d6) 5 10.94 (s, 1H), 10.73 (s, 1H), 9.51 (d, J = 6.1 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 4.1 Hz, 1H), 8.27 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 53.8, 3.4 Hz, 1H), 6.94 (s, 1H), 6.89 -6.45 (m, 2H), 5.30 - 5.00 (m, 2H), 4.77 (d, J = 18.5 Hz, 1H), 4.34 - 4.15 (m, 3H), 4.03 (s, 2H), 3.81 (dd, J = 27.9, 17.0 Hz, 4H), 3.64 (d, J = 10.5 Hz, 2H), 3.46 - 3.30 (m, 4H), 3.12 (t, J = 6.0 Hz, 2H), 2.91 (dd, J = 22.2, 8.9 Hz, 1H), 2.59 (d, J = 17.2 Hz, 2H), 2.41 - 2.31 (m, 1H), 2.13 -1.86 (m, 10H), 1.75 (dd, J = 22.3, 11.5 Hz, 3H), 1.18 (dd, J = 23.9, 11.7 Hz, 2H). LCMS (ESI) calcd. for C43H51F2N12O5+ [M+H]+: 853.41, found, 853.4.

[00530] Example 73 of compound of Formula (I): Preparation of compound GT-10050

[00531] With reference to the method of Scheme I-1, the target compound (GT-10050) was obtained (white solid, 24 mg, yield 46.97%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 10.16 (s, 1H), 9.51 (d, J = 6.4 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 4.1 Hz, 1H), 8.27 (t, J = 7.4 Hz, 1H), 7.77 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.30 - 6.98 (m, 1H), 6.96 (s, 1H), 6.91 -6.44 (m, 2H), 5.32 - 4.99 (m, 2H), 4.77 (d, J = 19.0 Hz, 1H), 4.36 - 4.12 (m, 3H), 3.87 - 3.72 (m, 2H), 3.68 - 3.51 (m, 5H), 3.35 - 3.23 (m, 2H), 3.18 - 2.81 (m, 6H), 2.59 (d, J = 17.2 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.13 - 1.74 (m, 12H), 1.21 (dd, J = 23.6, 11.6 Hz, 2H). LCMS (ESI) calcd. for C41H49F2N12O5+ [M+H]+: 827.39, found, 827.4.

[00532] Example 74 of compound of Formula (I): Preparation of compound GT-10051

[00533] With reference to the method of Scheme I-1, the target compound (GT-10051) was obtained (white solid, 20 mg, yield 39.24%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 10.51 (s, 1H), 9.51 (d, J = 6.2 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 4.1 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 7.53 - 7.44 (m, 1H), 7.14 (dd, J = 40.2, 36.8 Hz, 1H), 6.82 (ddd, J = 173.2, 89.2, 8.9 Hz, 3H), 5.32 - 4.99 (m, 2H), 4.77 (d, J = 19.0 Hz, 1H), 4.43 (s, 1H), 4.36 -4.14 (m, 4H), 3.86 - 3.36 (m, 10H), 3.33 - 3.30 (m, 1H), 3.05 (s, 1H), 2.97 - 2.82 (m, 2H), 2.59 (d, J = 16.6 Hz, 1H), 2.47 - 2.31 (m, 2H), 2.14 - 1.92 (m, 7H), 1.87 - 1.74 (m, 2H), 1.28 - 1.18 (m, 1H). LCMS (ESI) calcd. for C41H47F2N12O5+ [M+H]+: 825.38, found, 825.4.

[00534] Example 75 of compound of Formula (I): Preparation of compound GT-10052

[00535] With reference to the method of Scheme I-1, the target compound (GT-10052) was obtained (white solid, 23 mg, yield 45.12%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 10.51 (s, 1H), 9.51 (d, J = 6.2 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 4.1 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.89 (s, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.28 - 6.96 (m, 2H), 6.94 - 6.45 (m, 2H), 5.32 - 4.93 (m, 2H), 4.77 (d, J = 19.0 Hz, 1H), 4.27 (dt, J = 33.4, 21.2 Hz, 4H), 3.88 - 3.55 (m, 6H), 3.46 (s, 3H), 3.16 (d, J = 8.9 Hz, 2H), 3.10 - 2.84 (m, 2H), 2.59 (d, J = 16.9 Hz, 1H), 2.41 - 2.17 (m, 3H), 2.15 - 1.93 (m, 7H), 1.86 - 1.72 (m, 2H), 1.33 - 1.10 (m, 2H). LCMS (ESI) calcd. for C41H47F2N12O5+ [M+H]+: 825.38, found, 825.4.

[00536] Example 76 of compound of Formula (I): Preparation of compound GT-10023

[00537] With reference to the method of Scheme I-1, the target compound (GT-10023) was obtained (white solid, 32 mg, yield 61.80%). 1H NMR (400 MHz, DMSO-D6) 5 11.10 (s, 1H), 10.05 (s, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.46 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 2H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.44 (d, J = 13.2 Hz, 2H), 4.33 (s, 1H), 4.06 (d, J = 9.1 Hz, 1H), 3.58 (s, 3H), 3.20 (dd, J = 22.0, 10.8 Hz, 4H), 3.13 - 2.98 (m, 6H), 2.94 - 2.82 (m, 1H), 2.61 (s, 1H), 2.18 (s, 1H), 2.07 - 1.99 (m, 1H), 1.91 (d, J = 11.4 Hz, 2H), 1.23 (s, 8H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H50ClFN9O6+ [M+H]+: 854.36, found, 854.4.

[00538] Example 77 of compound of Formula (I): Preparation of compound GT-10053

[00539] With reference to the method of Scheme I-1, the target compound (GT-10053) was obtained (white solid, 24 mg, yield 46.35%). 1H NMR (400 MHz, DMSO-D6) 5 11.10 (d, J = 7.7 Hz, 1H), 10.58 (s, 1H), 8.92 (s, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.45 (d, J = 13.0 Hz, 2H), 4.34 (s, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.63 (s, 3H), 3.23 (s, 4H), 3.15 - 3.01 (m, 6H), 2.95 - 2.82 (m, 1H), 2.61 (s, 1H), 2.21 (s, 1H), 1.99 (dd, J = 17.3, 9.5 Hz, 3H), 1.26 (d, J = 21.3 Hz, 8H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H50ClFN9O6+ [M+H]+: 854.36, found, 854.4.

[00540] Example 78 of compound of Formula (I): Preparation of compound GT-08189

[00541] With reference to the method of Scheme I-1, the target compound (GT-08189) was obtained (white solid, 41 mg, yield 62.12%). 1H NMR (400 MHz, DMSO-d6) 5 11.01 (s, 1H), 10.71 (s, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 4.9 Hz, 2H), 7.09 (dd, J = 15.9, 7.7 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.54 - 4.16 (m, 6H), 4.08 (d, J = 9.1 Hz, 1H), 3.28 - 3.01 (m, 11H), 2.98 - 2.88 (m, 1H), 2.63 (d, J = 17.0 Hz, 1H), 2.40 (dd, J = 13.1, 4.5 Hz, 1H), 2.24 (s, 1H), 2.02 (dd, J = 17.1, 9.4 Hz, 3H), 1.40 - 1.26 (m, 2H), 1.24 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C44H53ClN9O5+ [M+H]+: 822.39, found, 822.4.

[00542] Example 79 of compound of Formula (I): Preparation of compound GT-09927

[00543] With reference to the method of Scheme I-1, the target compound (GT-09927) was obtained (white solid, 23 mg, yield 44.73%). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 10.48 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (t, J = 9.2 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 12.5 Hz, 2H), 4.35 - 4.25 (m, 2H), 4.18 (d, J = 16.7 Hz, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.90 (s, 2H), 3.38 - 3.35 (m, 1H), 3.22 -3.06 (m, 5H), 3.00 - 2.80 (m, 6H), 2.61 (s, 2H), 2.57 (s, 1H), 2.40 - 2.31 (m, 1H), 2.15 (s, 1H), 1.97 (dd, J = 18.3, 9.8 Hz, 3H), 1.36 - 1.22 (m, 8H), 1.13 (s, 6H). LCMS (ESI) calcd. for C46H55ClN9O5+ [M+H]+: 848.40, found, 848.4.

[00544] Example 80 of compound of Formula (I): Preparation of compound GT-09928

[00545] With reference to the method of Scheme I-1, the target compound (GT-09928) was obtained (white solid, 32 mg, yield 62.23%). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 10.36 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 8.3, 5.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.01 (dd, J = 8.8, 2.5 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 13.3 Hz, 2H), 4.25 (dd, J = 53.0, 16.5 Hz, 3H), 4.06 (t, J = 10.4 Hz, 3H), 3.32 (s, 2H), 3.08 (t, J = 11.7 Hz, 2H), 2.91 (td, J = 17.9, 8.7 Hz, 5H), 2.59 (d, J = 16.8 Hz, 1H), 2.36 (dd, J = 12.9, 8.1 Hz, 1H), 2.22 (s, 5H), 2.05 - 1.90 (m, 3H), 1.37 - 1.27 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C46H55ClN9O5+ [M+H]+: 848.40, found, 848.4.

[00546] Example 81 of compound of Formula (I): Preparation of compound GT-09929

[00547] With reference to the method of Scheme I-1, the target compound (GT-09929) was obtained (white solid, 35 mg, yield 66.96%). 1H NMR (400 MHz, DMSO-D6) 8 11.05 (s, 1H), 10.94 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 2.4 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 12.8 Hz, 2H), 4.38 - 4.16 (m, 3H), 4.12 - 4.00 (m, 3H), 3.85 (s, 4H), 3.38 - 3.25 (m, 2H), 3.16 - 3.06 (m, 4H), 2.96 - 2.83 (m, 2H), 2.59 (d, J = 16.5 Hz, 1H), 2.40 - 2.32 (m, 1H), 2.11 - 1.86 (m, 7H), 1.25 (d, J = 15.8 Hz, 8H), 1.13 (s, 6H). LCMS (ESI) calcd. for C47H57ClN9O5+ [M+H]+: 862.42, found, 862.4.

[00548] Example 82 of compound of Formula (I): Preparation of compound GT-09930

[00549] With reference to the method of Scheme I-1, the target compound (GT-09930) was obtained (white solid, 30 mg, yield %). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 10.68 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.45 (t, J = 10.4 Hz, 1H), 7.26 (d, J = 9.5 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (s, 1H), 6.90 (t, J = 9.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 12.7 Hz, 2H), 4.38 - 4.17 (m, 3H), 4.09 (s, 1H), 3.32 (d, J = 13.9 Hz, 5H), 3.13 (dd, J = 24.4, 9.9 Hz, 6H), 2.99 - 2.84 (m, 2H), 2.59 (d, J = 16.6 Hz, 1H), 2.43 - 2.30 (m, 1H), 2.04 (ddd, J = 34.2, 26.2, 16.7 Hz, 6H), 1.37 - 1.26 (m, 2H), 1.24 (s, 6H), 1.13 (s, 6H). LCMS (ESI) calcd. for C45H55ClN9O5+ [M+H]+: 836.40, found, 836.4.

[00550] Example 83 of compound of Formula (I): Preparation of compound GT-09931

[00551] With reference to the method of Scheme I-1, the target compound (GT-09931) was obtained (white solid, 16 mg, yield 31.64 %). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 10.51 (s, 1H), 8.64 - 8.59 (m, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 9.7 Hz, 1H), 7.49 (dd, J = 8.3, 3.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.03 - 6.84 (m, 3H), 5.03 (dd, J = 13.4, 4.9 Hz, 1H), 4.45 (d, J = 14.9 Hz, 3H), 4.31 (d, J = 14.1 Hz, 2H), 4.18 (d, J = 16.9 Hz, 1H), 4.06 (d, J = 9.1 Hz, 1H), 3.45 (s, 7H), 3.07 - 2.87 (m, 5H), 2.59 (d, J = 17.2 Hz, 1H), 2.40 - 2.28 (m, 1H), 2.07 (s, 1H), 1.99 - 1.82 (m, 3H), 1.22 (s, 8H), 1.12 (s, 6H). LCMS (ESI) calcd. for C45H53ClN9O5+ [M+H]+: 834.39, found, 834.4.

[00552] Example 84 of compound of Formula (I): Preparation of compound GT-09932

[00553] With reference to the method of Scheme I-1, the target compound (GT-09932) was obtained (white solid, 33 mg, yield 65.26%). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 10.71 (s, 1H), 9.70 (s, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 8.3, 6.1 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.08 (s, 1H), 7.04 - 6.96 (m, 2H), 6.90 (dd, J = 15.1, 8.4 Hz, 1H), 5.13 - 4.99 (m, 1H), 4.44 (s, 2H), 4.37 - 4.12 (m, 4H), 4.07 (d, J = 9.1 Hz, 1H), 3.59 (s, 6H), 3.17 (s, 2H), 3.05 (d, J = 10.8 Hz, 2H), 2.89 (dd, J = 21.9, 9.5 Hz, 1H), 2.61 (s, 1H), 2.43 - 2.32 (m, 1H), 2.22 (s, 2H), 1.99 (dd, J = 35.9, 10.1 Hz, 3H), 1.23 (s, 8H), 1.13 (s, 6H). LCMS (ESI) calcd. for C45H53ClN9O5+ [M+H]+: 834.39, found, 834.4.

[00554] Example 85 of compound of Formula (I): Preparation of compound GT-09764

[00555] With reference to the method of Scheme I-1, the target compound (GT-09764) was obtained (white solid, 10 mg, yield 19.77%). 1H NMR (400 MHz, DMSO-D6) S 11.15 (s, 1H), 11.07 (s, 1H), 10.72 (s, 1H), 10.19 (d, J = 11.4 Hz, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.50 (s, 1H), 8.00 (dd, J = 6.8, 2.6 Hz, 1H), 7.70 (ddd, J = 8.9, 4.3, 2.6 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.44 (s, 1H), 7.25 (s, 1H), 7.05 (d, J = 10.1 Hz, 1H), 6.99 (dd, J = 15.1, 7.4 Hz, 1H), 6.80 (d, J = 15.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.08 (s, 3H), 3.97 (d, J = 14.6 Hz, 2H), 3.57 (s, 6H), 3.10 (d, J = 11.9 Hz, 7H), 3.00 - 2.85 (m, 3H), 2.59 (d, J = 17.6 Hz, 2H), 2.11 (d, J = 11.4 Hz, 2H), 2.04 - 1.95 (m, 1H), 1.65 (d, J = 11.7 Hz, 2H). LCMS (ESI) calcd. for C42H45ClFN10O6+ [M+H]+: 839.32, found, 839.3.

[00556] Example 86 of compound of Formula (I): Preparation of compound GT-09920

[00557] With reference to the method of Scheme I-1, the target compound (GT-09920) was obtained (white solid, 20 mg, yield 33.19%). 1H NMR (400 MHz, DMSO-D6) S 11.24 (s, 1H), 11.07 (s, 2H), 10.49 (s, 1H), 10.14 (s, 1H), 9.12 (s, 1H), 8.83 (s, 1H), 8.48 (s, 1H), 8.01 (dd, J = 6.7, 2.6 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.65 (d, J = 10.2 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.44 (s, 1H), 7.06 - 6.95 (m, 1H), 6.80 (d, J = 15.5 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.07 (s, 3H), 3.97 (d, J = 15.2 Hz, 2H), 3.57 (s, 6H), 3.10 (d, J = 10.4 Hz, 7H), 3.00 -2.85 (m, 3H), 2.59 (d, J = 19.3 Hz, 2H), 2.20 - 1.96 (m, 4H), 1.66 (d, J = 13.7 Hz, 1H). LCMS (ESI) calcd. for C42H44ClF2N10O6+ [M+H]+: 857.31, found, 857.3.

[00558] Example 87 of compound of Formula (I): Preparation of compound GT-09921

[00559] With reference to the method of Scheme I-1, the target compound (GT-09921) was obtained (white solid, 15 mg, yield 25.86%). 1H NMR (400 MHz, DMSO-D6) S 11.34 (d, J = 32.5 Hz, 2H), 10.93 (s, 1H), 10.85 (s, 1H), 10.21 (d, J = 12.8 Hz, 1H), 9.16 (s, 1H), 8.88 (s, 1H), 7.99 (dd, J = 6.8, 2.5 Hz, 1H), 7.77 (s, 1H), 7.69 (ddd, J = 8.9, 4.3, 2.6 Hz, 1H), 7.54 (t, J = 9.0 Hz, 1H), 7.47 (dd, J = 14.4, 6.1 Hz, 2H), 7.02 (dt, J = 14.6, 7.2 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 15.4 Hz, 1H), 5.03 (dd, J = 13.1, 5.1 Hz, 1H), 4.37 - 4.15 (m, 2H), 4.08 (s, 3H), 3.95 (s, 2H), 3.55 (s, 6H), 3.19 - 3.02 (m, 7H), 2.92 (dd, J = 29.3, 11.7 Hz, 3H), 2.61 (s, 1H), 2.35 (td, J = 13.0, 9.6 Hz, 1H), 2.12 (d, J = 12.2 Hz, 3H), 2.00 - 1.91 (m, 1H), 1.68 (d, J = 12.4 Hz, 1H). LCMS (ESI) C42H47ClFN10O5+ [M+H]+: calcd. for 825.34, found, 825.3.

[00560] Example 88 of compound of Formula (I): Preparation of compound GT-09922 obtained (white solid, 15 mg, yield 25.31%). 1H NMR (400 MHz, DMSO-D6) 8 11.43 (s, 1H), 11.22 (s, 1H), 10.96 (s, 1H), 10.67 (s, 1H), 10.21 (d, J = 12.7 Hz, 1H), 9.15 (s, 1H), 8.86 (s, 1H), 8.00 (dd, J = 6.8, 2.5 Hz, 1H), 7.78 (s, 1H), 7.74 - 7.67 (m, 1H), 7.57 - 7.48 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.38 - 7.28 (m, 1H), 7.02 (dt, J = 14.1, 7.1 Hz, 1H), 6.80 (d, J = 15.3 Hz, 1H), 5.11 - 4.98 (m, 1H), 4.37 (dd, J = 71.8, 16.8 Hz, 2H), 4.08 (s, 3H), 3.95 (s, 2H), 3.56 (s, 5H), 3.24 (d, J = 15.4 Hz, 6H), 3.06 (s, 3H), 2.92 (dd, J = 26.4, 13.5 Hz, 3H), 2.59 (d, J = 17.5 Hz, 1H), 2.43 -2.33 (m, 1H), 2.10 (d, J = 11.8 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.68 (d, J = 12.6 Hz, 1H). LCMS (ESI) calcd. for C42H46ClF2N10O5+ [M+H]+: 843.33, found, 843.3.

[00562] Example 89 of compound of Formula (I): Preparation of compound GT-09923

[00563] With reference to the method of Scheme I-1, the target compound (GT-09923) was obtained (white solid, 18 mg, yield 30.08%). 1H NMR (400 MHz, DMSO-D6) 8 11.46 (s, 2H), 10.94 (s, 1H), 10.83 (s, 1H), 10.23 (s, 1H), 9.20 (s, 1H), 8.92 (s, 1H), 7.98 (dd, J = 6.8, 2.5 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.59 - 7.52 (m, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 6.81 (d, J = 15.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.24 (dd, J = 50.7, 16.7 Hz, 2H), 4.09 (s, 3H), 3.92 (d, J = 26.3 Hz, 3H), 3.53 (s, 4H), 3.37 - 3.32 (m, 3H), 3.20 (s, 3H), 2.97 (t, J = 31.0 Hz, 7H), 2.81 (s, 2H), 2.59 (d, J = 17.0 Hz, 2H), 2.33 (s, 1H), 2.14 (d, J = 13.5 Hz, 3H), 1.96 (d, J = 5.1 Hz, 1H), 1.69 (s, 1H). LCMS (ESI) calcd. for C44H49ClFN10O5+ [M+H]+: 851.36, found, 851.4.

[00564] Example 90 of compound of Formula (I): Preparation of compound GT-09924

[00565] With reference to the method of Scheme I-1, the target compound (GT-09924) was obtained (white solid, 16 mg, yield 26.74%). 1H NMR (400 MHz, DMSO-D6) 8 11.28 (d, J = 64.4 Hz, 2H), 10.94 (s, 1H), 10.66 (s, 1H), 10.20 (d, J = 12.3 Hz, 1H), 9.15 (s, 1H), 8.86 (s, 1H), 8.00 (dd, J = 6.7, 2.5 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.61 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.49 -7.43 (m, 2H), 7.07 - 6.98 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 15.7 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.25 (dd, J = 53.5, 17.0 Hz, 2H), 4.08 (s, 5H), 3.96 (s, 2H), 3.45 (s, 5H), 3.31 - 3.19 (m, 5H), 2.95 (d, J = 5.8 Hz, 5H), 2.59 (d, J = 17.5 Hz, 1H), 2.17 (d, J = 33.3 Hz, 5H), 2.00 - 1.91 (m, 1H), 1.71 (d, J = 12.8 Hz, 1H). LCMS (ESI) calcd. for C44H49ClFN10O5+ [M+H]+: 851.36, found, 851.4.

[00566] Example 91 of compound of Formula (I): Preparation of compound GT-09925

[00567] With reference to the method of Scheme I-1, the target compound (GT-09925) was obtained (white solid, 15 mg, yield 24.66%). 1H NMR (400 MHz, DMSO-D6) 8 11.40 (d, J = 56.0 Hz, 2H), 10.93 (s, 1H), 10.23 (s, 1H), 9.20 (s, 1H), 8.92 (s, 1H), 7.97 (dd, J = 6.8, 2.4 Hz, 1H), 7.71 - 7.65 (m, 1H), 7.59 - 7.51 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 14.9, 7.5 Hz, 1H), 6.93 (s, 1H), 6.83 (dd, J = 21.9, 12.1 Hz, 2H), 5.02 (dd, J = 13.1, 5.0 Hz, 1H), 4.38 -4.15 (m, 2H), 4.09 (s, 3H), 4.00 (s, 2H), 3.94 (s, 2H), 3.86 (s, 2H), 3.59 (s, 4H), 3.16 (s, 4H), 2.92 (d, J = 12.3 Hz, 3H), 2.58 (d, J = 18.0 Hz, 2H), 2.35 (dd, J = 12.8, 8.4 Hz, 1H), 2.18 - 1.82 (m, 7H), 1.63 (d, J = 12.1 Hz, 1H). LCMS (ESI) calcd. for C45H51ClFN10O5+ [M+H]+: 865.37, found, 865.4.

[00568] Example 92 of compound of Formula (I): Preparation of compound GT-09926

[00569] With reference to the method of Scheme I-1, the target compound (GT-09926) was obtained (white solid, 6 mg, yield 10.17%). 1H NMR (400 MHz, DMSO-D6) 5 11.29 (s, 2H), 10.93 (s, 1H), 10.75 (s, 1H), 10.21 (d, J = 13.8 Hz, 1H), 9.16 (s, 1H), 8.89 (s, 1H), 7.99 (dd, J = 6.8, 2.3 Hz, 1H), 7.81 (s, 1H), 7.72 - 7.65 (m, 1H), 7.54 (t, J = 9.0 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.07 - 6.91 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 15.3 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 - 4.15 (m, 2H), 4.08 (s, 3H), 3.94 (s, 2H), 3.50 (s, 6H), 3.11 (s, 7H), 3.01 - 2.86 (m, 4H), 2.61 (s, 1H), 2.34 (d, J = 7.9 Hz, 1H), 2.13 (d, J = 12.7 Hz, 4H), 1.95 (s, 1H), 1.65 (d, J = 11.2 Hz, 1H). LCMS (ESI) calcd. for C43H49ClFN10O5+ [M+H]+: 839.36, found, 839.4.

[00570] Example 93 of compound of Formula (I): Preparation of compound GT-09628

[00571] With reference to the method of Scheme I-1, the target compound (GT-09628) was obtained (white solid, 32 mg, yield 61.96%). 1H NMR (400 MHz, DMSO-D6) 5 11.68 (s, 1H), 11.06 (s, 1H), 10.78 (s, 1H), 10.37 (s, 1H), 8.86 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.11 (dd, J = 6.8, 2.6 Hz, 1H), 7.84 (ddd, J = 8.9, 4.3, 2.6 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 7.07 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.39 (t, J = 6.0 Hz, 2H), 4.02 (s, 3H), 3.59 (s, 3H), 3.30 - 3.17 (m, 9H), 3.10 (d, J = 19.1 Hz, 4H), 3.01 - 2.84 (m, 3H), 2.59 (d, J = 17.5 Hz, 2H), 2.33 (d, J = 1.9 Hz, 2H), 2.11 (d, J = 13.1 Hz, 2H), 2.06 - 1.96 (m, 1H), 1.63 (d, J = 12.3 Hz, 1H). LCMS (ESI) calcd. for C41H46ClFN9O6+ [M+H]+: 814.32, found, 814.3.

[00572] Example 94 of compound of Formula (I): Preparation of compound GT-10025

[00573] With reference to the method of Scheme I-1, the target compound (GT-10025) was obtained (white solid, 27 mg, yield 51.15%). 1H NMR (400 MHz, DMSO-D6) 5 11.58 (s, 1H), 11.10 (s, 1H), 10.40 (d, J = 42.9 Hz, 2H), 8.85 (s, 1H), 8.56 (s, 1H), 8.49 (d, J = 16.3 Hz, 1H), 8.11 (dd, J = 6.8, 2.6 Hz, 1H), 7.89 - 7.79 (m, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 5.7 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.39 (t, J = 5.9 Hz, 2H), 4.02 (s, 3H), 3.59 (s, 3H), 3.28 - 3.20 (m, 8H), 3.09 (d, J = 6.4 Hz, 4H), 3.00 - 2.84 (m, 3H), 2.59 (d, J = 21.4 Hz, 2H), 2.37 - 2.29 (m, 2H), 2.05 (dd, J = 28.1, 9.4 Hz, 4H), 1.63 (d, J = 12.6 Hz, 1H). LCMS (ESI) calcd. for C41H45ClF2N9O6+ [M+H]+: 832.31, found, 832.3.

[00574] Example 95 of compound of Formula (I): Preparation of compound GT-09630

[00575] With reference to the method of Scheme I-1, the target compound (GT-09630) was obtained (white solid, 21 mg, yield 39.78%). 1H NMR (400 MHz, DMSO-D6) S 11.74 (s, 1H), 11.09 (s, 1H), 10.48 (s, 2H), 8.86 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.12 (dd, J = 6.8, 2.5 Hz, 1H), 7.85 (dd, J = 8.2, 3.4 Hz, 1H), 7.65 (d, J = 10.3 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.40 (s, 1H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 4.01 (s, 3H), 3.59 (s, 3H), 3.28 (s, 8H), 3.10 (d, J = 10.6 Hz, 4H), 2.92 (dd, J = 37.9, 12.1 Hz, 3H), 2.59 (d, J = 18.2 Hz, 2H), 2.34 (s, 2H), 2.05 (dd, J = 29.7, 9.7 Hz, 4H), 1.65 (d, J = 13.6 Hz, 1H). LCMS (ESI) calcd. for C41H45ClF2N9O6+ [M+H]+: 832.31, found, 832.3.

[00576] Example 96 of compound of Formula (I): Preparation of compound GT-10153

[00577] With reference to the method of Scheme I-1, the target compound (GT-10153) was obtained (white solid, 19 mg, yield 35.99%). 1H NMR (400 MHz, DMSO-d6) S 11.75 (s, 1H), 11.09 (s, 1H), 10.84 (s, 1H), 10.40 (s, 1H), 8.93 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.11 (dd, J = 6.8, 2.3 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.40 (s, 1H), 6.95 (d, J = 81.9 Hz, 2H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.40 (d, J = 6.1 Hz, 2H), 4.02 (s, 3H), 3.60 (d, J = 9.7 Hz, 4H), 3.26 (s, 6H), 3.09 (d, J = 24.4 Hz, 4H), 3.00 - 2.83 (m, 3H), 2.60 (s, 2H), 2.33 (s, 2H), 2.11 (d, J = 12.1 Hz, 3H), 2.05 - 1.98 (m, 1H), 1.63 (d, J = 12.5 Hz, 2H). LCMS (ESI) calcd. for C41H45ClF2N9O6+ [M+H]+: 832.31, found, 832.3.

[00578] Example 97 of compound of Formula (I): Preparation of compound GT-10154

[00579] With reference to the method of Scheme I-1, the target compound (GT-10154) was obtained (white solid, 40 mg, yield 77.06%). 1H NMR (400 MHz, DMSO-d6) S 11.91 (s, 1H), 10.96 (s, 1H), 10.67 (s, 2H), 8.87 (s, 1H), 8.70 (s, 1H), 8.11 (dd, J = 6.8, 2.4 Hz, 1H), 7.86 (ddd, J = 8.9, 4.3, 2.6 Hz, 1H), 7.79 (s, 1H), 7.53 (dd, J = 9.9, 8.2 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 10.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 5.05 (dd, J = 13.2, 5.0 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 4.26 (dd, J = 50.1, 16.9 Hz, 2H), 4.01 (s, 3H), 3.58 (s, 3H), 3.24 (s, 7H), 3.07 (s, 3H), 3.01 - 2.86 (m, 3H), 2.59 (d, J = 16.4 Hz, 1H), 2.40 - 2.31 (m, 3H), 2.10 (d, J = 13.6 Hz, 3H), 2.01 - 1.88 (m, 1H), 1.72 - 1.64 (m, 1H). LCMS (ESI) calcd. for C41H47ClF2N9O5+ [M+H]+: 818.34, found, 818.4.

[00580] Example 98 of compound of Formula (I): Preparation of compound GT-09634

[00581] With reference to the method of Scheme I-1, the target compound (GT-09634) was obtained (white solid, 14 mg, yield 40.40%). 1H NMR (400 MHz, DMSO-D6) 8 11.78 (s, 1H), 10.96 (s, 1H), 10.53 (s, 2H), 8.86 (s, 1H), 8.66 (s, 1H), 8.12 (dd, J = 6.7, 2.5 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.77 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 5.05 (dd, J = 13.2, 5.0 Hz, 1H), 4.55 - 4.27 (m, 4H), 4.01 (s, 3H), 3.58 (s, 4H), 3.22 (s, 7H), 3.06 (s, 4H), 3.00 - 2.85 (m, 3H), 2.59 (d, J = 17.1 Hz, 1H), 2.38 (d, J = 26.4 Hz, 3H), 2.09 (d, J = 13.7 Hz, 3H), 1.95 (dd, J = 18.1, 12.7 Hz, 1H), 1.66 (d, J = 11.8 Hz, 1H). LCMS (ESI) calcd. for C41H47ClF2N9O5+ [M+H]+: 818.34, found, 818.4.

[00582] Example 99 of compound of Formula (I): Preparation of compound GT-09631

[00583] With reference to the method of Scheme I-1, the target compound (GT-09631) was obtained (white solid, 20 mg, yield 38.53%). 1H NMR (400 MHz, DMSO-D6) 8 11.79 (s, 1H), 10.95 (s, 1H), 10.81 (s, 1H), 10.45 (s, 1H), 8.87 (s, 1H), 8.65 (s, 1H), 8.11 (dd, J = 6.8, 2.5 Hz, 1H), 7.90 - 7.82 (m, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.41 (s, 1H), 6.71 (s, 1H), 6.63 (d, J = 12.0 Hz, 1H), 4.99 (dd, J = 13.1, 5.0 Hz, 1H), 4.30 (dt, J = 55.8, 11.7 Hz, 4H), 4.01 (s, 3H), 3.60 (d, J = 11.0 Hz, 4H), 3.26 (s, 8H), 3.07 (d, J = 11.5 Hz, 3H), 2.92 (dd, J = 32.2, 12.0 Hz, 3H), 2.58 (d, J = 17.7 Hz, 2H), 2.34 (s, 3H), 2.11 (d, J = 13.2 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.64 (d, J = 12.7 Hz, 1H). LCMS (ESI) calcd. for C41H47ClF2N9O5+ [M+H]+: 818.34, found, 818.4.

[00584] Example 100 of compound of Formula (I): Preparation of compound GT-09681

[00585] With reference to the method of Scheme I-1, the target compound (GT-09681) was obtained (white solid, 14 mg, yield 27.58%). 1H NMR (400 MHz, DMSO-D6) 8 11.73 (s, 1H), 11.01 (s, 1H), 10.79 (s, 1H), 10.44 (s, 1H), 8.86 (s, 1H), 8.63 (s, 1H), 8.11 (dd, J = 6.8, 2.5 Hz, 1H), 7.84 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.39 (d, J = 4.5 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.09 (dd, J = 13.5, 7.6 Hz, 2H), 5.10 (dd, J = 13.2, 5.0 Hz, 1H), 4.34 (dt, J = 51.9, 11.7 Hz, 4H), 4.01 (s, 3H), 3.67 - 3.53 (m, 4H), 3.28 (s, 5H), 3.12 (dd, J = 31.1, 17.0 Hz, 7H), 2.99 - 2.90 (m, 2H), 2.62 (d, J = 17.2 Hz, 1H), 2.42 - 2.30 (m, 3H), 2.22 - 1.99 (m, 4H), 1.65 (d, J = 12.7 Hz, 1H). LCMS (ESI) calcd. for C41H48ClFN9O5+ [M+H]+: 800.35, found, 800.4.

[00586] Example 101 of compound of Formula (I): Preparation of compound GT-09682

[00587] With reference to the method of Scheme I-1, the target compound (GT-09682) was obtained (white solid, 22 mg, yield 41.97%). 1H NMR (400 MHz, DMSO-D6) 8 11.97 (s, 1H), 10.94 (s, 1H), 10.64 (d, J = 77.1 Hz, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.10 (dd, J = 6.8, 2.6 Hz, 1H), 7.84 (ddd, J = 8.9, 4.3, 2.6 Hz, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.49 - 7.39 (m, 2H), 6.95 (s, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.42 (d, J = 5.8 Hz, 2H), 4.24 (dd, J = 50.6, 16.8 Hz, 2H), 4.01 (d, J = 3.5 Hz, 3H), 3.89 (s, 1H), 3.59 (s, 5H), 3.23 (d, J = 28.0 Hz, 6H), 2.98 (dd, J = 41.1, 15.4 Hz, 6H), 2.81 (s, 1H), 2.59 (d, J = 17.5 Hz, 2H), 2.34 (dd, J = 5.2, 3.5 Hz, 3H), 2.18 - 1.89 (m, 4H), 1.64 (d, J = 12.6 Hz, 1H). LCMS (ESI) calcd. for C43H50ClFN9O5+ [M+H]+: 826.36, found, 826.4.

[00588] Example 102 of compound of Formula (I): Preparation of compound GT-09632Preparation of compound

[00589] With reference to the method of Scheme I-1, the target compound (GT-09632) was obtained (white solid, 16 mg, yield 30.52%). 1H NMR (400 MHz, DMSO-D6) 8 11.76 (s, 1H), 10.94 (s, 1H), 10.54 (d, J = 37.1 Hz, 2H), 8.86 (s, 1H), 8.67 (d, J = 10.9 Hz, 1H), 8.12 (dd, J = 6.8, 2.4 Hz, 1H), 7.91 - 7.81 (m, 1H), 7.61 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 6.99 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.25 (dd, J = 53.3, 17.0 Hz, 2H), 4.04 (d, J = 23.1 Hz, 5H), 3.61 (d, J = 10.9 Hz, 2H), 3.29 - 3.14 (m, 5H), 3.02 - 2.86 (m, 6H), 2.59 (d, J = 17.0 Hz, 1H), 2.34 (d, J = 7.3 Hz, 3H), 2.25 - 2.07 (m, 6H), 2.00 - 1.91 (m, 1H), 1.68 (d, J = 12.1 Hz, 1H). LCMS (ESI) calcd. for C43H50ClFN9O5+ [M+H]+: 826.36, found, 826.4.

[00590] Example 103 of compound of Formula (I): Preparation of compound GT-09633

[00591] With reference to the method of Scheme I-1, the target compound (GT-09633) was obtained (white solid, 21 mg, yield 39.39%). 1H NMR (400 MHz, DMSO-D6) 8 11.98 (s, 1H), 11.23 (s, 1H), 10.93 (s, 1H), 10.49 (s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.10 (dd, J = 6.7, 2.5 Hz, 1H), 7.84 (dd, J = 4.7, 2.7 Hz, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 6.99 - 6.81 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.41 (d, J = 6.1 Hz, 2H), 4.33 - 4.15 (m, 2H), 4.02 (s, 5H), 3.85 (s, 2H), 3.20 (d, J = 40.5 Hz, 6H), 3.02 - 2.88 (m, 3H), 2.61 (s, 2H), 2.41 - 2.28 (m, 4H), 1.98 (dd, J = 33.5, 9.7 Hz, 8H), 1.60 (d, J = 12.5 Hz, 2H). LCMS (ESI) calcd. for C44H52ClFN9O5+ [M+H]+: 840.38, found, 840.4.

[00592] Example 104 of compound of Formula (I): Preparation of compound GT-09683

[00593] With reference to the method of Scheme I-1, the target compound (GT-09683) was obtained (white solid, 25 mg, yield 48.39%). 1H NMR (400 MHz, DMSO-D6) 8 11.88 (s, 1H), 10.94 (s, 1H), 10.77 (s, 1H), 10.45 (s, 1H), 8.88 (s, 1H), 8.66 (s, 1H), 8.10 (dd, J = 6.8, 2.6 Hz, 1H), 7.83 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.48 - 7.39 (m, 2H), 6.95 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 5.03 (dd, J = 13.3, 5.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 2H), 4.24 (dd, J = 53.2, 16.4 Hz, 2H), 4.02 (s, 3H), 3.60 (d, J = 10.9 Hz, 5H), 3.28 (d, J = 8.1 Hz, 6H), 3.11 (s, 3H), 3.03 - 2.84 (m, 4H), 2.39 - 2.27 (m, 3H), 2.13 (d, J = 12.9 Hz, 4H), 1.95 (s, 1H), 1.63 (d, J = 12.4 Hz, 1H). LCMS (ESI) calcd. for C42H50ClFN9O5+ [M+H]+: 814.36, found, 814.4.

[00594] Example 105 of compound of Formula (I): Preparation of compound GT-09684

[00595] With reference to the method of Scheme I-1, the target compound (GT-09684) was obtained (white solid, 17 mg, yield 32.99%). 1H NMR (400 MHz, DMSO-D6) 5 11.82 (s, 1H), 10.94 (s, 1H), 10.41 (s, 1H), 8.88 (s, 1H), 8.64 (d, J = 3.3 Hz, 1H), 8.14 - 8.05 (m, 1H), 7.91 -7.81 (m, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.46 (dd, J = 8.3, 4.0 Hz, 1H), 7.41 (s, 1H), 7.02 - 6.86 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (s, 2H), 4.35 - 4.17 (m, 2H), 4.02 (s, 3H), 3.60 (s, 3H), 3.22 (d, J = 44.8 Hz, 8H), 3.01 - 2.86 (m, 3H), 2.59 (d, J = 16.5 Hz, 1H), 2.40 - 2.28 (m, 4H), 2.24 (s, 2H), 2.08 (d, J = 12.5 Hz, 1H), 2.00 - 1.93 (m, 1H), 1.65 (d, J = 10.8 Hz, 2H). LCMS (ESI) calcd. for C42H48ClFN9O5+ [M+H]+: 812.35, found, 812.4.

[00596] Example 106 of compound of Formula (I): Preparation of compound GT-09765

[00597] With reference to the method of Scheme I-5, the target compound (GT-09765) was obtained (white solid, 25 mg, yield 40.58%). 1H NMR (400 MHz, DMSO-D6) 5 11.07 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.58 (s, 2H), 8.51 (d, J = 3.9 Hz, 1H), 8.40 (d, J = 7.4 Hz, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 6.90 (d, J = 3.9 Hz, 1H), 5.05 (dd, J = 12.8, 5.3 Hz, 1H), 3.78 (s, 2H), 3.41 (s, 4H), 3.36 - 3.34 (m, 3H), 2.86 (d, J = 11.9 Hz, 2H), 2.64 - 2.53 (m, 3H), 2.06 - 1.96 (m, 1H), 1.93 (s, 2H), 1.76 (d, J = 9.6 Hz, 2H), 1.46 (dd, J = 19.8, 10.2 Hz, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) C41H44N11O6+ [M+H]+: calcd. for 786.35, found, 786.4.

[00598] Example 107 of compound of Formula (I): Preparation of compound GT-10024

[00599] With reference to the method of Scheme I-5, the target compound (GT-10024) was obtained (white solid, 28 mg, yield 51.84%). 1H NMR (400 MHz, DMSO-D6) 5 11.10 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.54 - 7.46 (m, 1H), 6.91 (d, J = 3.9 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 3.78 (dd, J = 12.4, 7.0 Hz, 3H), 3.45 (s, 3H), 2.96 - 2.74 (m, 4H), 2.59 (d, J = 20.3 Hz, 4H), 2.07 - 1.97 (m, 1H), 1.93 (s, 2H), 1.76 (d, J = 9.4 Hz, 2H), 1.54 - 1.41 (m, 4H), 1.30 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H43FN11O6+ [M+H]+: 804.34, found, 804.4.

[00600] Example 108 of compound of Formula (I): Preparation of compound GT-09766

[00601] With reference to the method of Scheme I-5, the target compound (GT-09766) was obtained (white solid, 27 mg, yield 49.99%). 1H NMR (400 MHz, DMSO-D6) 6 11.09 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.63 (d, J = 10.3 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.98 - 3.66 (m, 3H), 3.41 (s, 3H), 3.36 - 3.34 (m, 2H), 2.96 - 2.79 (m, 3H), 2.64 - 2.52 (m, 3H), 2.08 - 1.98 (m, 1H), 1.93 (s, 2H), 1.76 (d, J = 9.7 Hz, 2H), 1.46 (dd, J = 19.4, 10.3 Hz, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H43FN11O6+ [M+H]+: 804.34, found, 804.3.

[00602] Example 109 of compound of Formula (I): Preparation of compound GT-10054

[00603] With reference to the method of Scheme I-5, the target compound (GT-10054) was obtained (white solid, 18 mg, yield 33.33%). 1H NMR (400 MHz, DMSO-D6) 6 11.09 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.0 Hz, 2H), 8.59 (s, 1H), 8.56 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.44 (d, J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.02 (s, 1H), 6.91 (d, J = 3.9 Hz, 1H), 6.81 (s, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.40 (s, 1H), 3.92 (s, 1H), 3.87 - 3.62 (m, 4H), 3.40 - 3.22 (m, 1H), 3.12 - 2.76 (m, 4H), 2.58 (d, J = 20.7 Hz, 3H), 2.06 - 1.97 (m, 1H), 1.93 (s, 2H), 1.75 (s, 2H), 1.58 - 1.40 (m, 4H), 1.30 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H43FN11O6+ [M+H]+: 804.34, found, 804.3.

[00604] Example 110 of compound of Formula (I): Preparation of compound GT-09767

[00605] With reference to the method of Scheme I-5, the target compound (GT-09767) was obtained (white solid, 26 mg, yield 50.13%). 1H NMR (400 MHz, DMSO-D6) 6 10.93 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.41 (d, J = 7.5 Hz, 1H), 8.04 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 3.9 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.02 (dd, J = 13.2, 5.1 Hz, 1H), 4.24 (dd, J = 54.9, 17.0 Hz, 2H), 3.77 (dd, J = 17.9, 11.8 Hz, 3H), 3.43 (s, 3H), 3.35 - 3.31 (m, 2H), 2.95 - 2.82 (m, 2H), 2.73 (s, 1H), 2.58 (d, J = 16.3 Hz, 3H), 2.34 (dd, J = 12.5, 4.2 Hz, 1H), 1.99 - 1.87 (m, 3H), 1.75 (d, J = 9.7 Hz, 2H), 1.45 (q, J = 9.9 Hz, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H46N11O5+ [M+H]+: 772.37, found, 772.4.

[00606] Example 111 of compound of Formula (I): Preparation of compound GT-09768

[00607] With reference to the method of Scheme I-5, the target compound (GT-09768) was obtained (white solid, 8 mg, yield 15.07%). 1H NMR (400 MHz, DMSO-D6) 5 10.96 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.57 (s, 2H), 8.51 (d, J = 3.9 Hz, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.06 (s, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 3.9 Hz, 1H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.36 (dd, J = 71.6, 16.8 Hz, 2H), 3.85 - 3.69 (m, 3H), 3.41 (s, 4H), 3.34 - 3.32 (m, 2H), 2.73 (s, 2H), 2.59 (d, J = 17.3 Hz, 2H), 2.39 (dd, J = 13.5, 4.7 Hz, 1H), 2.01 - 1.90 (m, 3H), 1.74 (s, 2H), 1.46 (dd, J = 19.3, 9.9 Hz, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H45FN11O5+ [M+H]+: 790.36, found, 790.3.

[00608] Example 112 of compound of Formula (I): Preparation of compound GT-09769

[00609] With reference to the method of Scheme I-5, the target compound (GT-09769) was obtained (white solid, 38 mg, yield 71.60%). 1H NMR (400 MHz, DMSO-D6) 5 10.95 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.04 (s, 1H), 7.43 (s, 1H), 7.33 (dd, J = 12.4, 9.0 Hz, 2H), 6.90 (d, J = 3.9 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.27 (dd, J = 53.8, 17.1 Hz, 2H), 3.83 - 3.67 (m, 3H), 3.43 (s, 3H), 2.95 - 2.69 (m, 5H), 2.59 (d, J = 17.1 Hz, 2H), 2.39 - 2.30 (m, 1H), 1.94 (dd, J = 21.5, 6.9 Hz, 3H), 1.75 (d, J = 10.4 Hz, 2H), 1.52 - 1.39 (m, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H45FN11O5+ [M+H]+: 790.36, found, 790.4.

[00610] Example 113 of compound of Formula (I): Preparation of compound GT-09770

[00611] With reference to the method of Scheme I-5, the target compound (GT-09770) was obtained (white solid, 38 mg, yield 71.60%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 2H), 8.58 (s, 1H), 8.50 (d, J = 3.9 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 6.91 (d, J = 3.9 Hz, 1H), 6.71 (s, 1H), 6.59 (d, J = 11.9 Hz, 1H), 4.98 (dd, J = 13.2, 5.1 Hz, 1H), 4.33 - 4.14 (m, 2H), 3.76 (d, J = 28.5 Hz, 3H), 3.46 (s, 3H), 3.38 - 3.35 (m, 2H), 2.91 - 2.80 (m, 2H), 2.58 (d, J = 17.1 Hz, 3H), 2.31 (dd, J = 12.6, 4.1 Hz, 1H), 1.96 - 1.87 (m, 3H), 1.74 (s, 2H), 1.45 (dd, J = 18.4, 9.3 Hz, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H45FN11O5+ [M+H]+: 790.36, found, 790.4.

[00612] Example 114 of compound of Formula (I): Preparation of compound GT-09771

[00613] With reference to the method of Scheme I-5, the target compound (GT-09771) was obtained (white solid, 35 mg, yield 67.49%). 1H NMR (400 MHz, DMSO-D6) 5 10.98 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.0 Hz, 2H), 8.59 (d, J = 3.1 Hz, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.06 (dd, J = 7.7, 3.1 Hz, 2H), 6.91 (d, J = 3.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (dd, J = 40.7, 17.5 Hz, 2H), 3.86 - 3.57 (m, 5H), 3.41 - 3.31 (m, 3H), 2.98 - 2.87 (m, 1H), 2.77 (d, J = 31.7 Hz, 2H), 2.61 (d, J = 16.8 Hz, 2H), 2.44 - 2.36 (m, 1H), 2.06 - 1.98 (m, 1H), 1.92 (d, J = 7.7 Hz, 2H), 1.76 (d, J = 10.5 Hz, 2H), 1.46 (dd, J = 19.9, 10.1 Hz, 4H), 1.29 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C41H46N11O5+ [M+H]+: 772.37, found, 772.37.

[00614] Example 115 of compound of Formula (I): Preparation of compound GT-09772

[00615] With reference to the method of Scheme I-5, the target compound (GT-09772) was obtained (white solid, 36 mg, yield 67.15%). 1H NMR (400 MHz, DMSO-D6) 5 10.93 (s, 1H), 8.82 (d, J = 1.9 Hz, 1H), 8.70 (t, J = 7.4 Hz, 2H), 8.60 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.46 (d, J = 7.5 Hz, 1H), 8.01 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 27.2, 6.3 Hz, 2H), 5.02 (dd, J = 13.3, 4.8 Hz, 1H), 4.24 (ddd, J = 22.2, 16.6, 6.7 Hz, 2H), 3.76 (s, 4H), 3.39 - 3.31 (m, 3H), 3.01 - 2.71 (m, 5H), 2.60 (s, 2H), 2.40 (dd, J = 37.1, 11.7 Hz, 2H), 1.99 - 1.77 (m, 5H), 1.47 (dd, J = 25.6, 12.2 Hz, 4H), 1.30 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C43H48N11O5+ [M+H]+: 798.38, found, 798.4.

[00616] Example 116 of compound of Formula (I): Preparation of compound GT-09773

[00617] With reference to the method of Scheme I-5, the target compound (GT-09773) was obtained (white solid, 39 mg, yield 72.75%). 1H NMR (400 MHz, DMSO-D6) 5 10.94 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.0 Hz, 2H), 8.60 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.46 (d, J = 7.4 Hz, 1H), 8.02 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 3.9 Hz, 2H), 6.83 (d, J = 7.5 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 - 4.40 (m, 2H), 4.25 (dd, J = 56.1, 16.9 Hz, 2H), 3.77 (d, J = 30.5 Hz, 3H), 3.02 - 2.83 (m, 3H), 2.63 - 2.56 (m, 3H), 2.34 (dd, J = 13.1, 4.6 Hz, 1H), 2.00 (dd, J = 46.7, 10.2 Hz, 6H), 1.78 (dd, J = 35.0, 10.5 Hz, 3H), 1.59 - 1.40 (m, 4H), 1.30 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C43H48N11O5+ [M+H]+: 798.38, found, 798.4.

[00618] Example 117 of compound of Formula (I): Preparation of compound GT-09774

[00619] With reference to the method of Scheme I-5, the target compound (GT-09774) was obtained (white solid, 24 mg, yield 44.00%). 1H NMR (400 MHz, DMSO-D6) 5 10.93 (s, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.55 (s, 2H), 8.49 (d, J = 3.9 Hz, 1H), 8.38 (d, J = 7.7 Hz, 1H), 8.03 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 3.9 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.00 (dd, J = 13.2, 5.0 Hz, 1H), 4.23 (dd, J = 55.8, 16.9 Hz, 2H), 3.90 (s, 2H), 3.74 (d, J = 26.5 Hz, 6H), 3.40 - 3.35 (m, 3H), 2.93 - 2.83 (m, 1H), 2.58 (d, J = 16.7 Hz, 2H), 2.39 - 2.29 (m, 1H), 2.18 (s, 1H), 1.99 - 1.87 (m, 3H), 1.78 (d, J = 34.3 Hz, 4H), 1.45 - 1.35 (m, 4H), 1.28 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C44H50N11O5+ [M+H]+: 812.40, found, 812.4.

[00620] Example 118 of compound of Formula (I): Preparation of compound GT-09775

[00621] With reference to the method of Scheme I-5, the target compound (GT-09775) was obtained (white solid, 33 mg, yield 62.50%). 1H NMR (400 MHz, DMSO-D6) 8 10.94 (s, 1H), 8.82 (s, 2H), 8.70 (s, 1H), 8.62 (d, J = 6.8 Hz, 1H), 8.55 - 8.44 (m, 2H), 7.99 (d, J = 2.5 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 3.8 Hz, 3H), 5.03 (dd, J = 13.3, 5.0 Hz, 1H), 4.24 (d, J = 37.8 Hz, 2H), 3.77 (d, J = 52.8 Hz, 6H), 3.51 - 3.34 (m, 3H), 2.90 (s, 3H), 2.64 - 2.54 (m, 2H), 2.35 (dt, J = 21.8, 11.0 Hz, 1H), 2.07 - 1.84 (m, 5H), 1.78 (s, 1H), 1.50 (dd, J = 18.5, 10.6 Hz, 4H), 1.30 (d, J = 6.2 Hz, 6H). LCMS (ESI) calcd. for C42H48N11O5+ [M+H]+: 786.38, found, 786.4.

[00622] Example 119 of compound of Formula (I): Preparation of compound GT-09776

[00623] With reference to the method of Scheme I-5, the target compound (GT-09776) was obtained (white solid, 28 mg, yield 53.16%). 1H NMR (400 MHz, DMSO-D6) 8 10.93 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 3.9 Hz, 2H), 6.82 (s, 1H), 5.02 (dd, J = 13.2, 5.0 Hz, 1H), 4.53 (s, 1H), 4.24 (dd, J = 54.2, 17.0 Hz, 3H), 3.79 (dd, J = 12.6, 6.4 Hz, 2H), 3.33 - 3.09 (m, 3H), 3.01 - 2.84 (m, 2H), 2.58 (d, J = 17.3 Hz, 2H), 2.35 (d, J = 15.8 Hz, 2H), 2.19 (s, 1H), 1.95 (d, J = 10.8 Hz, 3H), 1.84 (s, 2H), 1.44 (dd, J = 23.2, 12.4 Hz, 4H), 1.30 (d, J = 6.3 Hz, 6H). LCMS (ESI) calcd. for C42H46N11O5+ [M+H]+: 784.37, found, 784.4.

[00624] Example 120 of compound of Formula (I): Preparation of compound GT-09777

[00625] With reference to the method of Scheme I-5, the target compound (GT-09777) was obtained (white solid, 30 mg, yield 56.96%). 1H NMR (400 MHz, DMSO-D6) 8 10.93 (s, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.63 (s, 1H), 8.59 (d, J = 1.3 Hz, 1H), 8.53 -8.50 (m, 1H), 8.45 - 8.37 (m, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.45 (dd, J = 18.1, 10.4 Hz, 1H), 6.99 (s, 1H), 6.89 (dd, J = 13.5, 6.2 Hz, 2H), 5.03 (dd, J = 13.3, 4.9 Hz, 1H), 4.61 (s, 1H), 4.23 (dd, J = 54.2, 17.0 Hz, 2H), 3.79 (d, J = 6.3 Hz, 3H), 3.60 (s, 2H), 3.23 (d, J = 10.1 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.58 (d, J = 17.5 Hz, 2H), 2.34 (dt, J = 21.8, 11.0 Hz, 2H), 1.95 (d, J = 12.3 Hz, 5H), 1.79 (s, 2H), 1.44 (d, J = 22.6 Hz, 4H), 1.30 (d, J = 6.1 Hz, 6H). LCMS (ESI) calcd. for C42H46N11O5+ [M+H]+: 784.37, found, 784.4. Biological activity assay

[00626] Reagents and Materials Reagents and materials Human myeloid monocytic leukemia cell line: MV-4-11 Human T lymphocytic leukemia cell line: Jurkat Human acute lymphoblastic leukemia T lymphocyte: CCRF-CEM Human diffuse large B-cell lymphoma cell line: TMD8 Human prostate cancer cell line: 22RV1 Human breast cancer cell line: MCF-7 Human multiple myeloma cell line: MM.1S Human breast cancer cell line: MDA-MB-231 Human malignant meningioma cell line: JEKO-1 Human B lymphoblastoma cell line: RPMI-8226 Human acute T lymphoblastic leukemia cell line: Molt-4 Human small cell lung cancer cell line: H196 Human non-small cell lung cancer cell line: NCI-H1975 RPMI-1640 Medium IMDM Medium EMEM Medium CellTiter-Meiluncell Luminescent Cell Viability Assay Kit Fetal bovine serum (FBS) Penicillin-Streptomycin Mycoplasma detection kit STR genotype detection Suppliers or Source ATCC (American Type Culture Collection) ATCC Dalian Meilun Biotech Co., Ltd. Kyinno Biotechnology Co., Ltd ATCC ATCC ATCC ATCC ATCC ATCC ATCC ATCC ATCC ATCC Gibco company ATCC Dalian Meilun Biotech Co., Ltd. Sunrise Science Products company Beijing TransGen Biotech Co., Ltd. Beijing TransGen Biotech Co., Ltd. Shanghai     Biowing     Applied Biotechnology Co., Ltd.

[00627] Methods:

[00628] Cell cultures

[00629] The tumor cells used in the present disclosure were cultured in the cell culture media listed in Table A at 37 °C in an incubator containing 5% CO2. All cells were authenticated as the correct cell lines by STR profiling and confirmed to be mycoplasma-negative using a mycoplasma detection kit prior to the experiments. Table A. Tumor cells and cell culture medium used in the present disclosure Cell line Cell culture medium used Jurkat CCRF-CEM TMD8 22RV1 RPMI-8226 Molt-4 MM.1S H196 H1975 JEKO-1 RPMI 1640 culture medium supplemented with 10% FBS, as well as penicillin at a final concentration of 100 U / mL and streptomycin at a final concentration of 100 pg / mL MV-4-11 IMDM culture medium supplemented with 10% FBS, as well as penicillin at a final concentration of 100 U / mL and streptomycin at a final concentration of 100 pg / mL MCF-7 EMEM culture medium supplemented with 10% FBS, 10 pg / mL insulin, and penicillin at a final concentration of 100 U / mL and streptomycin at a final concentration of 100 pg / mL

[00630] I. Determination of half inhibitory concentration (IC50) of the compounds against tumor cells:

[00631] The IC50 values of the compounds of the present disclosure (including the compounds in Table 1, Table 2, and Examples) were determined using the CellTiter-Meiluncell Luminescent Cell Viability Assay Kit from Dalian Meilun Biotech Co., Ltd. The detailed procedures are as follows: Tumor cells were seeded in 96-well cell culture plates at the densities specified in Table B. On the following day, the test compounds of the present disclosure were subjected to serial dilution. The dilution can be performed according to one of the following two methods: (1) The first dilution method: the test compounds of the present disclosure (including the compounds in Tables 1 and 2, and Examples) were subjected to 5-fold serial dilutions starting from a highest concentration of 2000 pM, resulting in a total of 9 concentrations from high to low (2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512 pM). Subsequently, 0.5 pL of the test compound dilution was transferred into the 96-well plate containing the cells, with each well containing 100 pL of cell culture medium. This resulted in final test compound concentrations of 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, and 0.0000256 pM, respectively, or (2) As an alternative, a second dilution method can be used: the test compounds of the present disclosure (including the compounds in Tables 1 and 2, and the example compounds) were subjected to a 50-fold gradient dilution starting from the highest concentration of 100 pM, with a total of 2 concentrations (100 pM and 2 pM) being set. In a 96-well plate, the diluted test compounds of the present disclosure and the corresponding detection reagents were added to each well to ensure that the final test concentrations of the test compound in each well reached 500 nM and 10 nM, respectively, so as to evaluate the inhibitory activity of the test compound on tumor cell proliferation at these two concentration levels. The experimental procedure is described below using the diluted test compound at 2 pM as an example (the operating steps for the 100 pM concentration and the gradient concentrations obtained by the first dilution method are similar thereto).

[00632] 0.5 pL of the above diluted test compounds of the present disclosure (including the compounds in Tables 1 and 2, and the example compounds) were added to 100 pL of seeded cells, resulting in a final compound concentration of 10 nM. After the cells were treated with the compounds of the present disclosure for a certain period of time, a cell viability detection reagent was added to the culture medium according to the manufacturer's instructions of the kit to determine cell viability. The negative control was DMSO, and the reference compounds were the corresponding commercially available inhibitors (including PF06650833 (Zimlovisertib); Enzalutamide (CAS No. 915087-33-1); Ribociclib (CAS No. 1211443-58-1); and Erlotinib (CAS No. 183321-74-6)), all of which were used to treat the cells in the same manner as the compounds of the present disclosure. The growth inhibition of the cells by the compounds of the present disclosure was plotted using Prism GraphPad software, from which the IC50 values of the compounds of the present disclosure were calculated. Table B. Seeding protocol and treatment time for tumor cells Cells Cells seeding protocol The times for treating cells      with      the compounds   of  the present      disclosure (hours) Jurkat cells were seeded at a density of 10,000 cells per well in 100 pL of serum-containing RPMI-1640 medium per well 96 hours RPMI-8226 Molt-4 TMD8 MM.1S CCRF- CEM cells were seeded at a density of 4,000 cells per well in 100 pL of serum-containing RPMI-1640 medium per well 96 hours H1975 22RV1 JEKO-1 H196 cells were seeded at a density of 1,000 cells per well in 100 pL of serum-containing RPMI-1640 medium per well 96 hours MV-4-11 cells were seeded at a density of 10,000 cells per well in 100 pL of serum-containing IMDM medium per well 96 hours MCF-7 cells were seeded at a density of 4,000 cells per well in 100 pL of serum-containing EMEM medium per well 96 hours

[00633] The results of tumor cell proliferation inhibition are presented in Tables I-1, I-2, I-3, I-4, I-5, I-6, and I-7. Table I-1: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on the CDK4 / 6 inhibitors, against tumor cell proliferation Comp. No. / names 22RV1 MCF-7 MM.1S MDA-MB-231 MV-4- 11 Ribociclib E F F G F GT-07089 C - - - - GT-07095 A C B B - GT-07096 A+ - C - - GT-07097 A++ - - - - GT-07241 - - C - - GT-07194 - - C - - GT-06948 A+ - - - B GT-05207 - A - - - GT-07099 - - B - - Note: in table I-1, the symbols A+++, A++, A+, A, B, C, D, E, F, and G are defined as follows: 0 < A+++ < 10 nM; 10 nM < A++ < 50 nM; 50 nM < A+ < 100 nM; 100 nM < A < 200 nM; 200 nM < B < 400 nM; 400 nM < C < 800 nM; 800 nM < D < 1000 nM; 1000 nM < E < 5000 nM; 5000 nM < F < 10000 nM; 10000 nM < G. The symbol “-” indicates “not tested”. Table I-2: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on the CDK4 / 6 inhibitors, against tumor cell proliferation Comp. No. / names MCF-7 MV-4-11 JEKO-1 RPMI-8226 Molt-4 Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Riboci clib 1a5 1a5 1a5 1a1 1a5 1a4 1a2 1a4 1a1 1a2 GT- 10020 - - - - 1a7 1a5 - - - - GT- 10032 1a7 1a6 1a8 1a5 1a9 1a7 1a7 1a4 - - GT- 10033 1a8 1a7 1a8 1a5 1a8 1a7 - - - - GT- 10034 1a8 1a8 1a11 1a10 1a8 1a8 1a9 1a7 - - GT- 10035 1a8 1a7 1a11 1a10 1a8 1a8 1a8 1a7 - - GT- 10036 1a7 1a7 1a10 1a8 1a8 1a7 1a7 1a5 - - GT- 10037 1a7 1a6 1a10 1a8 1a8 1a5 - - - - GT- 10038 1a8 1a5 1a11 1a10 1a7 1a4 - - 1a9 1a8 Note: in table I-2, the symbols 1a1, 1a2, 1a3, 1a4, 1a5, 1a6, 1a7, 1a8, 1a9, 1a10, and 1a11 are defined as follows: -10% < 1a1 < 0, 0 < 1a2 < 5%, 5% < 1a3 < 10%, 10% < 1a4 < 20%, 20% < 1a5 < 35%, 35% < 1a6 < 40%, 40% < 1a7 < 50%, 50% < 1a8 < 60%, 60% < 1a9 < 70%, 70% < 1a10 < 80%, 80% < 1a11 < 100%. The symbol “-” indicates “not tested”. Table I-3: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on the AR inhibitors, against tumor cell proliferation Comp. No. / names TMD8 RPMI- 8226 CCRF- CEM MCF-7 Jurkat MV-4- 11 Enzalutamide F G G G G G GT-05234 A++ C A++ B A++ A+ GT-06950 B B C - - A GT-07108 B - C C - - GT-07107 A++ A A B B - GT-07196 A++ B C B C - GT-07195 A B - - - - GT-07100 A+ B B - C - GT-07090 A C - - - - GT-07179 B B B B C - GT-07112 B - - - - - GT-07101 B A - C - - GT-07102 B C - C - - GT-07110 B - - - - - GT-07181 C - - - - - GT-06949 A+ C A C - - GT-07098 A C - - - - GT-07180 B C - - - - Note: in table I-3, the symbols A+++, A++, A+, A, B, C, D, E, F, and G are defined as follows: 0 < A+++ < 10 nM; 10 nM < A++ < 50 nM; 50 nM < A+ < 100 nM; 100 nM < A < 200 nM; 200 nM < B < 400 nM; 400 nM < C < 800 nM; 800 nM < D < 1000 nM; 1000 nM < E < 5000 nM; 5000 nM < F < 10000 nM; 10000 nM < G. The symbol “-” indicates “not tested”. Table I-4: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on the AR inhibitors, against tumor cell proliferation Comp. No. / names MV-4-11 TMD 8 Molt-4 RPMI-8226 MCF-7 Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate at 10 nM (%) Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Inhibit ion Rate (%) at 500 nM Inhibit ion Rate (%) at 10 nM Enzaluta mide 1b5 1b3 1b5 1b5 1b4 1b4 1b5 1b4 1b2 1b2 GT- 10039 - - 1b11 1b10 1b9 1b5 1b9 1b7 1b9 1b7 GT- 10041 - - - - - - - - 1b7 1b6 GT- 10042 1b11 1b11 1b7 1b5 - - - - - - GT- 10043 1b11 1b8 - - - - - - - - GT- 10044 1b11 1b11 1b8 1b6 1b10 1b5 - - 1b7 1b4 GT- 10045 1b11 1b10 1b10 1b6 1b7 1b3 - - - - GT- 10023 - - 1b10 1b6 1b7 1b3 1b8 1b5 - - GT- 10021 1b11 1b8 1b11 1b9 1b10 1b5 1b10 1b7 1b7 1b4 GT- 08179 1b10 1b5 1b7 1b4 - - - - - - GT- 08189 1b9 1b1 1b8 1b5 - - - - 1b7 1b2 Note: in table I-4, the symbols 1b1, 1b2, 1b3, 1b4, 1b5, 1b6, 1b7, 1b8, 1b9, 1b10, and 1b11 are defined as follows: -20% < 1b1 < 0, 0 < 1b2 < 5%, 5% < 1b3 < 10%, 10% < 1b4 < 20%, 20% < 1b5 < 30%, 30% < 1b6 < 40%, 40% < 1b7 < 50%, 50% < 1b8 < 60%, 60% < 1b9 < 70%, 70% < 1b10 < 80%, 80% < 1b11 < 100%. The symbol “-” indicates “not tested”. Table I-5: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on interleukin-1 receptor-associated kinase (IRAK) inhibitors (IRAK1, IRAK2, IRAK-3, and IRAK4), against tumor cell proliferation Comp.     No. / names MV-4-11 Comp.     No. / names MV-4-11 PF06650833 E GT-06945 A+++ GT-06943 A++ GT-06941 A+++ GT-06946 A++ GT-06944 A+ GT-06947 A++ GT-05300 B GT-06951 A+ Note: in table I-5, the symbols A+++, A++, A+, A, B, C, D, E, F, and G are defined as follows: 0 < A+++ < 10 nM; 10 nM < A++ < 50 nM; 50 nM < A+ < 100 nM; 100 nM < A < 200 nM; 200 nM < B < 400 nM; 400 nM < C < 800 nM; 800 nM < D < 1000 nM; 1000 nM < E < 5000 nM; 5000 nM < F < 10000 nM; 10000 nM < G. The symbol “-” indicates “not tested”. Table I-6: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on IRAK inhibitors, against tumor cell proliferation Comp. No. / names MV-4-11 TMD8 MM.1S H196 Inhibiti on Rate (%)  at 500 nM Inhibiti on Rate (%)  at 10 nM Inhibiti on Rate (%)  at 500 nM Inhibiti on Rate (%)  at 10 nM Inhibiti on Rate (%)  at 500 nM Inhibiti on Rate (%)  at 10 nM Inhibiti on Rate (%)  at 500 nM Inhibiti on Rate (%)  at 10 nM PF066508 33 1c6 1c5 1c3 1c4 1c5 1c5 1c2 1c1 GT-06951 1c7 1c1 - - - - 1c9 1c8 GT-09549 1c9 1c6 - - - - 1c9 1c8 GT-09548 1c9 1c6 - - - - - - GT-09603 1c7 1c3 - - - - - - GT-10024 1c7 1c7 - - - - - - GT-10022 1c8 1c6 - - - - - - GT-10046 1c9 1c4 - - - - - - GT-10047 1c11 1c8 - - - - - - GT-10048 1c11 1c11 1c7 1c7 1c7 1c7 1c6 1c7 GT-10049 1c11 1c11 - - - - - - GT-10050 1c11 1c9 - - - - - - GT-10051 1c11 1c11 - - 1c8 1c6 1c8 1c8 GT-10052 1c11 1c7 - - 1c7 1c7 - - GT-09767 1c8 1c7 1c8 1c8 - - - - GT-09776 - - 1c9 1c6 1c7 1c6 - - GT-09765 - - 1c8 1c5 - - - - GT-09770 - - 1c9 1c7 - - - - GT-09769 1c10 1c9 1c8 1c8 - - - - GT-09773 1c10 1c8 1c9 1c8 - - - - GT-09771 - - 1c8 1c5 1c8 1c7 - - GT-09775 - - 1c7 1c4 - - - - GT-09766 - - 1c8 1c5 - - - - GT-07105 1c11 1c10 - - 1c8 1c7 - - GT-07103 1c9 1c4 - - - - - - GT-07104 1c11 1c11 1c7 1c5 1c7 1c5 - - GT-07126 1c11 1c8 - - - - - - GT-07111 - - - - 1c7 1c4 - - GT-07396 1c10 1c5 - - - - - - GT-08180 1c11 1c4 - - - - - - Note: in table I-6, the symbols 1c1, 1c2, 1c3, 1c4, 1c5, 1c6, 1c7, 1c8, 1c9, 1c10, and 1c11 are defined as follows: -10% < 1c1 < 0, 0 < 1c2 < 5%, 5% < 1c3 < 10%, 10% < 1c4 < 20%, 20% < 1c5 < 30%, 30% < 1c6 < 40%, 40% < 1c7 < 50%, 50% < 1c8 < 60%, 60% < 1c9 < 70%, 70% < 1c10 < 80%, 80% < 1c11 < 100%. The symbol “-” indicates “not tested”. Table I-7: Inhibitory activity (IC50, nM) of the compounds of the present disclosure, designed based on EGFR inhibitors, against tumor cell proliferation Comp. No. / names MV-4-11 MM.1S H196 H1975 Inhibitio n Rate (%)   at 500 nM Inhibitio n Rate (%)   at 10 nM Inhibitio n Rate (%)   at 500 nM Inhibitio n Rate (%)   at 10 nM Inhibitio n Rate (%)   at 500 nM Inhibitio n Rate (%)   at 10 nM Inhibitio n Rate (%)   at 500 nM Inhibitio n Rate (%)   at 10 nM erlotinib 1d4 1d3 1d6 1d5 1d4 1d1 1d3 1d2 GT- 09928 1d11 1d10 - - - - - - GT- 09924 1d7 1d3 - - 1d8 1d7 1d9 1d5 GT- 09930 1d11 1d10 - - - - - - GT- 09926 1d7 1d1 - - - - 1d9 1d4 GT- 09929 1d10 1d8 - - - - - - GT- 09927 1d9 1d6 - - 1d7 1d7 - - GT- 09921 1d7 1d5 1d7 1d6 1d9 1d9 1d9 1d5 GT- 10025 1d7 1d4 - - 1d9 1d8 - - GT- 09932 1d11 1d10 - - - - - - GT- 09931 1d11 1d11 - - - - - - GT- 10154 - - - - 1d7 1d7 - - GT- 09631 1d7 1d7 - - - - - - GT- 09634 1d8 1d8 1d9 1d8 - - - - GT- 09684 1d7 1d6 1d8 1d6 - - - - GT- 09632 1d7 1d5 - - - - - - GT- 09681 - - 1d10 1d9 1d7 1d5 - - GT- 09683 1d7 1d6 1d7 1d6 - - - - GT- 09633 1d7 1d6 - - - - - - GT- 09682 1d8 1d6 - - - - - - GT- 09764 - - 1d8 1d3 - - 1d9 1d5 GT- 09922 - - - - - - 1d8 1d4 Note: in table I-7, the symbols 1d1, 1d2, 1d3, 1d4, 1d5, 1d6, 1d7, 1d8, 1d9, 1d10, and 1d11 are defined as follows: -5% < 1d1 < 0, 0 < 1d2 < 5%, 5% < 1d3 < 10%, 10% < 1d4 < 20%, 20% < 1d5 < 30%, 30% < 1d6 < 40%, 40% < 1d7 < 50%, 50% < 1d8 < 60%, 60% < 1d9 < 70%, 70% < 1d10 < 80%, 80% < 1d11 < 100%. The symbol “-” indicates “not tested”. Table I-8: Inhibitory activity (IC50, nM) of the compounds of the present disclosure against tumor cell proliferation Comp.    No. / names MV-4-11 H196 Inhibition Rate (%) at    500 nM Inhibition Rate (%) at 10 nM Inhibition Rate (%) at    500 nM Inhibition Rate (%) at 10 nM pomalidomide 1e4 1e5 1e5 1e5 GT-08009 1e8 1e9 - - GT-08006 1e7 1e7 - - GT-08195 1e8 1e8 - - GT-09916 - - 1e7 1e7 Note: in table I-8, the symbols 1e1, 1e2, 1e3, 1e4, 1e5, 1e6, 1e7, 1e8, 1e9, 1e10, and 1e11 are defined as follows: -5% < 1e1 < 0, 0 < 1e2 < 5%, 5% < 1e3 < 10%, 10% < 1e4 < 20%, 20% < 1e5 < 30%, 30% < 1e6 < 40%, 40% < 1e7 < 50%, 50% < 1e8 < 60%, 60% < 1e9 < 70%, 70% < 1e10 < 80%, 80% < 1e11 < 100%. The symbol “-” indicates “not tested”.

[00634] The results showed that the compounds of the present disclosure (including the compounds in Tables 1 and 2, and the example compounds) exhibited significant inhibitory effects on proliferation across a variety of tumor cell lines. These tumor cell lines included MV-4-11 cells (human myelomonocytic leukemia cells), Jurkat cells (human T lymphoblastic leukemia cells), CCRF-CEM cells (human acute lymphoblastic leukemia T lymphocytes), TMD8 cells (human diffuse large B-cell lymphoma cells), 22RV1 cells (human prostate cancer cells), MCF-7 cells (human breast cancer cells), MM.1S cells (human multiple myeloma cells), MDA-MB-231 cells (human breast cancer cells), JEKO-1 cells (human mantle cell lymphoma cells), RPMI-8226 cells (human B lymphoblastoma cells), Molt-4 cells (human acute T lymphoblastic leukemia cells), H196 cells (human small cell lung cancer cells), NCI-H1975 cells (human non-small cell lung cancer cells), and others. The inhibitory effects of the compounds of the present disclosure were superior to those of the corresponding positive control drugs.

[00635] II. Determining the Effect of Compounds of the present disclosure on Target Protein Expression by Western Blot

[00636] Conventional Western blot assay was performed to evaluate the effects of the compounds of the present disclosure on the expression of target proteins in cells. Cell lines selected for WB detection based on the target of interest were summarized in Table II-1. Table II-1 Cell Type Cell Line Corresponding Target(s) hPBMC Cell hPBMC Cell IKZF1 / 2 / 3, Wee1, CK1a, GSPT1, IRAK1 / 2 / 3 / 4 Adherent Cells MDA-MB-231 Cell CDK4 / 6 LnCap Cell AR H1975 Cell EGFR 22RV1 Cell AR-V7 (Androgen Receptor Splice Variant 7)

[00637] (1) Cell Seeding and Protein Harvesting: The selected cells were processed according to the cell seeding procedure and protein harvesting procedure in Table II-2. Table II-2 Cell Seeding and Protein Harvesting Procedures Cell Type Cell Line Cell Plating Procedures for Various Cell Types hPBMC Cell hPBMC Cell Human peripheral blood mononuclear cells (hPBMCs) at a density of 1*106 cells / mL were thawed according to the PBMC Recovery Protocol (Milecell Biotechnologies Inc, Shanghai). The cells were then treated with the compounds of the present disclosure (including the compounds listed in Tables 1 and 2, and the Examples compounds) at concentrations of 50 nM and 500 nM. Controls included a negative control (DMSO) and a positive control (the commercial immunomodulatory drug, e.g., lenalidomide),  both  processed  following  the  identical experimental protocol as the compounds of the present disclosure. After 24 hours of compounds treatment, cells were harvested and lysed in RIPA protein lysate containing protease inhibitors on ice for 30 min, followed by centrifugation. The supernatant was aspirated as the extracted total cell protein. The protein concentration of the supernatant was determined using the conventional BCA (Bicinchoninic Acid) assay. Adherent Cells MDA-MB- 231     Cell, LnCap Cell, H1975 Cell, 22RV1 Cell Adherent cells (e.g., MDA-MB-231 cells) were added to 6-well plates at a seeding density of 2.5*105 / mL, with a total volume of 2 mL of cell suspension per well, cultured for 12 hours, and then treated with the compounds of the present disclosure (including the compounds listed in Tables 1 and 2, and the Examples compounds) at concentrations of 500 nM and 50 nM. Controls included a negative control (DMSO) and a positive control (corresponding   commercial   inhibitors),   both  processed following the identical experimental protocol as the compounds of the present disclosure. After 24 hours of compounds treatment, the culture medium was removed. The cells were washed once with PBS and then lysed with RIPA protein lysate containing protease inhibitors. The resulting lysed proteins were subsequently scraped with a cell scraper, placed on ice for 30 minutes, and centrifuged. The supernatant was aspirated as the extracted total cell protein. The protein concentration of the supernatant was determined using the conventional BCA assay.

[00638] (2) To the collected supernatant, 5X SDS sample loading buffer was added, followed by denaturation at 95°C for 5 minutes. The denatured samples were then separated by SDS-PAGE electrophoresis on a polyacrylamide gel. Proteins were transferred to a nitrocellulose membrane (0.45 pm NC membrane), blocked with blocking buffer at room temperature for 1 hour, and subjected to antibody incubation and development procedures according to the antibody manufacturer’s instructions (Cell Signaling Technology).

[00639] Half-Maximal Degradation Concentration value (the drug concentration required for degrading proteins by 50%, abbreviated as DC50) reads method: comparing the grayscale values of Western blot bands from drug-treated samples with those from blank DMSO-treated controls, and identifying the drug concentration range at which the grayscale value is half that of the DMSO-treated control bands.

[00640] DC50 values can be calculated using ImageJ software to measure grayscale values of Western blot bands from drug-treated samples. The concentration-response curve is fitted to estimate the drug concentration corresponding to half the grayscale value.

[00641] Target protein remaining (%) refers to the percentage of target protein remaining in cells after treatment with protein degrader compounds.

[00642] Calculation method for target protein remaining (%): Use ImageJ software to measure grayscale values of Western blot bands from drug (protein degrader)-treated samples. The grayscale value of drug-treated bands is divided by that of internal control protein bands, and the resulting quotient is normalized to obtain the relative percentage of remaining target protein after protein degrader treatment.

[00643] Target protein degradation rate (%) = 1 - target protein remaining (%).

[00644] The effects of the compounds of the present disclosure (including the compounds listed in Tables 1 and 2, and the Examples compounds) on substrate proteins expression in cells were shown in Tables IIA1- IIA5 below. Table IIA1 Degradation of substrate proteins CDK4 and CDK6 by the Example compounds of the present disclosure designed based on CDK4 / 6 inhibitors Comp. No. CDK4 CDK6 Comp. No. CDK4 CDK6 GT-08188 B A GT-10032 A A GT-07097 B A GT-10033 A B GT-07109 A A GT-10034 A B GT-07241 A A GT-10035 A B GT-07194 A A GT-10036 A B GT-10038 A A GT-10037 A A Table IIA2 Degradation of substrate proteins AR and AR-V7 by the Example compounds of the present disclosure designed based on AR inhibitors Comp. No. AR AR-V7 GT-08189 A GT-07196 A GT-07195 A GT-07179 A GT-10023 A Table IIA3 Degradation of substrate proteins IRAK2, IRAK3, and IRAK4 by the compounds of the present disclosure designed based on IRAK inhibitors Comp. No. IRAK4 IRAK2 IRAK3 GT-06943 A A A GT-06946 A B A GT—06947 A B A GT-06945 A B A GT-06941 A B A GT—06944 A B A GT-05300 A B A GT-06951 A B A GT-07105 A GT-07103 A GT-07104 A GT-07126 A GT-07111 A GT-07394 A GT-07396 A GT-09767 A GT-09776 A GT-09777 A GT-09770 A GT-09769 A GT-09768 A GT-09773 A GT-09775 A GT-09774 A GT-09772 A GT-09766 A GT-10046 A GT-10047 A GT-10048 A GT-10049 A GT-10050 A GT-10051 A GT-10054 A GT-09549 A GT-09548 A Table IIA4 Degradation of substrate protein EGFR by the compounds of the present disclosure designed based on EGFR inhibitors Comp. No. EGFR Comp. No. EGFR Osimertinib No degradation GT-10153 A GT-09922 A GT-10154 A Table IIA5 Degradation of substrate proteins WEE1, IKZF1, IKZF2, IKZF3, CK1a, and GSPT1 by the compounds of Formula (II) of the present disclosure Comp. No. WEE1 IKZF1 IKZF2 IKZF3 GSPT 1 CK1a Lenalidomi de B A B A B B GT-08008 B B B B B A GT-08009 B B B B B A GT-08007 B B B B B A GT-08006 B B B B A A GT-06988 B B B B B A GT-07966 B B B B B A GT-07965 B B B B B A GT-07008 A B B B A A GT-07368 B B B A B B Note: In Tables IIA1 to IIA5, "A" is defined as 0% < substrate protein remaining % < 80%, and "B" is defined as 80%< substrate protein remaining %< 100%.

[00645] The degradation effects of the designed and synthesized compounds of Formula (I) and Formula (II) of the present invention on the target substrate proteins are shown in Tables IIA1-IIA5 and Figure 1. The experimental results from Tables IIA1 through IIA5 and Figure 1 demonstrated that the compounds of formula (I) and formula (II) of the present invention can significantly degrade the target substrate proteins. The commercially available inhibitor cannot degrade the target protein (with 100% target protein remaining), whereas the compounds of formula (I) of the present invention achieve significant degradation of the target substrate proteins. Compared to lenalidomide, the compounds of formula (II) of the present invention show a significant improvement in the efficiency of inducing substrate protein degradation and can also selectively induce the degradation of substrate proteins. In summary, the structural diversity of the compounds of the present invention enables the effective degradation of diverse substrate proteins, thereby potentially enabling their use in treating indications associated with these substrate proteins.

[00646] III. Determination of CRBN-binding affinity of compounds

[00647] The CEREBLON BINDING kits (specification: 10,000 tests; product number: Catalog # 64BDCRBNPEH; CISBIO company) was used to determine the CRBN binding ability of the compounds to be tested through a HTRF method (homogeneous time-resolved fluorescence). The specific methods are as follows: 1. According to the instructions of the CEREBLON BINDING KITS, serial dilutions were performed for the test compounds of the present disclosure (including the compounds in Table 1, Table 2, and Examples) and for lenalidomide. Specifically, diluent #9 (1X) solution was used as the diluent, and multiple concentration gradients were set. The dilution operation can be performed according to one of the following two methods: (1) The first dilution method: The test compounds of the present disclosure (including the compounds in Table 1, Table 2, and Examples) were subjected to 5-fold serial dilutions starting from a highest concentration of 40 gM, resulting in a total of 7 concentrations from high to low (40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256 gM). Subsequently, the diluted test compounds and corresponding detection reagents were added to each well of a 96-well plate, resulting in final test compound concentrations of 10, 2, 0.4, 0.08, 0.016, 0.0032, and 0.00064 gM, respectively. (2) As an alternative, a second dilution method can be used: The test compounds of the present disclosure (including the compounds in Table 1, Table 2, and Examples) were subjected to 4-fold gradient dilutions starting from a highest concentration of 8 gM, resulting in 2 concentrations (8 gM, 2 gM). Into the 96-well plate, the diluted test compounds and corresponding detection reagents were added, resulting in final test compound concentrations of 2 gM and 0.5 gM, respectively. The experimental procedure is described below using the diluted 8 gM test compound and lenalidomide solutions as examples. 2. 2.5 gL of the above 8 gM of the tested compounds and lenalidomide solution, as well as the same volume of diluent #9 (1X) solution (solvent control group, Std0) were added to each well of a 96-well plate, respectively. Then, 2.5 gL of human Cereblon WT GST-tagged protein solution was added to each well. Finally, 5 gL of the thoroughly mixed Thalidomide-Re reagent and GST Eu antibody working solution were added to each of the aforementioned wells. The final concentration of the tested compounds and lenalidomide in each well was 2 gM. 3. The blank control wells were sequentially added with 2.5 gL of diluent #9 (1X) solution, 2.5 gL of PROTAC binding buffer, and 5 gL of thoroughly mixed Thalidomide-Re reagent and GST Eu antibody working solution. 4. After sealing and incubating the solutions in the aforementioned wells at room temperature for 3 hours, the absorbance values at emission wavelengths of 620 nm and 665 nm were detected by the HTRF method using a Spark microplate reader (V3.1 SP1). The corresponding CRBN binding inhibition rate was calculated using the following method: R compound = OD 665 nm compound / OD 620 nm compound - OD 665 nm control / OD 620 nm control Rstd0 = OD 665 nm std0 / OD 620 nm std0 - OD 665 nm control / OD 620 nm control inhibition rate (%) = (1 - R compound / Rstdo) * 100 Note: OD 665 nm compound is the absorbance value of each well of the compounds to be tested of the present disclosure at an emission wavelength of 665 nm. OD 620 nm compound is the absorbance value of each well of the compounds to be tested of the present disclosure at an emission wavelength of 620 nm. OD 665 nm control is the absorbance value of the blank control well at an emission wavelength of 665 nm. OD 620 nm control is the absorbance value of the blank control well at an emission wavelength of 620 nm. OD 665 nm Std0 is the absorbance value of the solvent control well at an emission wavelength of 665 nm. OD 620 nm Std0 is the absorbance value of the solvent control well at an emission wavelength of 620 nm.

[00648] The test results were shown in Tables III-1 and III-2 below. Table III-1. HTRF inhibitory activity (IC50, pM) of the compounds of the present disclosure (including the compounds in Tables 1, 2, and the Examples compounds) Comp. No. HTRF IC50 (pM) Comp. No. HTRF IC50 (pM) Lenalidomide e GT-07008 a GT-05579 a GT-07007 c GT-06989 b GT-07368 c GT-06988 d GT-07051 a Note: in Table III-1, the symbols a, b, c, d, e, and f are defined as follows: 0<a<0.5pM, 0.5pM<b<1pM, 1pM<c<1.5pM, 1.5pM<d<1.9pM, 1.9pM < e <10pM, 10pM < f. Table III-2: Screening of CRBN Binding Affinity of the Compounds of the Present Invention (including the compounds in Tables 1 and 2, and Examples Compounds) at Concentrations of 2 pM and 0.5 pM Comp. No. Inhibit ion Rate (%) at 2 pM Inhibitio n  Rate (%)   at 0.5 pM Comp. No. Inhibiti on Rate (%) at 2 pM Inhibitio n   Rate (%)   at 0.5 pM Comp. No. Inhibiti on Rate (%) at 2 pM Inhibitio n  Rate (%)   at 0.5 pM Lenalido mide a4 a2 GT- 07097 a7 a1 GT- 09922 a7 a2 GT-08179 a5 a3 GT- 07109 a8 a3 GT- 09928 a7 a7 GT-08189 a5 a3 GT- 07194 a5 a1 GT- 09924 a8 a4 GT-08180 a8 a3 GT- 07195 a5 a1 GT- 09930 a8 a6 GT-08195 a5 a3 GT- 07100 a5 a2 GT- 09926 a8 a6 GT-07105 a7 a2 GT- 07090 a7 a2 GT- 09929 a8 a3 GT-07103 a8 a4 GT- 07179 a5 a2 GT- 09925 a8 a4 GT-07104 a8 a1 GT- 07112 a7 a4 GT- 09927 a8 a3 GT-07111 a8 a4 GT- 07102 a7 a4 GT- 09923 a8 a4 GT-07396 a8 a5 GT- 07110 a6 a3 GT- 09921 a8 a7 GT-07395 a5 a3 GT- 07181 a7 a3 GT- 09932 a8 a8 GT-07966 a7 a4 GT- 09631 a6 a2 GT- 09931 a8 a6 GT-07965 a5 a2 GT- 09634 a8 a3 GT- 10033 a8 a8 GT-09767 a7 a6 GT- 09684 a8 a2 GT- 10034 a8 a5 GT-09776 a8 a7 GT- 09632 a7 a2 GT- 10035 a8 a7 GT-09777 a8 a4 GT- 09681 a6 a1 GT- 10036 a8 a7 GT-09770 a6 a3 GT- 09683 a8 a1 GT- 10037 a8 a7 GT-09769 a6 a4 GT- 09633 a8 a3 GT- 10038 a8 a6 GT-09773 a7 a6 GT- 09682 a8 a2 GT- 10040 a8 a6 GT-09775 a8 a5 GT- 07091 a6 a3 GT- 10041 a6 a4 GT-09774 a7 a6 GT- 10047 a8 a7 GT- 10042 a8 a7 GT-09772 a8 a5 GT- 10048 a8 a6 GT- 10043 a8 a4 GT-06947 a6 a4 GT- 10049 a8 a3 GT- 10044 a8 a6 GT-06941 a8 a3 GT- 10050 a8 a7 GT- 10045 a8 a6 GT-07089 a8 a3 GT- 10051 a8 a8 GT- 09548 a6 a3 GT-07096 a7 al GT- 10052 a8 a7 Note: in table III-2, the symbols a, a1, a2, a3, a4, a5, a6, a7, and a8 are defined as follows: 0% < a < 10%, 10% < al < 20%, 20% < a2 < 30%, 30% < a3 < 40%, 40% < a4 < 53%, 53% < a5 < 60%, 60% < a6 < 70%, 70% < a7 < 80%, 80% < a8 < 100%.

[00649] The results in Table III-1 and Table III-2 demonstrate that the compounds of the present invention (including but not limited to the compounds in Tables 1 and 2, and Examples) exhibit lower or comparable IC50 values, or higher inhibition rates compared to lenalidomide, indicating stronger binding affinity to CRBN.

[00650] IV. TNF-a Activity Inhibition Assay

[00651] PBMCs cells were cultured at 37°C with 5% CO2 and seeded in 96-well plates at 1*107 cells / well. The compounds to be tested (including those listed in Tables 1 and 2, and Examples compounds) were dissolved in DMSO and diluted to appropriate concentrations, ensuring that the final DMSO concentration in cell culture did not exceed 0.5%. After 1-hour incubation in medium with or without the compounds, the cells were stimulated with Lipopolysaccharide (LPS, 1 ng / ml) and continued to be cultured for 18-20 hours. Culture supernatants were then collected, diluted with serum-free medium, and analyzed for TNF-a levels using an ELISA kit. IC50 values were calculated using GraphPad Prism 7.0.

[00652] TNF-a downregulation is a key mechanism for the anti-tumor action of immunomodulators. The compounds of the present disclosure demonstrated dose-dependent inhibition of TNF-a levels.

[00653] V. Pharmacokinetic Study of the compounds of the present disclosure

[00654] The pharmacokinetic properties of the compounds of the present disclosure were evaluated using conventional pharmacokinetic experimental methods.

[00655] The test compounds of the present disclosure (including the compounds in Tables 1 and 2, and the Examples compounds) were orally administered to experimental animals to evaluate their pharmacokinetic properties. The experimental animals used may be those commonly used in pharmacokinetic experiments, e.g., adult and healthy rodents (e.g., mice, rats (such as Sprague-Dawley (SD) rats), guinea pigs, or non-rodents (rabbits, dogs, and monkeys). The experimental animals used in this study were mice.

[00656] The experimental animals were divided into two groups: a control group (for collecting blank plasma) and an oral administration group (administered at a dose of 10 mg / kg). Blood samples were collected at predetermined time points after administration, such as 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose. Blank plasma was collected from the control group.

[00657] Prior to analysis, plasma samples were processed as follows: To 10 pL of plasma sample were added 10 pL of 50% acetonitrile and 200 pL of internal standard solution (containing 50 ng / mL dexamethasone in acetonitrile). For blank control plasma samples, no internal standard was added, instead an equivalent volume of acetonitrile was supplemented. The processed samples were vortex-mixed, centrifuged, and the supernatant was subjected to LC-MS / MS analysis.

[00658] After preparation of calibration curves and QC samples, the concentrations of compounds in plasma samples were determined by LC-MS / MS analysis. The pharmacokinetic parameters of the test compounds were calculated using the pharmacokinetic calculation software WinNonlin v8.1 with non-compartmental analysis based on the plasma concentration data obtained from LC-MS / MS.

[00659] The results demonstrated that the compounds of the present disclosure administered via oral route exhibited favorable drug metabolism and pharmacokinetic (DMPK) properties, indicating their potential as therapeutic agents for cancer patients.

[00660] VI. Effects of the compounds of the present disclosure on the release of inflammatory cytokines, including TNF-a, IL-2, IL-12, IL-10, IL-1a, IL-ip, IL-6, IL-8, and IFN-Y, from PBMCs induced by phytohemagglutinin (PHA) or the eBioscience™ Cell Stimulation Cocktail (PMA + Ionomycin)

[00661] The present inventors examined the effects of the compound of the present invention on the release of a panel of inflammatory cytokines from peripheral blood mononuclear cells (PBMCs) triggered by phytohemagglutinin (PHA) or the eBioscience™ Cell Stimulation Cocktail (containing PMA and lonomycin). These inflammatory cytokines include TNF-a, IL-2, IL-5, IL-12, IL-10, IL-1a, IL-6, IL-8, IFN-y, IL-ip, and granulocyte-macrophage colonystimulating factor (GM-CSF), among others. Previous studies have suggested that these inflammatory cytokines may play important roles in the onset and progression of cancer, autoimmune diseases, infectious diseases, and inflammatory diseases. In autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), the expression level of TNF-a is significantly elevated, and it exerts its effects by stimulating synovial cell proliferation and promoting inflammatory responses. IL-ia is associated with cancer, autoimmune diseases, infectious diseases, and other inflammatory conditions, and participates in the inflammatory processes of autoimmune diseases. In diseases such as rheumatoid arthritis and systemic lupus erythematosus, elevated IL-ip levels can reflect the extent and activity of inflammatory responses. IL-2, IL-5, IL-10, IFN-y, and GM-CSF are also associated with various inflammatory diseases and autoimmune diseases.

[00662] The following materials were used in this study:

[00663] VI.1 Reagents and Consumable materials Name Supplier or Source Human PBMC cell Milestone Biotechnologies eBioscience™ Cell Stimulation Cocktail Invitrogen Phytohemagglutinin (PHA) MCE RPMI 1640 Medium Gibco Human IFN-y CBA Flex Set E7 100Tst Becton, Dickinson and Company Human IL-2 CBA Flex Set A4 100Tst Becton, Dickinson and Company Human TNF-a CBA Flex Set D9 100Tst Becton, Dickinson and Company Human IL-10 CBA Flex Set B7 100Tst Becton, Dickinson and Company Human IL-6 CBA Flex Set A7 100Tst Becton, Dickinson and Company Human IL-8 CBA Flex Set A9 100Tst Becton, Dickinson and Company Human IL-ip CBA Flex Set B4 100Tst Becton, Dickinson and Company Human IL-12 / IL-23p40 CBA Flex Set E5 100Tst Becton, Dickinson and Company Human IL-17A CBA Flex Set B5 100Tst Becton, Dickinson and Company Human IL-la CBA Flex Set D6 100Tst Becton, Dickinson and Company Human IL-5 CBA Flex Set A6 100Tst Becton, Dickinson and Company Human IL-13 CBA Flex Set E6 100Tst Becton, Dickinson and Company Human IL-4 CBA Flex Set A5 100Tst Becton, Dickinson and Company Human GM-CSF CBA Flex Set C9 100Tst Becton, Dickinson and Company Sheath Fluid for Flow Cytometric Analysis (20L) Becton, Dickinson and Company Human Solbl Ptein CBA Buf Kit 500Tst Becton, Dickinson and Company

[00664] VI.2 Methods

[00665] VI.2.1 Cell Thawing and Plating

[00666] A complete medium was prepared and pre-warmed to 37OC. Cryovials containing the cells were retrieved from liquid nitrogen, and the area immediately below the cap-notch interface was firmly gripped with forceps. The cryovials were immersed in a 37°C water bath, and shaken occasionally to facilitate thawing. The cell suspension was aspirated and transferred to a centrifuge tube containing 10 mL complete medium, followed by thorough mixing and centrifugation at 400 x g for 10 min at room temperature. The supernatant was discarded, and the pellet was resuspended in fresh complete medium. After cell counting and the cell density adjustment, the cell suspension was seeded in 96-well plates at a density of 1x105 cells / well (75 pL / well) and incubated in an incubator for 2 h at 37°C with 5% CO2 under high humidity conditions.

[00667] VI.2.2 Compound Preparation and Addition to Cell Plates 1) The test compounds (including the compounds in Tables 1 and 2, and the Examples compounds) were prepared as 10 mM stock solutions in DMSO. 2) The test compounds were serially diluted 10-fold in DMSO starting from 1 mM (highest concentration) to generate 2 concentration gradients, i.e., 1 mM and 0.1 mM. 3) The test compounds were further diluted in culture medium to five times their final working concentration intended for use. 4) The diluted compounds were added to designated wells according to the plate layout at 25 pL / well, achieving final concentrations starting from 1 pM with 10-fold serial dilution (2 concentration points in total), i.e., 1 pM and 0.1 pM. 5) After 1 h incubation, PHA or PMA+Ionomycin (25 pL / well) was added to the cell wells to reach final concentrations of: 1 pg / mL PHA (TNF-a, IL-10, IL-6, IL-10, IFN-y, IL-2, IL-12p40, IL-1a, IL-8), 81nM / mL PMA (IL-4, IL-5, IL-13, GM-CSF, and IL-17A), or 1.34 pM / mL Ionomycin (IL-4, IL-5, IL-13, GM-CSF, and IL-17A). 6) The cell plates were incubated in an incubator for 24 h at 37°C with 5% CO2 under high humidity. The negative control was DMSO, and the positive control drugs were the corresponding commercial immunomodulatory agents (e.g., lenalidomide) or the corresponding commercial inhibitors (including emavusertib (CAS No.: 1801344-14-8)), all of which were used to treat the cells in the same manner as the compound of the present disclosure. Cell plate layout: 1 2 3     4     5     6     7     8     9     10    11    12 A H2O B DMSO PHA / PMA+Ionomycin Cmpd 1-5# (1 pM and 0.1pM, 2 points) C Cmpd 6-11# (1 pM and 0.1pM, 2 points) D Cmpd 12-17# (1 pM and 0.1pM, 2 points) E Cmpd 18-23# (1 pM and 0.1pM, 2 points) F Cmpd 24-29# (1 pM and 0.1pM, 2 points) G Cmpd 30-35# (1 pM and 0.1pM, 2 points) H Cmpd 36-41# (1 pM and 0.1pM, 2 points)

[00668] VI.2.3 Detection (1) The cell plate was centrifuged and the culture supernatant was aspirated. TNF-a, IL-10, IL-6, IL-1P, IFN-y, IL-2, IL-12p40, IL-1a, IL-8, IL-4, IL-5, IL-13, GM-CSF, and IL-17A cytokines in the culture supernatant were detected according to the instructions of the flow cytometry CBA (Cytometric Bead Array) assay. (2) The flow cytometry CBA assay was performed as follows: Dilution of standards and samples: Standards and samples were diluted at appropriate ratios to enable accurate quantitative analysis in the assay. Bead mixing: Capture beads were mixed with samples or standards and incubated in the dark for 1 hour. Antibody mixing: Detection antibodies were mixed with samples or standards and incubated in the dark for 2 hours. These two steps are the core of the flow cytometry CBA technique, enabling quantitative detection of cytokines through the binding of beads to target molecules. Flow cytometric detection: The mixtures were analyzed using a flow cytometer. The flow cytometer excites fluorescent labels on the beads with a laser, collects and analyzes the fluorescence signals, thereby quantitatively determining the cytokine concentrations in the samples. (3) Data collected by the flow cytometer were further analyzed, typically using software (FACP) for data processing, to generate detailed cytokine concentration reports (for TNF-a, IL-10, IL-6, IL-1P, IFN-y, IL-2, IL-12p40, IL-1a, IL-8, IL-4, IL-5, IL-13, GM-CSF, and IL-17A). The inhibition rate (%) was calculated as follows: Inhibition rate (%) = [(Ac - As) / (Ac - Ab)] x 100% where: As = OA of the sample (cells + PHA / PMA+Ionomycin + test compound) Ac = OA of the positive cell control (cells + PHA / PMA+Ionomycin + DMSO) Ab = OA of the blank control (cells + medium + DMSO) (4) IC50 curve fitting and IC50 value calculation were performed using GraphPad Prism 6 software with the following formula / analysis: XY-analysis / Nonlinear regression (curve fit) / Dose response-Inhibition / log (inhibitor) vs. response-Variable slope (four parameters).

[00669] The results are presented in Table IV below. Table IV: Inhibition rates (%) of the compounds of the present disclosure (including but not limited to the compounds in Tables 1 and 2, and the Example compounds) on inflammatory cytokines at concentrations of 1 ^M and 0.1 liM. Comp IL-10 IL-1a IL-10 IL-12 TNF-a IL-2 ifn-y IL-6 IL-8 . No. 1    0.1 1    0.1 1    0.1 1    0.1 1    0.1 1    0.1 1    0.1 1    0.1 1    0.1 l  l l  l l  l l  l l  l l  l l  l l  l l  l M M M M M M M M M M M M M M M M M M lenali I   IV I   IV I   IV I   IV I   IV I   IV -      - I   IV I   IV domi V  5 V  10 V  12 V  12 V 6 V  1 V  11 V  3 de 4 1 1 1 4 0 1 2 0 2 3 0 GT- -      - I   IV I   IV I   IV I   IV I   IV I   IV I   IV I   IV 0800 V  7 V  8 V  6 V 6 V  7 V  8 V  7 V  8 8 7 8 7 6 8 1 7 6 0 GT- -      - I   IV I   IV I   IV I   IV I   IV I   IV I   IV I   IV 0800 V  10 V  11 V  10 V  8 V  8 V  13 V  10 V  8 9 6 7 7 6 7 8 8 7 GT- -      - I   IV I   IV I   IV I   IV I   IV I   IV I   IV I   IV 0800 V  8 V  6 V  7 V  5 V  6 V  8 V 7 V  7 6 1 1 9 8 5 1 1 1 2 2 1 1 0 GT- - - - - - - - - - - I IV I IV I IV - - 0431 V 6 V 12 V 7 0 7 9 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0557 V 8 V 9 V 11 V 9 V 10 V 10 V 13 V 10 V 7 9 1 1 1 1 1 1 1 1 1 0 2 3 4 3 0 4 2 3 GT- - - I IV I IV - - - - - - - - I IV I IV 0698 V 9 V 9 V 9 V 8 9 1 1 1 1 1 1 0 0 GT- - - I IV I IV I IV I IV I - I - I IV I IV 0796 V 5 V 5 V 5 V 5 V V V 5 V 5 6 1 1 8 8 7 9 9 9 0 0 GT- I IV I IV I IV - - - - - - I IV I IV I IV 0819 V 8 V 11 V 9 V 15 V 9 V 8 5 9 1 9 1 8 7 0 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0700 V 12 V 13 V 14 V 13 V 13 V 10 V 14 V 13 V 12 8 1 1 1 1 1 9 1 1 1 1 2 3 2 2 4 2 0 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0700 V 8 V 9 V 10 V 9 V 9 V 9 V 11 V 9 V 8 7 1 8 9 1 9 9 1 9 8 0 0 1 GT- - - I IV I IV I IV I IV I IV I IV I IV I IV 0736 V 9 V 8 V 8 V 5 V 5 V 8 V 9 V 6 8 1 1 1 8 5 1 1 8 1 2 2 1 1 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0991 V 9 V 9 V 8 V 5 V 7 V 10 V 12 V 8 V 6 6 8 8 8 6 8 1 1 9 8 0 1 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0999 V 9 V 15 V 12 V 10 V 9 V 11 V 12 V 12 V 14 5 1 1 1 1 1 1 1 1 1 5 5 5 5 5 2 4 5 5 emav I IV I IV I IV I IV I IV I IV - - I IV I IV userti V 3 V 3 V 3 V 3 V 2 V 2 V 6 V 7 b 4 1 1 1 8 2 1 1 3 4 4 4 1 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0710 V 12 V 14 V 14 V 14 V 14 V 13 V 15 V 13 V 12 5 1 1 1 1 1 1 1 1 1 3 4 4 4 4 3 5 3 3 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0710 V 10 V 14 V 14 V 14 V 13 V 10 V 15 V 13 V 12 3 1 1 1 1 1 5 1 1 1 2 4 4 4 4 5 3 2 GT- I IV I IV I IV I IV I IV - - I IV I - I IV 0710 V 14 V 14 V 14 V 14 V 14 V 15 V V 13 4 1 1 1 1 1 1 1 1 4 4 4 4 5 5 4 3 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0712 V 12 V 14 V 14 V 14 V 13 V 10 V 15 13 V 12 6 1 1 1 1 1 1 1 1 4 5 4 5 4 2 5 4 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0711 V 13 V 14 V 14 V 14 V 14 V 10 V 15 14 V 13 1 1 1 1 1 1 7 1 1 3 4 5 5 4 5 3 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0739 V 8 V 9 V 8 V 10 V 8 V 7 V 15 V 8 V 7 4 1 1 1 1 1 8 1 1 1 3 4 4 4 4 5 3 1 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0739 V 8 V 9 V 7 V 6 V 6 V 6 V 15 V 5 V 5 6 1 1 1 1 1 7 1 1 9 2 4 4 3 3 5 0 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0818 V 9 V 12 V 12 V 10 V 11 V 13 V 15 V 7 V 5 0 1 1 1 1 1 1 1 1 1 3 4 4 4 4 4 5 2 1 GT- I IV I - I - I IV I IV I IV I IV - IV I IV 0976 V 12 V V V 8 V 6 V 12 V 12 9 V 9 7 1 1 1 1 1 1 1 1 2 4 5 4 3 3 4 3 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0977 V 8 V 11 V 10 V 7 V 8 V 12 V 11 V 8 V 5 6 9 1 1 1 1 1 1 1 1 2 2 0 0 0 2 1 0 GT- I IV I - I - I IV I IV I IV I IV I IV I IV 0977 V 11 V V V 8 V 8 V 12 V 11 V 6 V 5 7 1 1 1 1 1 1 1 1 1 0 4 4 4 3 1 4 4 3 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0976 V 8 V 14 V 14 V 13 V 12 V 9 V 15 12 V 11 5 1 1 1 1 1 1 1 1 3 4 4 5 3 0 5 3 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0977 V 8 V 7 V 5 V 5 V 5 V 9 V 9 V 7 V 8 0 7 1 1 1 1 9 1 1 9 4 4 3 1 3 3 GT- I IV I IV I IV I - I IV I IV I IV I IV I IV 0976 V 10 V 5 V 5 V V 5 V 9 V 7 V 5 V 6 9 8 1 1 1 1 8 1 1 1 4 4 4 2 4 4 1 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0976 V 9 V 5 V 5 V 5 V 5 V 8 V 8 V 7 V 7 8 7 1 1 1 1 1 1 1 8 3 4 2 2 1 3 2 GT- I IV I IV I IV I IV I IV I IV I IV - IV I - 0977 V 8 V 8 V 6 V 6 V 7 V 13 V 12 5 V 3 1 1 1 1 1 1 1 1 2 4 5 4 3 2 4 4 GT- I IV I IV I IV I IV I IV I IV I IV I - I - 0977 V 9 V 5 V 5 V 5 V 5 V 12 V 9 V V 1 1 1 1 1 1 1 1 1 1 4 4 4 4 4 4 4 4 2 GT- I IV I IV I IV I IV I IV I IV I IV I IV I - 0977 V 8 V 7 V 6 V 7 V 6 V 13 V 11 V 5 V 5 1 1 1 1 1 5 1 1 1 0 4 4 4 1 3 4 1 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0977 V 7 V 9 V 8 V 5 V 7 V 12 V 10 V 5 V 5 4 1 1 1 1 1 1 1 1 1 0 4 4 3 2 0 4 3 2 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 0977 V 7 V 8 V 7 V 6 V 6 V 10 V 11 V 5 V 5 2 9 1 1 1 1 1 1 1 8 3 3 1 1 3 3 0 GT- I IV I IV I IV I IV I IV I IV I IV - - I IV 0694 V 12 V 14 V 15 V 14 V 13 V 10 V 14 V 13 3 1 1 1 1 1 1 1 1 1 4 5 5 4 0 4 4 GT- I IV I IV I IV I IV I IV I IV I IV - - I IV 0694 V 13 V 14 V 15 V 15 V 14 V 10 V 14 V 14 6 1 1 1 1 1 9 1 1 2 4 5 5 4 4 4 GT- I IV I IV I IV I IV I IV I IV I IV - - I IV 0694 V 13 V 14 V 15 V 15 V 14 V 10 V 14 V 14 7 1 1 1 1 1 8 1 1 1 4 5 5 4 4 4 GT- I IV I IV I IV I IV I IV - IV I IV - IV I IV 0694 V 13 V 14 V 14 V 14 V 14 12 V 14 14 V 13 5 1 1 1 1 1 1 1 4 4 5 5 5 5 4 GT- I IV I IV I IV I IV I IV - IV I IV - IV I IV 0694 V 12 V 14 V 14 V 14 V 14 12 V 14 13 V 12 1 1 1 1 1 1 1 1 4 4 5 5 5 5 4 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0694 V 7 V 10 V 10 V 6 V 6 V 7 V 8 9 V 8 4 1 1 1 1 1 9 1 1 2 4 5 5 4 4 4 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0530 V 7 V 12 V 13 V 13 V 11 V 8 V 13 11 V 8 0 1 1 1 1 1 7 1 1 2 4 4 4 4 4 3 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1002 V 9 V 14 V 10 V 6 V 6 V 8 V 10 V 10 V 12 4 8 1 1 9 8 9 1 1 1 3 2 0 3 4 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1002 V 9 V 13 V 9 V 8 V 7 V 10 V 11 V 11 V 13 2 1 1 1 1 1 5 1 1 1 3 5 5 5 3 4 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1004 V 7 V 11 V 10 V 6 V 7 V 8 V 9 V 13 V 15 6 1 1 1 1 1 6 1 1 1 2 5 5 5 4 4 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1004 V 11 V 15 V 10 V 9 V 8 V 10 V 11 V 14 V 15 7 1 1 1 1 1 8 1 1 1 0 5 5 4 2 3 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1004 V 10 V 15 V 10 V 9 V 7 V 7 V 10 V 15 V 15 8 1 1 1 1 1 7 1 1 1 4 5 5 5 5 4 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1004 V 9 V 13 V 9 V 6 V 5 V 6 V 9 V 13 V 15 9 8 1 1 1 1 5 1 1 1 5 5 4 1 3 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1005 V 7 V 12 V 9 V 7 V 5 V 5 V 8 V 8 V 11 0 1 1 1 1 1 1 1 1 1 5 5 5 5 5 4 5 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1005 V 7 V 13 V 9 V 6 V 6 V 5 V 9 V 10 V 13 1 1 1 1 1 1 1 1 1 1 3 5 5 5 4 4 4 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1005 V 10 V 15 V 11 V 9 V 8 V 9 V 11 V 11 V 15 2 1 1 1 1 1 1 1 1 1 4 5 5 5 5 0 4 5 5 GT- I IV I IV I IV I IV I IV I IV I IV I IV I IV 1005 V 8 V 14 V 10 V 8 V 8 V 8 V 10 V 10 V 13 4 9 1 1 1 1 9 1 1 1 5 5 5 1 4 5 5 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0695 V 10 V 13 V 14 V 14 V 13 V 9 V 14 13 V 12 1 1 1 1 1 1 1 1 1 3 4 5 5 4 0 4 4 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0954 V 5 V 10 V 10 V 11 V 6 V 5 V 11 8 V 7 9 1 1 1 1 1 9 1 1 3 5 5 5 4 4 4 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0954 V 6 V 13 V 14 V 13 V 11 V 7 V 13 12 V 10 8 1 1 1 1 1 9 1 1 3 4 5 5 4 4 3 GT- I IV I IV I IV I IV I IV I IV I IV - IV I IV 0960 V 8 V 12 V 12 V 10 V 8 V 7 V 11 11 V 10 3 1 1 1 1 1 5 1 1 3 4 5 4 3 4 3 Note: in table IV, the symbols IV0, IV1, IV2, IV3, IV4, IV5, IV6, IV7, IV8, IV9, IV10, IV11, IV12, IV13, IV14, and IV15 are defined as follows: -320% < IV0 < -200%, -200% < IV1 < -100%, -100% < IV2 < -50%, -50% < IV3 < -20%, -20% < IV4 < 0%, 0% < IV5 < 10%, 10% < IV6 < 20%, 20% < IV7 < 30%, 30% < IV8 < 40%, 40% < IV9 < 50%, 50% < IV10 < 60%, 60% < IV11 < 70%, 70% < IV12 < 80%, 80% < IV13 < 90%, 90% < IV14 < 100%, 100% < IV15 < 110%. The symbol “-” indicates “not tested”.

[00670] The experimental results demonstrate that the compounds of the present disclosure (including the compounds in Tables 1 and 2, and the Example compounds) exhibit excellent modulatory capacity in regulating the production levels of cytokines associated with inflammatory diseases and autoimmune diseases, with inhibitory effects significantly more pronounced than those of the positive control drugs lenalidomide and emavusertib. The positive control drugs lenalidomide and emavusertib elevate IL-2 or IL-10 levels, thereby activating immune responses; in contrast, the compounds of the present disclosure suppress IL-2 and IL-10 or show no significant stimulatory effect, which confers greater advantages in the treatment of immune system disorders. The compounds of the present disclosure (including the compounds in Tables 1 and 2, and the Example compounds) hold broad promise as potential therapeutic agents for the treatment of various inflammatory diseases and autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, systemic lupus erythematosus, atopic dermatitis, and hidradenitis suppurativa, among others.

[00671] VII. Efficacy experiment of the compounds of the present disclosure on Psoriasislike skin lesions induced by Imiquimod in mice

[00672] The compounds of the present disclosure (test compounds, including the compounds in Tables 1, 2, and Examples) were administered orally via gavage once daily for 7 consecutive days to mice with psoriasis-like skin lesions induced by imiquimod, to investigate their efficacy on such lesions.

[00673] A total of 60 female C57BL / 6J mice (purchased from Shanghai SLAC Laboratory Animal Co., Ltd.) were randomly divided into 6 groups (n=10 per group) based on body weight: Group Drug Number of Animals Dose (mg / kg) Administration volume (mL / kg) Administratio n concentration (mg / mL) Route and Duration 1 Control: Vehicle 10 NA 10 NA ig. qd. 7 days 2 Model: Vehicle 10 NA 10 NA ig. qd. 7 days 3 Positive Control 10 3 10 0.3 sc. qd. 7 days 4 Low-dose test compounds group 10 3 10 0.3 ig. qd. 7 days 5 Mediumdose    test compounds group 10 10 10 1 ig. qd. 7 days 6 High-dose test compounds group 10 30 10 3 ig. qd. 7 days Note: ig., oral gavage; sc., subcutaneous injection; qd., once daily.

[00674] After grouping the experimental animals, the backs of all mice were shaved. Except for the Control group, the remaining groups were topically treated with imiquimod cream once daily for 7 consecutive days. Simultaneously, each group was administered with a vehicle control, a positive control drug, or the test compounds, according to the above table, once daily for 7 consecutive days.

[00675] All clinical symptoms of each animal were observed at the beginning and throughout the experiment. The animals’ weights were measured and recorded every 2 days.

[00676] Scoring

[00677] Gross Observation Scoring of Skin Lesions (PASI Method): during the last 3 days of modeling and drug administration, the changes in skin lesions of mice in each group were observed once daily. PASI Method: the erythema, scaling, and thickening / infiltration of the lesions were scored separately, and the scores were summed to obtain the total score. PASI Scoring Criteria: 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

[00678] The skin lesions were photographed once daily during the last 3 days of modeling and drug administration.

[00679] After the experiment, the mice were euthanized by CO2 inhalation. Three different areas of skin from the lesion site on the back were collected using a 6 mm punch, weighed, and recorded, and the average weight was calculated.

[00680] The skin tissue from the lesion site was homogenized and the levels of IL-23p19, IL-12p40, IL-17, and TNF-a were determined.

[00681] The local lesion tissue was fixed, stained with HE, and subjected to pathological scoring (based on epidermal thickness, degree of epidermal keratinization, thickness of the basal layer, and degree of dermal inflammatory cell infiltration). Scoring Criteria: 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

[00682] Experimental data were presented as Mean ± SD. Statistical analysis between two groups was performed using SPSS, with p < 0.05 considered statistically significant.

[00683] The experimental results demonstrated that the compounds of the present disclosure exhibited ameliorative effects on psoriasis-like skin lesions on the back of mice induced by imiquimod and can be used for the treatment of psoriasis.

[00684] VIII. Efficacy Experiment of the compounds of the present disclosure on the CIA Model in Rats Induced by Type II Collagen

[00685] The compounds of the present disclosure (test compounds, including the compounds in Tables 1, 2, and Examples) were administered orally via gavage once daily for 21 consecutive days to Wistar rats with collagen-induced arthritis (CIA) that was induced using bovine type II collagen (Chondrex, Inc.), in order to investigate their efficacy in the rat arthritis model.

[00686] Preparation of the Modeling Agent: 10 mg of CII (Immunization Grade Bovine Type II Collagen, purchased from Chondrex, Inc.) was dissolved in 5 mL of 0.05M acetic acid solution, allowing it to be fully dissolved, thereby preparing a solution with a concentration of 2 mg / mL, which was then stored at 4°C in the dark overnight. On the day of the experiment, the 2 mg / mL CII solution was mixed with an equal volume of a 4 mg / mL solution of Complete Freund's Adjuvant (CFA, also purchased from Chondrex, Inc.) on ice, and was thoroughly emulsified into an emulsion.

[00687] On day 0, 10 Wistar rats (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were randomly selected as the blank control group and were not immunized. The remaining 100 Wistar rats were intradermally injected at the base of the tail with an emulsion prepared by mixing equal volumes of CII (2 mg / mL) and CFA (4 mg / mL) for the first immunization. A second booster immunization was administered to them on day 7. Between days 10 and 14, i.e., 3 to 7 days after the second booster immunization, 50 rats with an arthritis index (AI) score ranging from 1 to 2 were selected from the modeled animals and were divided into 5 groups based on their body weight, foot volume, and AI score, with 10 rats per group: Group Drug Number of Animals Dose (mg / k g) Administration volume (mL / kg) Administration concentration (mg / mL) Route  and Duration 1 Control: Vehicle 10 NA 10 NA ig. qd. 21 days 2 Model: Vehicle 10 NA 10 NA ig. qd. 21 days 3 Positive Control 10 0.1 10 0.01 sc. qd. 21 days 4 Low-dose test compounds group 10 3 10 0.3 ig. qd. days 21 5 Mediumdose    test compounds group 10 10 10 1 ig. qd. days 21 6 High-dose test compounds group 10 30 10 3 ig. qd. days 21 Note: ig. = oral gavage; sc. = subcutaneous injection

[00688] Administration commenced between 3 and 7 days after the second booster immunization, once the AI score of the affected paws reached 1-2. According to the table above, animals in each group received daily oral gavage (or subcutaneous injection) of either the vehicle control, positive control drug, or the test compounds for 21 consecutive days.

[00689] Beginning on day 3 after the second booster immunization, the volume of both hind paws (or toes) was measured and recorded twice weekly.

[00690] Foot Volume Measurement: Before the measurement, a line was marked on the rat's ankle joint with a marker pen to indicate the position. After clean water was added to the instrument, the instrument's reading was reset to zero in preparation for the measurement. The hind limb of the rat was placed in the water so that the marked line at the ankle joint was at the surface of the liquid. The reading obtained by pressing the foot pedal at this time was the foot volume of the rat. After the measurement was completed, the foot pedal was pressed again to reset the instrument to zero, preparing it for the measurement of the next rat.

[00691] Scoring Arthritis Index (AI): The foot volume was measured twice a week, and the swelling of the four toes was scored simultaneously. Each foot was scored on a scale from 0 to 4, with a maximum score of 16 for each rat. Arthritis Index (AI) Scoring Criteria: Score Degree 0 No swelling, normal appearance 1 Mild swelling or redness of the ankle, wrist, or finger joints 2 Moderate swelling or redness of the ankle, wrist, or finger joints 3 Severe swelling or redness of the ankle, wrist, or finger joints 4 Very severe swelling or redness of the ankle, wrist, or finger joints

[00692] The day of starting drug administration is recorded as Day 0. Five days after starting drug administration, i.e., 2 hours after Day 5 administration, blood was collected from the jugular vein of the experimental animals, allowed to stand for more than 30 minutes, centrifuged to separate the serum, which was stored at -80°C. The levels of TNF-a, IL-ip, and IL-6 in serum were measured by ELISA.

[00693] After the experiment, the animals were euthanized by CO2 inhalation. The spleen and thymus of the animals were collected and weighed, and the organ coefficients were calculated.

[00694] Pathological Examination: One side of the foot joint tissue was fixed in 10% neutral formalin solution, followed by decalcification and paraffin embedding to prepare pathological sections. The sections were then stained with hematoxylin and eosin (HE) for pathological observation. Observation Indices: 1. Infiltration of synovial inflammatory cells (lymphocytes, plasma cells); 2. Synovial tissue hyperplasia; 3. Synovial pannus; 4. Fibrinoid necrosis on the synovial surface. Scoring and Counting Method: 0, 1, 2, 3, and 4 levels, where "0" indicates no observation; "1" is mild; "2" is moderate; "3" is severe; and "4" is extremely severe.

[00695] Experimental data were presented as Mean ± SEM. Data between two groups were analyzed using Excel-T test, with p<0.05 considered statistically significant. Scoring data were analyzed using the non-parametric Mann-Whitney U test in SPSS, with p<0.05 considered statistically significant.

[00696] The experimental results demonstrated that the compounds of the present disclosure regulated the serum inflammatory cytokines levels in the bovine type II collagen-induced rat model of collagen-induced arthritis (CIA), significantly ameliorated limb swelling in the rats, and thus can be applicable for the treatment of arthritis.

[00697] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that various changes and modifications may be made thereto without departing from the spirit and scope of the present invention, and such changes and modifications all fall within the scope of the invention as claimed. The scope of protection sought by the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound of Formula (I)PBM-LIN-ULM(I)or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof,wherein PBM represents a protein-binding moiety capable of binding to a target protein, and is covalently linked to ULM through LIN;ULM represents a ligand moiety capable of binding to an E3 ubiquitin ligase, and represents the structure of the following Formula (ULM):(ULM)wherein Z represents C(O) or CH2;Ra1, Ra2, Ra3, and Ra4 are identical or different and each independently represents 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, wherein each Ra5 is identical or different and independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, or halogenated C1-6 alkoxy;m represents an integer of 0, 1, 2, or 3;Ra6 represents:**   ^2-(Rd1 )n1wherein ring Y1 represents heterocyclylene containing at least two nitrogen atoms, and (Rd1)n1 indicates that ring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 0-20;R1 represents N(Rw), where Rw represents hydrogen or C1-3 alkyl, and R2 represents abond; or R2 represents CH2, C(O), **-NHC(O)-, or **-N(CH3)C(O)-; or R2 represents a structure of the following formula:(Rd2)n2**wherein ring Y2 represents cycloalkylene, or heterocyclylene containing at least one nitrogen atom, and (Rd2)n2 indicates that ring Y2 is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n2 represents an integer of 0-20;orR1 represents a bond, and R2 represents N(Rw), where Rw represents hydrogen or C1-3 alkyl; or R2 represents **C(O)N(Rw), where Rw represents hydrogen or C1-3 alkyl; or R2 represents **-CH=N-; orR a6 represents:** Rx—N—wherein Rx represents NH or **-CH=N-; orR a6 represents:wherein ring Y3 represents heterocyclylene containing one nitrogen atom, and (Rd3)n3 indicates that ring Y3 is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n3 represents an integer of 0-20; and** * * Swherein Rsi represents         0-2   , symbol **** indicates the point of attachment toring Y3; and Rs2 represents N(Rw) or **C(O)N(Rw), where Rw represents hydrogen or C1-3 alkyl;symbol ** in each of the above formulae indicates the point of attachment to LIN; and LIN represents a bond, or a structure of the following formula:wherein Rw2 is linked to PBM, and Rw1 is linked to Ra6;Rw2 represents a bond, C(O), C(O)NH, or NHC(O);each ring A1 is identical or different and each independently represents heterocyclylene, cycloalkylene, arylene, or heteroarylene, y1 represents an integer of 0, 1, 2, or 3, and (Ry1)a1 indicates that each ring A1 is independently optionally substituted with a1 Ry1 substituents, wherein each Ry1 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, carboxyl, C2-6 alkynyl or C2-6 alkenyl, and a1 represents an integer of 0-10;each ring A2 is identical or different and each independently represents heterocyclylene, cycloalkylene, arylene, or heteroarylene, y2 represents an integer of 0, 1, 2, or 3, and (Ry2)a2 indicates that each ring A2 is independently optionally substituted with a2 Ry2 substituents, wherein each Ry2 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, carboxyl, C2-6 alkynyl, or C2-6 alkenyl, and a2 represents an integer of 0-10;each ring A3 is identical or different and each independently represents heterocyclylene, cycloalkylene, arylene, or heteroarylene, y3 represents an integer of 0, 1, 2, or 3, and (Ry3)a3 indicates that each ring A3 is independently optionally substituted with a3 Ry3 substituents, wherein each Ry3 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, carboxyl, C2-6 alkynyl, or C2-6 alkenyl, and a3 represents an integer of 0-10;Rw1 represents a bond or an optionally substituted linear or branched C1-20 alkylene, wherein any one or more methylene groups in the main carbon chain skeleton of the linear or branched C1-20 alkylene are optionally replaced by one or more groups selected from: Ra, Rb, and any combination thereof; wherein each Ra is independently selected from the group consisting of O, C(O), OC(O), S, S(O), S(O)2, S(O)2N(Ra7), N(Ra7)S(O)2, C(O)N(Ra7), N(Ra7)C(O), N(Ra7), and N(Ra7)C(O)N(Ra7), where each Ra7 independently represents H or C1-3 alkyl, and when any two or more methylene in the main carbon chain skeleton of the linear or branched C1-20 alkylene are replaced by two or more Ra groups, the Ra groups are not directly connected to each other; and wherein each Rb is independently selected from the group consisting of: optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, alkynylene, alkenylene, and any combination thereof.

2. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 1, wherein the PBM represents a small molecule ligand binding to the following protein: epidermal growth factor receptor (EGFR), Cyclin-dependent kinase 4 / 6 (CDK4 / 6), breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) (BCR-ABL) tyrosine kinase, Androgen receptor (AR), orInterleukin-1 receptor-associated kinase 1 / 2 / 3 / 4 (IRAK1 / 2 / 3 / 4).

3. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 1, wherein said PBM comprises a structure selected from the following formula:wherein (R1a)p1a in Formula (PBM-1) indicates that the benzene ring to which it is attached is optionally substituted with p1a R1a groups, wherein each R1a is identical or different and each independently represents deuterium, halogen, hydroxy, NH2, NO2, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy;p1a represents an integer of 0, 1, 2, 3, 4, or 5;R1b represents a bond, or C1-2 alkylene optionally substituted with a substituent selected from the group consisting of C1-3 alkyl, deuterated C1-3 alkyl, halogenated C1-3 alkyl, and halogen;(R1c)p1b indicates that the quinazoline ring in Formula (PBM-1) is optionally substituted with p1b R1c groups, wherein each R1c is identical or different and each independently represents deuterium, halogen, NO2, cyano, halogenated C1-6 alkyl, C1-10 alkyl, deuterated C1-10 alkyl, C1-10 alkoxy, halogenated C1-10 alkoxy, -O-optionally substituted heterocyclyl, or -NHC(O)R1e, where R1e represents C1-10 alkyl, deuterated C1-10 alkyl, or C2-10 alkenyl, for example, R1c representsmethyl, methoxy,        , or ^'o     , such as        ;p1b represents an integer of 1, 2, or 3;R1d represents hydrogen, deuterium, or C1-3 alkyl;R2a in Formula (PBM-2) represents -NHC(O)- or -C(O)NH-;R2b represents -NH-, -N(C1-6 alkyl)-, or ethynylene;ring A in Formula (PBM-2) represents a 5- to 20-membered monocyclic, bicyclic, or polycyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, and (R2c)p2a indicates that the ring A is optionally substituted with p2a R2c, wherein each R2c is identical or different and each independently represents optionally substituted 5- to 15-membered heteroaryl,deuterium, halogen, hydroxy, cyano, amino, NO2, C1-6 alkyl, halogenated C1-6 alkyl, deuteratedC1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy;p2a represents an integer of 0, 1, 2, or 3;each (R2d)p2b in Formula (PBM-2) independently indicates that the benzene ring to which it is attached is independently optionally substituted with p2b R2d, wherein each R2d is identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, NO2, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 alkyl, deuterated C1-6 alkyl or halogenated C1-6 alkyl;each p2b is identical or different and each independently represents an integer of 0, 1, 2, 3,or 4;each (R3a)p3a in Formula (PBM-3) independently indicates that the benzene ring to which it is attached is independently optionally substituted with p3a R3a, wherein each R3a is identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, NO2, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;p3a represents an integer of 1, 2, 3, 4, or 5;R3b represents halogen, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;Xi in Formula (PBM-4) represents CR4e or a fragment R4e ##, wherein symbol # indicatesthe point of attachment to N atom adjacent to X1, symbol ## indicates the point of attachment to X2, and each R4e independently represents deuterium, hydrogen, halogen, Ci-6 alkyl, deuterated Ci-6 alkyl, halogenated Ci-6 alkyl, -C(O)-Ci-6 alkyl, -C(O)-deuterated Ci-6 alkyl, or -C(O)NR4fR4g, where R4f and R4g are identical or different and each independently represents hydrogen, Ci-6 alkyl, or deuterated Ci-6 alkyl, and R4f and R4g are not both hydrogen at the same time;X2 in Formula (PBM-4) represents N or CR4h, wherein R4h represents hydrogen, deuterium,halogen, Ci-6 alkyl, deuterated Ci-6 alkyl, or halogenated Ci-6 alkyl;X3 and X4 each independently represent CH or N;R4a represents a bond, or optionally substituted heteroarylene (e.g., heteroarylene substituted with halogen or deuterium);R4b represents hydrogen, Ci-6 alkyl, halogenated Ci-6 alkyl, deuterated Ci-6 alkyl, or optionally substituted C3-i2 cycloalkyl;(R4c)p4a in Formula (PBM-4) indicates that the pyridine ring to which it is attached is optionally substituted with p4a R4c, wherein each R4c is identical or different and each independently represents deuterium, halogen, Ci-6 alkyl, deuterated Ci-6 alkyl, halogenated Ci-6 alkyl, Ci-6 alkoxy, or halogenated Ci-6 alkoxy, and p4a represents an integer of 0, i, 2, or 3;(R4d)p4b in Formula (PBM-4) indicates that the nitrogen-containing bicyclic heteroaryl ringto which it is attached is optionally substituted with p4b R4d, wherein each R4d is identical or different and each independently represents deuterium, halogen, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy, and p4b represents an integer of 0 or 1;ring B in Formula (PBM-5) represents a 5- to 20-membered monocyclic, bicyclic, or polycyclic heteroarylene group containing 1 to 4 heteroatoms selected from N, O, and S;R5b represents optionally substituted 5- to 15-membered heteroaryl, optionally substituted 5-to 15-membered heterocyclyl, deuterium, halogen, hydroxy, cyano, amino, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy;R5a represents hydrogen, halogen, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy;Rx1 in Formula (PBM-6) represents a bond or C(O), or Rx1 represents -C(O)NH-Rx2-C(O)-***, wherein symbol *** indicates the point of attachment to Rc, and Rx2 represents optionally substituted C3-15 cycloalkyl;(R6a)p6a indicates that the 1H-pyrrolo[2,3-b]pyridine ring to which it is attached is optionally substituted with p6a R6a, wherein each R6a independently represents cyano, halogen, hydroxy, amino, nitro, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy, and p6a represents an integer of 0, 1, 2, 3, 4, or 5;(R6b)p6b indicates that the pyridine ring to which it is attached is optionally substituted with p6b R6b, wherein each R6b independently represents cyano, halogen, hydroxy, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy, or NR6cR6d, where R6c and R6d are identical or different and each independently represents hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, optionally substituted C3-15 cycloalkyl, or optionally substituted 4- to 15-membered heterocyclyl, and p6b represents an integer of 0, 1, 2, or 3;ring C in Formula (PBM-7) represents C6-10 aryl or a 5- to 20-membered heteroaryl (e.g., a 5- to 20-membered heteroaryl comprising one or two 5- to 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S), wherein said ring C is optionally substituted with one or more R7a, and each R7a is identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, nitro, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, or C2-6 alkynyl;ring D in Formula (PBM-7) represents C3-15 cycloalkyl or 4- to 20-membered heterocyclyl (e.g., a 4- to 20-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S), wherein said ring D is optionally substituted with one or more R7b, and each R7b is identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, nitro,C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy;ring E in Formula (PBM-7) represents a 5- to 20-membered heteroaryl (e.g., a 5- to 20-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S), wherein said ring E is optionally substituted with one or more R7c, and each R7c is identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, nitro, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, or halogenatedC1-6 alkoxy;R8a in Formula (PBM-8) represents N or CH;R8b represents NHC(O), C(O)NH, NHS(O)2, or S(O)2NH;(R8c)p8a indicates that the 6-membered ring containing R8a to which it is attached is substituted with p8a R8c, wherein each R8c is identical or different and each independentlyrepresents halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl,deuterated C1-6 alkyl, C1-6 alkoxy, or halogenated C1-6 alkoxy, and p8a represents an integer of 0, 1, 2, 3, or 4;ring F represents 5- to 15-membered heteroarylene, and (R8d)p8b indicates that the ring F to which it is attached is optionally substituted with p8b R8d, and each R8d is identical or different and each independently represents halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, or optionally substituted C3-15 cycloalkyl, and p8b represents an integer of 0, 1, 2, or 3; andRc in each general formula independently represents a bond, -O-, -N(Rd)-, -NHC(O)-*, -C(O)NH-*, -N(Rd)-Rf-N(Re)-*, -Rf-C(O)NH-*, -Rf-NHC(O)-*, -Rf-C(O)O-*, -Rf-OC(O)-*, -oH C(O)O-*,   -OC(O)-*,   -Rf-,   -Rf-N(Rd)-*,   -O-Rf-N(Rd)-*,nitrogen-containing heterocyclylene, cycloalkylene, arylene, or heteroarylene, t1 represents an integer of 0, 1, or 2, and (Rc1)m1 indicates that each ring W1 is independently optionally substituted with m1 Rc1 groups, wherein each Rc1 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or Rc4-Rc3-, wherein Rc3 represents optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, Rc4 represents halogen, Rc5Rc6N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc5 and Rc6 are identical or different and each independently represents hydrogen or C1-3 alkyl, and m1 represents an integer of 0-20;each ring W2 is identical or different and each independently represents nitrogencontaining heterocyclylene, cycloalkylene, arylene, or heteroarylene, t2 represents an integer of 0 or 1, and (Rc2)m2 indicates that each ring W2 is independently optionally substituted with m2 Rc2 groups, wherein each Rc2 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or Rc8-Rc7-, wherein Rc7 represents optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, Rc8 represents halogen, Rc9Rc10N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc9 and Rc10 are identical or different and each independently represents hydrogen or C1-3 alkyl, and m2 represents an integer of 0-20; andRd and Re each independently represent hydrogen or C1-6 alkyl; Rf and Rg each independently represent optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene; and symbol * indicates the point of attachment to LIN.

4. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 3, wherein the PBM represents a structure of the following formula:(PBM-2-1)                           (PBM-3-1)                          (PBM-4-1)                       (PBM-4-2)(PBM-5-1)(PBM-5-2)(PBM-5-3)(PBM-5-4)(PBM-8-1)                   (PBM-8-2)                    (PBM-8-3)                    (PBM-8-4)                     (PBM-8-5)(PBM-8-6)(PBM-8-7)(PBM-8-8)(PBM-8-9)(PBM-8-10)wherein Rc is as defined in claim 3.

5. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 3, whereineach Rc independently represents a bond, -O-, -NHC(O)-*, -C(O)NH-*, -C(O)O-*, -OC(O)-*, or -NH-, oreach Rc independently represents a structure of the following formula:-N(Rd)-, -N(Rd)-Rf-N(Re)-*, - Rf-,   -Rf-N(Rd)-*,   -O-Rf-N(Rd) H                           s -Z / N—TV W2 yrR W1    *          yt (RC2)m2 (RCl)m1 , Rf-C(O)NH-*, -Rf-NHC(O)-*, -Rf-C(O)O-*, -Rf-OC(O)-*, - I                     H / 'N^Rr# w24r+( w1^4-^*     '^N'RfK w277 \kw17T^* H       ^~T t2 ^~T t1               o             t2        t1 . *,                   (Rc2)m2 (RCl)m1        ,                  (RC2)m2 (Rc1)m1        , ° / A~A\                     o                 i )1—H- w2 Tt-H; w1 *           -V 'RfTV w2     w1 7p- * H      T 12       t1                            t27^F t1 (RG2)m2 (RCl)m1                                  (RC2)m2 (RCl)m1 ,                                                                                                  , *w1w2Nw2w2'T 12 (RC2)m2T t2 (RC2)m2'Y 11 (RCl)m1RdNRd7T t2 (RC2)m2w1 77s* "y ii (RCl)m1,NRd7w2 fr'T 12 (RC2)m2W1 #" 711 (RCl)m1w1w2(RC / ml(RC2)m2,ZRfW1 / 1'-f 11 (RCl)m1w1w2(RCl)m1(RC2)m2N \Re(RC Jm1(RC2)m2Rdw1(RC1)m1Rfw2t2(RC2)m2,,,V9 oww2(RCl)m1(RC2)m2(RC )m1(RC2)m2,w2(R / m1(RC2)m2w1w2(RC2)m2(RCl)m1 ■ ;, wherein each ring W1, oris identical or different and each independently represents 4- to20-membered nitrogen-containing heterocyclylene, C3-20 cycloalkylene, C5-20 arylene, or 5-to 20-membered heteroarylene, t1 represents an integer of 0, 1, or 2, and (Rc1)m1 indicates that each ring W1 is independently optionally substituted with m1 Rc1 groups, wherein each Rc1 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or Rc4-Rc3-, wherein Rc3 represents optionally substituted C1-6 alkylene or optionally substituted C2-6alkenylene, Rc4 represents halogen, Rc5Rc6N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc5 and Rc6 are identical or different and each independently represents hydrogen or C1-3 alkyl, and m1 represents an integer of 0-20;each ring W2 is identical or different and each independently represents 4- to 20membered nitrogen-containing heterocyclylene, C3-20 cycloalkylene, C5-20 arylene, or 5- to 20-membered heteroarylene, t2 represents an integer of 0 or 1, and (Rc2)m2 indicates that each ring W2 is independently optionally substituted with m2 Rc2 groups, wherein each Rc2 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or Rc8-Rc7-, wherein Rc7 represents optionally substituted C1-6 alkylene, or optionally substituted C2-6 alkenylene, Rc8 represents halogen, Rc9Rc10N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc9 and Rc10 are identical or different and each independently represents hydrogen or C1-3 alkyl, and m2 represents an integer of 0-20; andRd and Re each independently represent hydrogen or C1-6 alkyl; Rf and Rg each independently represent optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene;the C1-6 alkylene and C2-6 alkenylene are each independently optionally substituted with one or more substituents optionally selected from the group consisting of: deuterium, halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, and halogenated C1-6 alkoxy; andsymbol * indicates the point of attachment to LIN.

6. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 3-5, wherein each ring W1 is identical or different and each independently represents 4- to 15-membered nitrogen-containing heterocyclylene, C3-15 cycloalkylene, 6- to 15-membered arylene, or 5- to 15-membered heteroarylene, such aspiperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene,      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, 3-azaspiro[5.5]undecanylene, 8-azaspiro[4.5]decanylene, 2-oxo-8-azaspiro[4.5]decanylene, 3-methyl-2-oxo-8-azaspiro[4.5]decanylene, cyclopropylene,cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene,     2,3-dihydro-1H-indenylene,     spiro-cycloalkylene,     adamantanylene,noradamantanylene, norbornylene, phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene,     pyrazinylene,     indolylene,     isoindolylene,     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, 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, or imidazo[2,1-b]thiazolylene, orwherein each ring W1 is independently optionally substituted with m1 Rc1 groups, wherein each Rc1 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or Rc4-Rc3-, wherein Rc3 represents optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, Rc4 represents halogen, Rc5Rc6N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc5 and Rc6 are identical or different and each independentlyrepresents hydrogen or C1-3 alkyl, and said C1-6 alkylene and C2-6 alkenylene are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, and halogenated C1-6 alkoxy, and m1 represents an integer of 0-20; and / oreach ring W2 is identical or different and each independently represents 4- to 15-membered nitrogen-containing heterocyclylene, C3-15 cycloalkylene, 6- to 15-membered arylene, or 5- to 15-membered heteroarylene, such as,piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene,      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, 3-azaspiro[5.5]undecanylene, 8-azaspiro[4.5]decanylene, 2-oxo-8-azaspiro[4.5]decanylene, 3-methyl-2-oxo-8-azaspiro[4.5]decanylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene,     2,3-dihydro-1H-indenylene,     spiro-cycloalkylene,     adamantanylene,noradamantanylene, norbornylene, phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene,     pyrazinylene,     indolylene,     isoindolylene,     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, 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, or imidazo[2,1-b]thiazolylene, orwherein each ring W2 is independently optionally substituted with m2 Rc2 groups, wherein each Rc2 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or Rc8-Rc7-, wherein Rc7 represents optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, and Rc8 represents halogen, Rc9Rc10N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc9 and Rc10 are identical or different and each independently represents hydrogen or C1-3 alkyl, and the C1-6 alkylene and C2-6 alkenylene are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, and halogenated C1-6 alkoxy, and m2 represents an integer of 0-20.

7. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 3-5, whereinthe        12     t1 moiety of Rc in each general formula represents the following groups:i-^zzy^zz^ ^ziz^zz1^wherein the groups are each independently optionally substituted with one or more 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, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, Rc12-Rc11, and any combination thereof, wherein Rc11 represents optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, Rc12 represents halogen, Rc13Rc14N-, hydroxy, carboxyl, ethynyl, or vinyl, wherein Rc13 and Rc14 are identical or different and each independently represents hydrogen or C1-3 alkyl, and the C1-6 alkylene and C2-6 alkenylene are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, and halogenated C1-6 alkoxy.

8. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 3-5, wherein the Rc represents the following groups:a bond, -O-, -NHC(O)-*, -C(O)NH-*, -C(O)O-*, -OC(O)-*, -CH2C(O)O-*, -CH2OC(O)-*, -NH-, -N(CH3)-, -NH-CH2-*, -N(CH3)-CH2-*, -N(CH3)-(CH2)2-N(CH3)-*, -N(CH3)-(CH2)3-N(CH3)-*, -NH-(CH2)2-N(CH3)-*, -N(CH3)-(CH2)3-NH-*, -CH2-NHC(O)-*, -CH2-C(O)NH-*, -CH2-NH-*, -O-(CH2)2-N(CH3)-*, -O-(CH2)2-NH-*, or -CH2-N(CH3)-*, or.^+                          1-€H- 1-€H- AnCtvtN(>-NXNH            ^n^_^n|-. K^n-<J)4-.4-£yN>hDwherein the groups are each independently optionally substituted with one or more 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, deuterated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, Rc12-Rc11-, and any combination thereof, wherein Rc11 represents optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, Rc12 represents halogen, Rc13Rc14N-, hydroxy, carboxyl,ethynyl, or vinyl, wherein Rc13 and Rc14 are identical or different and each independently represents hydrogen or C1-3 alkyl, and the C1-6 alkylene and C2-6 alkenylene are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, mercapto, cyano, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, and halogenated C1-6 alkoxy; and symbol * indicates the point of attachment to LIN.

9. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-5, wherein the PBM represents a structure of the following Formula (PBM-1-1-1), Formula (PBM-1-1-2), Formula (PBM-2-1-1), Formula (PBM-3-1-1), Formula (PBM-4-1-1), Formula (PBM-4-2-1), Formula (PBM-5-2-1), Formula (PBM-5-4-1), Formula (PBM-6-4-1), Formula (PBM-7-1-1), Formula (PBM-7-4-1), Formula (PBM-8-12-1), Formula (PBM-8-12-2), or Formula (PBM-8-13-1):

10. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopicallyenriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-9, whereinthe ULM represents a structure of the following Formula (ULM-1-1), Formula (ULM-1-2), Formula (ULM-1-3), or Formula (ULM-1-4):(ULM-1-1)                    (ULM-1-2)                    (ULM-1-3)(ULM-1-4)wherein Z, Ra1, Ra2, Ra3, Ra4, (Ra5)m, and Ra6 are as defined in claim 1.

11. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopicallyenriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-9, whereinthe ULM represents a structure of the following Formula (ULM-2-1), Formula (ULM-2-2), Formula (ULM-2-3), or Formula (ULM-2-4):(ULM-2-1)                    (ULM-2-2)                     (ULM-2-3)(ULM-2-4)wherein Z, (Ra5)m, and Ra6 are as defined in claim 1.

12. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-11, whereinring Y1 represents 4- to 20-membered heterocyclylene containing at least two nitrogen atoms, and (Rd1)n1 indicates that ring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 0-20; orring Y2 represents C3-20 cycloalkylene, or 4- to 20-membered heterocyclylene containing at least one nitrogen atom, and (Rd2)n2 indicates that ring Y2 is optionally substituted with n2 Rd2 groups, wherein each Rd2 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n2 represents an integer of 0-20; orring Y3 represents 4- to 20-membered heterocyclylene containing one nitrogen atom, and (Rd3)n3 indicates that ring Y3 is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n3 represents an integer of 0-20.

13. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-12, wherein (i) ring Y1 represents 4- to 20-membered heterocyclylene containing 2 to 4 nitrogen atoms; e.g., ring Y1 represents:diazetidinylene, imidazolidylene, pyrazolidylene, piperazinylene, 1,2,3,4-tetrahydropyrazinylene,        hexahydropyrimidinylene,        hexahydropyridazinylene,diazacycloheptanylene,        diazacyclooctylene,        diazabicyclo[3.1.1]heptanylene,diazabicyclo[2.2.1]heptanylene,                              diazabicyclo[3.2.1]octanylene,diazabicyclo[2.2.2]octanylene,diazaspiro[2.4]heptanylene,diazaspiro[4.4]nonanylene,diazaspiro[2.3]hexylene, diazaspiro[3.4]octanylene, diazaspiro[4.5]decanylene,diazaspiro[3.3]heptanylene,diazaspiro[3.5]nonanylene,diazaspiro[5.5]undecanylene,octahydropyrrolo[3,4-c]pyrrolylene, or decahydronaphthyridinylene, orring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independentlyrepresents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl,deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy;n1 represents an integer of 0-20; or(ii) ring Y2 represents C3-20 cycloalkylene, or 4- to 20-membered heterocyclylene containing 1 to 4 nitrogen atoms; e.g., ring Y2 represents:cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, C5-15 spiro-cycloalkylene, C5-15 bridged cycloalkylene (e.g., adamantanylene, noradamantanylene, and norbornylene), azetidinylene, diazetidinylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, piperidinylene, tetrahydropyridylene, piperazinylene, 1,2,3,4-tetrahydropyrazinylene, hexahydropyrimidinylene, hexahydropyridazinylene, azepanylene, 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, azaspiro[3.3]heptanylene, azaspiro[3.5]nonanylene, azaspiro[5.5]undecanylene, diazaspiro[2.4]heptanylene, diazaspiro[4.4]nonanylene,diazabicyclo[2.2.2]octanylene, azaspiro[2.4]heptanylene, azaspiro[4.4]nonanylene, diazaspiro[2.3]hexylene, diazaspiro[3.4]octanylene,diazaspiro[4.5]decanylene,azaspiro[2.3]hexyleneazaspiro[3.4]octanyleneazaspiro[4.5]decanylenediazaspiro[3.3]heptanylenediazaspiro[3.5]nonanylenediazaspiro[5.5]undecanyleneoctahydrocyclopenta[c]pyrrolylene, decahydronaphthyridinylene, oroctahydropyrrolo[3,4-c]pyrrolylene,orring Y2 is optionally substituted with n2 Rd2 groups, wherein each Rd2 independentlyrepresents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy; andn2 represents an integer of 0-20; or(iii) ring Y3 represents 4- to 20-membered heterocyclylene containing one nitrogen atom; e.g., ring Y3 represents:azetidinylene, pyrrolidinylene, piperidinylene, tetrahydropyridylene, azepanylene,azacyclooctylene,azabicyclo[3.1.1]heptanylene,azabicyclo[2.2.1]heptanylene,azabicyclo[3.2.1]octanylene, azaspiro[3.3]heptanylene, azaspiro[3.5]nonanylene, azaspiro[5.5]undecanylene,azabicyclo[2.2.2]octanylene, azaspiro[2.4]heptanylene, azaspiro[4.4]nonanylene, octahydrocyclopenta[c]pyrrolylene,azaspiro[2.3]hexylene, azaspiro[3.4]octanylene, azaspiro[4.5]decanylene, or octahydropyrrolo[3,4-c]pyrrolylene, orthe ring Y3 is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy; andn3 represents an integer of 0-20.

14. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-13, wherein(i) each ring A1 is identical or different and each independently represents 4- to 20membered heterocyclylene, C3-20 cycloalkylene, C5-20 arylene, or 5- to 20-membered heteroarylene, e.g., each ring A1 independently represents:azetidinylene, diazetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene,pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene,tetrahydrothiopyranylene,      oxazolidinylene,      thiazolidinylene,      piperidinylene,tetrahydropyridylene,            piperazinylene,            1,2,3,4-tetrahydropyrazinylene,hexahydropyrimidinylene, hexahydropyridazinylene, morpholinylene, thiomorpholinylene, azacycloheptanylene, azacyclooctylene, dioxacyclohexylene, azepanylene, azacyclooctylene,diazacycloheptanylene, diazacyclooctylene, azabicyclo[3.1.1]heptanylene (e.g.,   6-azabicyclo[3.1.1]heptanylene), azabicyclo[2.2.1]heptanylene, azabicyclo[3.2.1]octanylene(e.g.,             3-azabicyclo[3.2.1]octanylene), azabicyclo[2.2.2]octanylene, diazabicyclo[3.1.1]heptanylene (e.g., 3,6-diazabicyclo[3.1.1]heptanylene), diazabicyclo[2.2.1]heptanylene (e.g., 2,5-diazabicyclo[2.2.1]heptanylene), diazabicyclo[3.2.1]octanylene (e.g., 3,8-diazabicyclo[3.2.1]octanylene),diazabicyclo[2.2.2]octanylene (e.g., 2,5-diazabicyclo[2.2.2]octanylene), 5- to 20-membered azaspirocycloalkylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, C5-15 spirocycloalkylene, adamantanylene, noradamantanylene, norbornylene, phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, 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, 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, or imidazo[2,1-b]thiazolylene, orDory1 represents an integer of 0, 1, 2, or 3, and (Ry1)a1 indicates that each ring A1 isindependently optionally substituted with a1 Ry1 groups, wherein each Ry1 independentlyrepresents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy,halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, orC2-6 alkenyl, and a1 represents an integer of 0-10; and / or(ii) each ring A2 is identical or different and each independently represents 4- to 20-membered heterocyclylene, C3-20 cycloalkylene, C5-20 arylene, or 5- to 20-membered heteroarylene; e.g., each ring A2 independently represents:azetidinylene, diazetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene,tetrahydrothiopyranylene,      oxazolidinylene,      thiazolidinylene,      piperidinylene,tetrahydropyridylene,            piperazinylene,1,2,3,4-tetrahydropyrazinylene,hexahydropyrimidinylene, hexahydropyridazinylene, morpholinylene, thiomorpholinylene, azepanylene, azacyclooctylene, dioxacyclohexylene, azepanylene, azacyclooctylene,diazacycloheptanylene, diazacyclooctylene, azabicyclo[3.1.1]heptanylene (e.g.,   6-azabicyclo[3.1.1]heptanylene), azabicyclo[2.2.1]heptanylene, azabicyclo[3.2.1]octanylene(e.g.,         3-         azabicyclo[3.2.1]octanylene),         azabicyclo[2.2.2]octanylene,diazabicyclo[3.1.1]heptanylene (e.g., 3,6-diazabicyclo[3.1.1]heptanylene), diazabicyclo[2.2.1]heptanylene (e.g., 2,5-diazabicyclo[2.2.1]heptanylene), diazabicyclo[3.2.1]octanylene (e.g., 3,8-diazabicyclo[3.2.1]octanylene),diazabicyclo[2.2.2]octanylene (e.g., 2,5-diazabicyclo[2.2.2]octanylene), 5- to 20-membered azaspirocycloalkylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, C5-15 spirocycloalkylene, adamantanylene, noradamantanylene, norbornylene, phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, 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, 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, or imidazo[2,1-b]thiazolylene, ory2 represents an integer of 0, 1, 2, or 3, and (Ry2)a2 indicates that each ring A2 is independently optionally substituted with a2 Ry2 groups, wherein each Ry2 independentlyrepresents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, or C2-6 alkenyl, and a2 represents an integer of 0-10; and / or(iii) each ring A3 is identical or different and each independently represents 4- to 20membered heterocyclylene, C3-20 cycloalkylene, C5-20 arylene, or 5- to 20-membered heteroarylene; e.g., each ring A3 independently represents:azetidinylene, pyrazolidylene,diazetidinylene, oxetanylene, pyrrolidinylene, imidazolidylene,tetrahydrofuranylene, tetrahydropyranylene,tetrahydrothiopyranylene, tetrahydropyridylene,oxazolidinylene, piperazinylene,thiazolidinylene,tetrahydrothienylene, piperidinylene,1,2,3,4-tetrahydropyrazinylene,hexahydropyrimidinylene, hexahydropyridazinylene, morpholinylene, thiomorpholinylene, azepanylene, azacyclooctylene, dioxacyclohexylene, azepanylene, azacyclooctylene, diazacycloheptanylene, diazacyclooctylene, azabicyclo[3.1.1]heptanylene (e.g.,   6-azabicyclo[3.1.1]heptanylene), azabicyclo[2.2.1]heptanylene, azabicyclo[3.2.1]octanylene(e.g.,3-azabicyclo[3.2.1]octanylene),diazabicyclo[3.1.1]heptanylenediazabicyclo[2.2.1]heptanylenediazabicyclo[3.2.1]octanylene(e.g., (e.g., (e.g.,azabicyclo[2.2.2]octanylene,3,6-diazabicyclo[3.1.1]heptanylene),2,5-diazabicyclo[2.2.1]heptanylene),3,8-diazabicyclo[3.2.1]octanylene),diazabicyclo[2.2.2]octanylene (e.g., 2,5-diazabicyclo[2.2.2]octanylene), 5- to 20-membered azaspirocycloalkylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, C5-15 spirocycloalkylene, adamantanylene, noradamantanylene, norbornylene, phenylene, naphthylene,furanylene, oxazolylene, isoxazolylene, oxadiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene,thienylene, thiazolylene, pyrazolylene, triazolylene, indolylene, isoindolylene,benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene,benzoxazolylene, benzotriazolylene,benzisoxazolylene,     benzothiazolylene,     benzisothiazolylene,benzo[2,1,3]oxadiazolylene,benzo[2,1,3]thiadiazolylene,benzo[1,2,3]thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, 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, or imidazo[2,1-b]thiazolylene, ory3 represents an integer of 0,1, 2, or 3, and (Ry3)a3 indicates that each ring A3 isindependently optionally substituted with a3Ry3 groups, wherein each Ry3 independentlyrepresents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy,halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, or C2-6 alkenyl, and a3 represents an integer of 0-10; and / or(iv) Rw1 represents a bond or an optionally substituted linear or branched C1-20 alkylene, wherein any one or more methylene groups in the main carbon chain skeleton of the linear or branched C1-20 alkylene are optionally replaced by one or more groups selected from: Ra, Rb, and any combination thereof; wherein each Ra is independently selected from the group consisting of: O, C(O), OC(O), S, S(O), S(O)2, S(O)2N(Ra7), N(Ra7)S(O)2, C(O)N(Ra7), N(Ra7)C(O), N(Ra7),and N(Ra7)C(O)N(Ra7), where each Ra7 independently represents H or C1-3 alkyl, and when any two or more methylene in the main carbon chain skeleton of the linear or branched C1-20 alkylene are replaced by two or more Ra groups, the Ra groups are not directly connected to each other; and wherein each Rb is independently selected from the group consisting of: optionally substituted cycloalkylene (e.g., optionally substituted C3-20 cycloalkylene), optionally substituted arylene (e.g., optionally substituted C5-20 arylene), optionally substituted heterocyclylene (e.g., optionally substituted 4- to 20-membered heterocyclylene), optionally substituted heteroarylene (e.g., optionally substituted 5- to 20-membered heteroarylene), alkynylene (e.g., C2-6 alkynylene), alkenylene (e.g., C2-6 alkenylene), and any combination thereof, wherein the cycloalkylene, arylene, heterocyclylene, and heteroarylene are each independently optionally substituted with a substituent selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and any combination thereof; and wherein one or more hydrogens of said linear or branched C1-20 alkylene are optionally replaced by a substituentselected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and any combination thereof.

15. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-14, wherein a3) / 4( a2a1 yG” y y3^       y2^ y1the (^y3)a3   (Ry2)a2 (Ry1)ai moiety in the general formula of LIN represents:■^GX'Clh                           -KG-CTH■KZKZX-v«^- -,W    -^ao hM>^cyC"h      -ck^■i-C^NE"'^ ’!a^XnEn4 -^aD^nEn+-s<xh-                -soa> e>o-i-OET* -0-0 -ChO> E3H> -s-G-^- -<y<ZHX>3H n>(G- <XG- X» «XG--hG-O -ivX"+ G<H G>"D-! -gg-wherein the 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, carboxyl, C2-6 alkynyl, and C2-6 alkenyl; and / orRw1 represents a bond, orRw1 represents:-C1-15 alkylene-;-(C(Ra8)(Ra9))n4-(Ra(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(Ra(C(Ra10)(Ra11))n5)m3-(Ra(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-(Ra(C(Ra10)(Ra11))n5)m3-(Ra(C(Ra12)(Ra13))n6)m4-(Ra(C(Ra14)(Ra15))n7)m5-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Ra)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Ra)m3-((C(Ra12)(Ra13))n6Ra)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Ra)m3-((C(Ra12)(Ra13))n6Ra)m4-((C(Ra14)(Ra15))n7Ra)m5-;-(C(Ra8)(Ra9))n4-(Rb(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(Rb(C(Ra10)(Ra11))n5)m3-(Rb(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-(Rb(C(Ra10)(Ra11))n5)m3-(Rb(C(Ra12)(Ra13))n6)m4-(Rb(C(Ra14)(Ra15))n7)m5-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Rb)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Rb)m3-((C(Ra12)(Ra13))n6Rb)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Rb)m3-((C(Ra12)(Ra13))n6Rb)m4-((C(Ra14)(Ra15))n7Rb)m5-;-(C(Ra8)(Ra9))n4-(Ra-Rb-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(Ra(C(Ra10)(Ra11))n5)m3-(Rb(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-(Rb-Ra-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(Rb(C(Ra10)(Ra11))n5)m3-(Ra(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-Ra-Rb)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Ra)m3-((C(Ra12)(Ra13))n6Rb)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-Rb-Ra)m3-; or-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5Rb)m3-((C(Ra12)(Ra13))n6Ra)m4-;wherein each Ra is independently selected from the group consisting of O, C(O), OC(O), S, S(O), S(O)2, S(O)2N(Ra7), N(Ra7)S(O)2, C(O)N(Ra7), N(Ra7)C(O), N(Ra7), and N(Ra7)C(O)N(Ra7), where each Ra7 independently represents H or C1-3 alkyl; and each Rb is independently selected from the group consisting of optionally substituted cycloalkylene (e.g., optionally substituted C3-20 cycloalkylene), optionally substituted arylene (e.g., optionally substituted C5-20 arylene), optionally substituted heterocyclylene (e.g., optionally substituted 4- to 20-membered heterocyclylene), optionally substituted heteroarylene (e.g., 5- to 20-membered heteroarylene), alkynylene (e.g., C2-6 alkynylene), alkenylene (e.g., C2-6 alkenylene), and any combination thereof, wherein the cycloalkylene, arylene, heterocyclylene, and heteroarylene are each independently optionally substituted with a substituent selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and anycombination thereof;Ra8, Ra9, Ra10, Ra11, Ra12, Ra13, Ra14, and Ra15 each independently represent H, deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and any combination thereof; andn4, n5, n6, n7, m3, m4, and m5 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; andany one or more hydrogens in the main carbon chain skeleton of said C1-15 alkylene are optionally replaced by a substituent selected from the group consisting of: deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and any combination thereof.

16. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-15, wherein the Rw1 represents a structure of the following formula:-(C(Ra8)(Ra9))n4-(O(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(O(C(Ra10)(Ra11))n5)m3-(O(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-(O(C(Ra10)(Ra11))n5)m3-(O(C(Ra12)(Ra13))n6)m4- (O(C(Ra14)(Ra15))n7)m5-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5O)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5O)m3-((C(Ra12)(Ra13))n6O)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5O)m3-((C(Ra12)(Ra13))n6O)m4- ((C(Ra14)(Ra15))n7O)m5-;-(C(Ra8)(Ra9))n4-(N(Ra7)(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(N(Ra7)(C(Ra10)(Ra11))n5)m3-(N(Ra7)(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-(N(Ra7)(C(Ra10)(Ra11))n5)m3-(N(Ra7)(C(Ra12)(Ra13))n6)m4-(N(Ra7)(C(Ra14)(Ra15))n7)m5-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5N(Ra7))m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5N(Ra7))m3-((C(Ra12)(Ra13))n6N(Ra7))m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5N(Ra7))m3-((C(Ra12)(Ra13))n6N(Ra7))m4-((C(Ra14)(Ra15))n7N(Ra7))m5-;-(C(Ra8)(Ra9))n4-(C(O)N(Ra7)-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(C(O)N(Ra7)-(C(Ra10)(Ra11))n5)m3-(C(O)N(Ra7)-(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-(C(O)N(Ra7)-(C(Ra10)(Ra11))n5)m3-(C(O)N(Ra7)-(C(Ra12)(Ra13))n6)m4-(C(O)N(Ra7)-(C(Ra14)(Ra15))n7)m5-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-C(O)N(Ra7))m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-C(O)N(Ra7))m3-((C(Ra12)(Ra13))n6-C(O)N(Ra7))m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-C(O)N(Ra7))m3-((C(Ra12)(Ra13))n6-C(O)N(Ra7))m4-((C(Ra14)(Ra15))n7-C(O)N(Ra7))m5-;-(C(Ra8)(Ra9))n4-(C(O)N(Ra7)-(C(Ra10)(Ra11))n5)m3-(O-(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-C(O)N(Ra7)-(C(Ra10)(Ra11))n5-(O(C(Ra12)(Ra13))n6)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-C(O)N(Ra7))m3-( (C(Ra12)(Ra13))n6O)m4-;-(C(Ra8)(Ra9))n4-(C(Ra10)(Ra11))n5-C(O)N(Ra7)-((C(Ra12)(Ra13))n6O)m3-;-(C(Ra8)(Ra9))n4-(N(Ra7)C(O)-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(N(Ra7)C(O)-(C(Ra10)(Ra11))n5)m3-(O-(C(Ra12)(Ra13)))n6)m4-;-(C(Ra8)(Ra9))n4-(N(Ra7)C(O)-(C(Ra10)(Ra11))n5)m3-(O-(C(Ra12)(Ra13))n6)m4-(O-(C(Ra14)(Ra15))n7)m5-;-(C(Ra8)(Ra9))n4-N(Ra7)C(O)-(C(Ra10)(Ra11))n5-(O(C(Ra12)(Ra13))n6)m3-;-(C(Ra8)(Ra9))n4-N(Ra7)C(O)N(Ra7)-(C(Ra10)(Ra11))n5-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-N(Ra7)C(O))m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-N(Ra7)C(O))m3-((C(Ra12)(Ra13)))n6-O)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-N(Ra7)C(O))m3-((C(Ra12)(Ra13))n6O)m4-((C(Ra14)(Ra15))n7O)m5-;-(C(Ra8)(Ra9))n4- (C(Ra10)(Ra11))n5-N(Ra7)C(O)-((C(Ra12)(Ra13))n6O)m3-;-(C(Ra8)(Ra9))n4-( arylene-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-( arylene-(C(Ra10)(Ra11))n5)m3- arylene-(C(Ra12)(Ra13))n6-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5- arylene)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5- arylene)m3-(C(Ra12)(Ra13))n6- arylene-;-(C(Ra8)(Ra9))n4-(heterocyclylene-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(heterocyclylene-(C(Ra10)(Ra11))n5)m3-(heterocyclylene-(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-heterocyclylene)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-heterocyclylene)m3-((C(Ra12)(Ra13))n6-heterocyclylene)m4-;-(C(Ra8)(Ra9))n4-(heteroarylene-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(heteroarylene-(C(Ra10)(Ra11))n5)m3-(heteroarylene-(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-heteroarylene)m3-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-heteroarylene)m3-((C(Ra12)(Ra13))n6-heteroarylene)m4-;-(C(Ra8)(Ra9))n4-(cycloalkylene-(C(Ra10)(Ra11))n5)m3-;-(C(Ra8)(Ra9))n4-(cycloalkylene-(C(Ra10)(Ra11))n5)m3-(cycloalkylene-(C(Ra12)(Ra13))n6)m4-;-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-cycloalkylene)m3-; or-(C(Ra8)(Ra9))n4-((C(Ra10)(Ra11))n5-cycloalkylene)m3-((C(Ra12)(Ra13))n6-cycloalkylene)m4-;wherein each Ra7 independently represents H or C1-3 alkyl;the cycloalkylene (e.g., C3-20 cycloalkylene), arylene (e.g., C5-20 arylene), heterocyclylene(e.g., 4- to 20-membered heterocyclylene), and heteroarylene (e.g., 5- to 20-memberedheteroarylene) are each independently optionally substituted with a substituent selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and any combination thereof;Ra8, Ra9, Ra10, Ra11, Ra12, Ra13, Ra14, and Ra15 each independently represent H, deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, or any combination thereof; andn4, n5, n6, n7, m3, m4, and m5 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

17. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-16, wherein Rw1 represents:-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2)10-, -(CH2)11-, -(CH2)12-, -(CH2)13-, -(CH2)14-, -(CH2)15-; -O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)7-, -O-(CH2)8-, -O-(CH2)9-, -O-(CH2)10-, -(CH2)1-O-, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)7-O-, -(CH2)8-O-, -(CH2)9-O-, -(CH2)10-O-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -(CH2)1-O-(CH2)3-, -(CH2)1-O-(CH2)4-, -(CH2)1-O-(CH2)5-, -(CH2)1-O-(CH2)6-, -(CH2)1-O-(CH2)7-, -(CH2)1-O-(CH2)8-, -(CH2)1-O-(CH2)9-, -(CH2)1-O-(CH2)10-, -(CH2)2-O-(CH2)1-,  -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-,  -(CH2)2-O-(CH2)5-,  -(CH2)2-O-(CH2)6-,  -(CH2)2-O-(CH2)7-,  -(CH2)2-O-(CH2)8-, -(CH2)2-O-(CH2)9-, -(CH2)2-O-(CH2)10-,  -(CH2)3-O-(CH2)1-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-,  -(CH2)3-O-(CH2)4-,  -(CH2)3-O-(CH2)5-,  -(CH2)3-O-(CH2)6-,  -(CH2)3-O-(CH2)7-, -(CH2)4-O-(CH2)1-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-, -(CH2)4-O-(CH2)5-, -(CH2)4-O-(CH2)6-, -(CH2)5-O-(CH2)1-, -(CH2)5-O-(CH2)2-, -(CH2)5-O-(CH2)3-, -(CH2)5-O-(CH2)4-, -(CH2)5-O-(CH2)5-, -(CH2)6-O-(CH2)1-, -(CH2)6-O-(CH2)2-, -(CH2)6-O-(CH2)3-, -(CH2)6-O-(CH2)4-, -(CH2)7-O-(CH2)1-, -(CH2)7-O-(CH2)2-, -(CH2)7-O-(CH2)3-, -(CH2)8-O-(CH2)1-, -(CH2)8-O-(CH2)2-,  -CH(CH3)-O-(CH2)1-,  -CH(CH3)-O-(CH2)2-,  -CH(CH3)-O-(CH2)3-, -CH(CH3)-O-(CH2)4-,  -CH(CH3)-O-(CH2)5-,  -CH(CH3)-O-(CH2)6-,  -CH(CH3)-O-(CH2)7-, -CH(CH3)-O-(CH2)8-, -CH(CH3)-O-(CH2)9-, -CH(CH3)-O-(CH2)10-, -(O(CH2)2)2-, -(O(CH2)2)3-, -(O(CH2)2)4-, -(O(CH2)2)5-, -(O(CH2)2)6-, -(O(CH2)2)7-, -CH2-(O(CH2)2)2-, -CH2-(O(CH2)2)3-, -CH2-(O(CH2)2)4-, -CH2-(O(CH2)2)5-, -CH2-(O(CH2)2)6-, -CH2-(O(CH2)2)7-, -CH2-(O(CH2)2)1-OCH2-, -CH2-(O(CH2)2)2-OCH2-, -CH2-(O(CH2)2)3-OCH2-, -CH2-(O(CH2)2)4-OCH2-,-CH2-(O(CH2)2)5-OCH2-, -(CH2)2-(O(CH2)2)2-, -(CH2)2-(O(CH2)2)3-, -(CH2)2-(O(CH2)2)4-,  -(CH2)2-(O(CH2)2)5-, -(CH2)2-(O(CH2)2)6-, -(CH2)3-(O(CH2)2)2-, -(CH2)3-(O(CH2)2)3-, -(CH2)3-(O(CH2)2)4-,   -(CH2)3-(O(CH2)2)5-, -(CH2)4-(O(CH2)2)2-,   -(CH2)4-(O(CH2)2)3-,   -(CH2)4-(O(CH2)2)4-, -(CH2)4-(O(CH2)2)5-, -CH2-(O(CH2)3)2-, -CH2-(O(CH2)3)3-, -CH2-(O(CH2)3)4-, -(CH2)2-(O(CH2)3)2-, -(CH2)2-(O(CH2)3)3-, -(CH2)2-(O(CH2)3)4-, -(CH2)3-(O(CH2)3)2-, -(CH2)3-(O(CH2)3)3-, -(CH2)3-(O(CH2)3)4-, -CH2-O-(CH2)2-O-(CH2)3-, -CH2-(O(CH2)2)2-(O(CH2)3)2-, (CH2)2-O-(CH2)2-O-(CH2)3-, -(CH2)2-(O(CH2)2)2-(O(CH2)3)2-, -(CH2)3-O-(CH2)2-O-(CH2)3-, -(CH2)3-(O(CH2)2)2-(O(CH2)3)2-, -CH2-O-(CH2)3-O-(CH2)2-, -CH2-(O(CH2)3)2-(O(CH2)2)2-, -(CH2)2-O-(CH2)3-O-(CH2)2-, -(CH2)2-(O(CH2)3)2-(O(CH2)2)2-, -(CH2)3-O-(CH2)3-O-(CH2)2-, -(CH2)3-(O(CH2)3)2-(O(CH2)2)2-, -CH2-O-(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-O-CH2-, -(CH2)2-(O(CH2)2)2-O-(CH2)3-, -(CH2)2-(O(CH2)2)3-O-(CH2)3-, -(CH2)2-(O(CH2)2)4-O-(CH2)3-, -(CH2)5-(O(CH2)2)2-O-(CH2)5-, -(CH2)5-(O(CH2)2)2-O-(CH2)6-, -(CH2)1-N(Ra7)-(CH2)1-, -(CH2)1-N(Ra7)-(CH2)2-, -(CH2)1-N(Ra7)-(CH2)3-, -(CH2)1-N(Ra7)-(CH2)4-, -(CH2)1-N(Ra7)-(CH2)5-, -(CH2)1-N(Ra7)-(CH2)6-, -(CH2)1-N(Ra7)-(CH2)7-, -(CH2)1-N(Ra7)-(CH2)8-, -(CH2)1-N(Ra7)-(CH2)9-,  -(CH2)1-N(Ra7)-(CH2)10-, -N(Ra7)-(CH2)1-, -N(Ra7)-(CH2)2-, -N(Ra7)-(CH2)3-, -N(Ra7)-(CH2)4-, -N(Ra7)-(CH2)5-, -N(Ra7)-(CH2)6-, -N(Ra7)-(CH2)7-, -N(Ra7)-(CH2)8-, -N(Ra7)-(CH2)9-, -N(Ra7)-(CH2)10-, -(CH2)2-N(Ra7)-(CH2)1-, -(CH2)2-N(Ra7)-(CH2)2-, -(CH2)2-N(Ra7)-(CH2)3-, -(CH2)2-N(Ra7)-(CH2)4-, -(CH2)2-N(Ra7)-(CH2)5-, -(CH2)2-N(Ra7)-(CH2)6-, -(CH2)2-N(Ra7)-(CH2)7-,  -(CH2)2-N(Ra7)-(CH2)8-, -(CH2)2-N(Ra7)-(CH2)9-, -(CH2)2-N(Ra7)-(CH2)10-, -(CH2)3-N(Ra7)-(CH2)1-, -(CH2)3-N(Ra7)-(CH2)2-, -(CH2)3-N(Ra7)-(CH2)3-, -(CH2)4-N(Ra7)-(CH2)1-, -(CH2)4-N(Ra7)-(CH2)2-, -(CH2)4-N(Ra7)-(CH2)3-, -(CH2)4-N(Ra7)-(CH2)4-, -(CH2)5-N(Ra7)-(CH2)1-,  -(CH2)5-N(Ra7)-(CH2)2-, -(CH2)5-N(Ra7)-(CH2)3-, -(CH2)5-N(Ra7)-(CH2)4-, -(CH2)5-N(Ra7)-(CH2)5-, -(CH2)6-N(Ra7)-(CH2)1-, -(CH2)6-N(Ra7)-(CH2)2-, -(CH2)6-N(Ra7)-(CH2)3-, -(CH2)7-N(Ra7)-(CH2)1-, -(CH2)7-N(Ra7)-(CH2)2-, -(CH2)7-N(Ra7)-(CH2)3-, -(CH2)8-N(Ra7)-(CH2)1-,  -(CH2)8-N(Ra7)-(CH2)2-, -(CH2)8-N(Ra7)-(CH2)3-, -CH(CH3)-N(Ra7)-(CH2)1-, -CH(CH3)-N(Ra7)-(CH2)2-, -CH(CH3)-N(Ra7)-(CH2)3-, -CH(CH3)-N(Ra7)-(CH2)4-, -CH(CH3)-N(Ra7)-(CH2)5-, -CH(CH3)-N(Ra7)-(CH2)6-, -CH(CH3)-N(Ra7)-(CH2)7-, -CH(CH3)-N(Ra7)-(CH2)8-, -CH(CH3)-N(Ra7)-(CH2)9-, -CH(CH3)-N(Ra7)-(CH2)10-, -C(O)NHCH2-, -C(O)NH(CH2)2-, -C(O)NH(CH2)3-, -C(O)NH(CH2)4-,   -C(O)NH(CH2)5-,   -CH2C(O)NHCH2-,   -(CH2)2C(O)NH(CH2)2-,   -(CH2)2C(O)NH(CH2)3-,       -(CH2)2C(O)NH(CH2)4-,       -(CH2)2C(O)NH(CH2)5-,       -(CH2)3C(O)NH(CH2)3-,       -(CH2)3C(O)NH(CH2)4-,       -(CH2)4C(O)NH(CH2)4-,       -(CH2)5C(O)NH(CH2)5-,       -(CH2)6C(O)NH(CH2)7-,       -(CH2)6C(O)NH(CH2)6-,       -(CH2)7C(O)NH(CH2)7-, -(CH2)2C(O)NH(CH2)2-O-(CH2)2-, -NHC(O)CH2-, -NHC(O)(CH2)2-, -NHC(O)(CH2)3-,     -NHC(O)(CH2)4-,     -NHC(O)(CH2)5-,     -CH2NHC(O)CH2-,     -(CH2)2NHC(O)(CH2)2-,       -(CH2)2NHC(O)(CH2)3-,       -(CH2)2NHC(O)(CH2)4-,       -(CH2)2NHC(O)(CH2)5-,(CH2)4NHC(O)(CH2)4-,(CH2)6NHC(O)(CH2)6-,-(CH2)3NHC(O)(CH2)3-,-(CH2)5NHC(O)(CH2)5-,-(CH2)7NHC(O)(CH2)7-,-(CH2)3NHC(O)(CH2)4-(CH2)6NHC(O)(CH2)7-(CH2)4NHC(O)(CH2)8(CH2)2NHC(O)(CH2)2-O-(CH2)2-, -(CH2)4NHC(O)CH2-, -phenylene-CH2-, -phenylene-(CH2)2-, -phenylene-(CH2)3-, -phenylene-(CH2)4-, -phenylene-(CH2)5-, -phenylene-(CH2)6-, -phenylene-(CH2)7-, -phenylene-(CH2)8-, -CH2-phenylene-CH2-, -CH2-phenylene-(CH2)2-, -CH2-phenylene-(CH2)3-, -CH2-phenylene-(CH2)4-, -CH2-phenylene-(CH2)5-, -CH2-phenylene-(CH2)6-, -CH2-phenylene-(CH2)7-, -CH2-phenylene-(CH2)8-, -(CH2)2-phenylene-(CH2)1-, -(CH2)2-phenylene-(CH2)2-, -(CH2)2-phenylene-(CH2)3-, -(CH2)2-phenylene-(CH2)4-, -(CH2)2-phenylene-(CH2)5-, -(CH2)2-phenylene-(CH2)6-, -(CH2)2-phenylene-(CH2)7-, -(CH2)2-phenylene-(CH2)8-, -(CH2)3-phenylene-CH2-, -(CH2)3-phenylene-(CH2)2-, -(CH2)3-phenylene-(CH2)3-, -(CH2)3-phenylene-(CH2)4-, -(CH2)3-phenylene-(CH2)5-, -(CH2)3-phenylene-(CH2)6-, -(CH2)3-phenylene-(CH2)7-, -(CH2)3-phenylene-(CH2)8-, -(CH2)4-phenylene-CH2-, -(CH2)4-phenylene-(CH2)2-, -(CH2)4-phenylene-(CH2)3-, -(CH2)4-phenylene-(CH2)4-, -(CH2)4-phenylene-(CH2)5-, -(CH2)4-phenylene-(CH2)6-, -(CH2)4-phenylene-(CH2)7-, -(CH2)4-phenylene-(CH2)8-, -(CH2)5-phenylene-(CH2)1-, -(CH2)5-phenylene-(CH2)2-, -(CH2)5-phenylene-(CH2)3-, -(CH2)5-phenylene-(CH2)4-, -(CH2)5-phenylene-(CH2)5-, -(CH2)5-phenylene-(CH2)6-, -(CH2)5-phenylene-(CH2)7-, -(CH2)5-phenylene-(CH2)8-, -(CH2)6-phenylene-(CH2)1-, -(CH2)6-phenylene-(CH2)2-, -(CH2)6-phenylene-(CH2)3-, -(CH2)6-phenylene-(CH2)4-, -(CH2)6-phenylene-(CH2)5-, -(CH2)6-phenylene-(CH2)6-, -(CH2)6-phenylene-(CH2)7-, -(CH2)6-phenylene-(CH2)8-, -(CH2)7-phenylene-(CH2)1-, -(CH2)7-phenylene-(CH2)2-, -(CH2)7-phenylene-(CH2)3-, -(CH2)7-phenylene-(CH2)4-, -(CH2)7-phenylene-(CH2)8-, -(CH2)8-phenylene-CH2-, -(CH2)8-phenylene-(CH2)2-, -(CH2)8-phenylene-(CH2)3-, -(CH2)8-phenylene-(CH2)4-, -(CH2)8-phenylene-(CH2)5-, -(CH2)8-phenylene-(CH2)6-, -(CH2)8-phenylene-(CH2)7-,    -N(Ra7)-CH2-phenylene-CH2-,    -N(Ra7)-CH2-phenylene-(CH2)2-,    -N(Ra7)-CH2-phenylene-(CH2)3-, -N(Ra7)-CH2-phenylene-(CH2)4-, -N(Ra7)-CH2-phenylene-(CH2)5-, -N(Ra7)-CH2-phenylene-(CH2)6-, -N(Ra7)-CH2-phenylene-(CH2)7-, -N(Ra7)-CH2-phenylene-(CH2)8-, -CH2-N(Ra7)-CH2-phenylene-CH2-, -CH2-N(Ra7)-CH2-phenylene-(CH2)2-, -CH2-N(Ra7)-CH2-phenylene-(CH2)3-, -CH2-N(Ra7)-CH2-phenylene-(CH2)4-, -CH2-N(Ra7)-CH2-phenylene-(CH2)5-, -CH2-N(Ra7)-CH2-phenylene-(CH2)6-, -CH2-N(Ra7)-CH2-phenylene-(CH2)7-, -CH2-N(Ra7)-CH2-phenylene-(CH2)8-,   -CH2-N(Ra7)-(CH2)2-phenylene-CH2-,   -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)2-, -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)3-, -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)4-, -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)5-,    -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)6-,    -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)7-,    -CH2-N(Ra7)-(CH2)2-phenylene-(CH2)8-,    -(CH2)2-N(Ra7)-CH2-phenylene-CH2-,   -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)2-,   -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)3-, -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)4-, -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)5-, -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)6-,    -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)7-,    -(CH2)2-N(Ra7)-CH2-phenylene-(CH2)8-, -(CH2)3-N(Ra7)-CH2-phenylene-CH2-, -(CH2)3-N(Ra7)-CH2-phenylene-(CH2)2-, -(CH2)3-N(Ra7)-CH2-phenylene-(CH2)3-, -(CH2)3-N(Ra7)-CH2-phenylene-(CH2)8-, -(CH2)4-N(Ra7)-CH2-phenylene-CH2-, -(CH2)4-N(Ra7)-CH2-phenylene-(CH2)2-, -(CH2)4-N(Ra7)-CH2-phenylene-(CH2)3-, -(CH2)4-N(Ra7)-CH2-phenylene-(CH2)8-, -(CH2)5-N(Ra7)-CH2-phenylene-(CH2)3-, -(CH2)5-N(Ra7)-CH2-phenylene-(CH2)8-, -(CH2)6-N(Ra7)-CH2-phenylene-(CH2)3-, -(CH2)6-N(Ra7)-CH2-phenylene-(CH2)8-, -(CH2)7-N(Ra7)-CH2-phenylene-(CH2)3-, -(CH2)8-N(Ra7)-CH2-phenylene-CH2-, -(CH2)8-N(Ra7)-CH2-phenylene-(CH2)2-, -(CH2)8-N(Ra7)-CH2-phenylene-(CH2)3-,     -(CH2)8-N(Ra7)-CH2-phenylene-(CH2)4-,     -(CH2)8-N(Ra7)-CH2-phenylene-(CH2)5-,    -(CH2)8-N(Ra7)-CH2-phenylene-(CH2)6-,    -piperidinylene-CH2-,    -piperidinylene-(CH2)2-, -piperidinylene-(CH2)3-, -piperidinylene-(CH2)4-, -piperidinylene-(CH2)5-, -piperidinylene-(CH2)6-, -piperidinylene-(CH2)7-, -piperidinylene-(CH2)8-,  -CH2-piperidinylene-CH2-,   -CH2-piperidinylene-(CH2)2-,   -CH2-piperidinylene-(CH2)3-,   -CH2-piperidinylene-(CH2)4-, -CH2-piperidinylene-(CH2)5-, -CH2-piperidinylene-(CH2)6-, -CH2-piperidinylene-(CH2)7-, -CH2-piperidinylene-(CH2)8-, -(CH2)2-piperidinylene-(CH2)1-, -(CH2)2-piperidinylene-(CH2)2-, -(CH2)2-piperidinylene-(CH2)3-, -(CH2)2-piperidinylene-(CH2)4-, -(CH2)2-piperidinylene-(CH2)5-, -(CH2)2-piperidinylene-(CH2)6-, -(CH2)2-piperidinylene-(CH2)7-, -(CH2)2-piperidinylene-(CH2)8-, -(CH2)3-piperidinylene-CH2-, -(CH2)3-piperidinylene-(CH2)2-, -(CH2)3-piperidinylene-(CH2)3-, -(CH2)3-piperidinylene-(CH2)4-, -(CH2)3-piperidinylene-(CH2)5-, -(CH2)3-piperidinylene-(CH2)6-, -(CH2)3-piperidinylene-(CH2)7-, -(CH2)3-piperidinylene-(CH2)8-, -(CH2)4-piperidinylene-CH2-, -(CH2)4-piperidinylene-(CH2)2-, -(CH2)4-piperidinylene-(CH2)3-, -(CH2)4-piperidinylene-(CH2)4-, -(CH2)4-piperidinylene-(CH2)5-, -(CH2)4-piperidinylene-(CH2)6-, -(CH2)4-piperidinylene-(CH2)7-, -(CH2)4-piperidinylene-(CH2)8-, -(CH2)5-piperidinylene-(CH2)1-, -(CH2)5-piperidinylene-(CH2)2-, -(CH2)5-piperidinylene-(CH2)3-, -(CH2)5-piperidinylene-(CH2)4-, -(CH2)5-piperidinylene-(CH2)5-, -(CH2)5-piperidinylene-(CH2)6-, -(CH2)5-piperidinylene-(CH2)7-, -(CH2)5-piperidinylene-(CH2)8-, -(CH2)6-piperidinylene-(CH2)1-, -(CH2)6-piperidinylene-(CH2)2-, -(CH2)6-piperidinylene-(CH2)3-, -(CH2)6-piperidinylene-(CH2)4-, -(CH2)6-piperidinylene-(CH2)5-, -(CH2)6-piperidinylene-(CH2)6-, -(CH2)6-piperidinylene-(CH2)7-, -(CH2)6-piperidinylene-(CH2)8-, -(CH2)7-piperidinylene-(CH2)1-, -(CH2)7-piperidinylene-(CH2)2-, -(CH2)7-piperidinylene-(CH2)3-, -(CH2)7-piperidinylene-(CH2)4-, -(CH2)7-piperidinylene-(CH2)8-, -(CH2)8-piperidinylene-CH2-, -(CH2)8-piperidinylene-(CH2)2-, -(CH2)8-piperidinylene-(CH2)3-, -(CH2)8-piperidinylene-(CH2)4-, -(CH2)8-piperidinylene-(CH2)5-, -(CH2)8-piperidinylene-(CH2)6-, -(CH2)8-piperidinylene-(CH2)7-, -N(Ra7)-CH2-piperidinylene-CH2-,      -N(Ra7)-CH2-piperidinylene-(CH2)2-,      -N(Ra7)-CH2-piperidinylene-(CH2)3-,    -N(Ra7)-CH2-piperidinylene-(CH2)4-,    -N(Ra7)-CH2-piperidinylene-(CH2)5-, -N(Ra7)-CH2-piperidinylene-(CH2)6-, -N(Ra7)-CH2-piperidinylene-(CH2)7-, -N(Ra7)-piperidinylene-(CH2)2-, piperidinylene-(CH2)4-, piperidinylene-(CH2)6-, piperidinylene-(CH2)8-, piperidinylene-(CH2)2-, piperidinylene-(CH2)4-, piperidinylene-(CH2)6-, piperidinylene-(CH2)8-, piperidinylene-(CH2)2-, piperidinylene-(CH2)4-, piperidinylene-(CH2)6-, piperidinylene-(CH2)8-, piperidinylene-(CH2)2-, piperidinylene-(CH2)8-, piperidinylene-(CH2)2-, piperidinylene-(CH2)8-, piperidinylene-(CH2)8-, piperidinylene-(CH2)8-,piperidinylene-CH2-, piperidinylene-(CH2)3-,-CH2-N(Ra7)-CH2-piperidinylene-(CH2)3-,-CH2-N(Ra7)-CH2-piperidinylene-(CH2)5-,-CH2-N(Ra7)-CH2-piperidinylene-(CH2)7-,-CH2-N(Ra7)-(CH2)2-piperidinylene-CH2-,-CH2-N(Ra7)-(CH2)2-piperidinylene-(CH2)3-,-CH2-N(Ra7)-(CH2)2-piperidinylene-(CH2)5-,-CH2-N(Ra7)-(CH2)2-piperidinylene-(CH2)7-,-(CH2)2-N(Ra7)-CH2-piperidinylene-CH2-,-(CH2)2-N(Ra7)-CH2-piperidinylene-(CH2)3-,-(CH2)2-N(Ra7)-CH2-piperidinylene-(CH2)5-,-(CH2)2-N(Ra7)-CH2-piperidinylene-(CH2)7-,-(CH2)3-N(Ra7)-CH2-piperidinylene-CH2-,-(CH2)3-N(Ra7)-CH2-piperidinylene-(CH2)3-,-(CH2)4-N(Ra7)-CH2-piperidinylene-CH2-,-(CH2)4-N(Ra7)-CH2-piperidinylene-(CH2)3-,-(CH2)5-N(Ra7)-CH2-piperidinylene-(CH2)3-,-(CH2)6-N(Ra7)-CH2-piperidinylene-(CH2)3-,-(CH2)7-N(Ra7)-CH2-piperidinylene-(CH2)3-,-(CH2)8-N(Ra7)-CH2-piperidinylene-(CH2)2-,-(CH2)8-N(Ra7)-CH2-piperidinylene-(CH2)4-,-CH2-N(Ra7)-CH2--CH2-N(Ra7)-CH2--CH2-N(Ra7)-CH2--CH2-N(Ra7)-(CH2)2--CH2-N(Ra7)-(CH2)2--CH2-N(Ra7)-(CH2)2--CH2-N(Ra7)-(CH2)2--(CH2)2-N(Ra7)-CH2--(CH2)2-N(Ra7)-CH2--(CH2)2-N(Ra7)-CH2--(CH2)2-N(Ra7)-CH2--(CH2)3-N(Ra7)-CH2--(CH2)3-N(Ra7)-CH2--(CH2)4-N(Ra7)-CH2--(CH2)4-N(Ra7)-CH2--(CH2)5-N(Ra7)-CH2--(CH2)6-N(Ra7)-CH2--(CH2)8-N(Ra7)-CH2--(CH2)8-N(Ra7)-CH2--(CH2)8-N(Ra7)-CH2-piperidinylene-(CH2)5-, -(CH2)8-N(Ra7)-CH2-piperidinylene-(CH2)6-,  -piperazinylene-CH2-,  -piperazinylene-(CH2)2-,  -piperazinylene-(CH2)3-,  -piperazinylene-(CH2)4-,  -piperazinylene-(CH2)5-, -piperazinylene-(CH2)6-, -piperazinylene-(CH2)7-, -piperazinylene-(CH2)8-,  -CH2-piperazinylene-CH2-,   -CH2-piperazinylene-(CH2)2-,   -CH2-piperazinylene-(CH2)3-,   -CH2-piperazinylene-(CH2)4-, -CH2-piperazinylene-(CH2)5-, -CH2-piperazinylene-(CH2)6-, -CH2-piperazinylene-(CH2)7-, -CH2-piperazinylene-(CH2)8-, -(CH2)2-piperazinylene-(CH2)1-, -(CH2)2-piperazinylene-(CH2)2-, -(CH2)2-piperazinylene-(CH2)3-, -(CH2)2-piperazinylene-(CH2)4-, -(CH2)2-piperazinylene-(CH2)5-, -(CH2)2-piperazinylene-(CH2)6-, -(CH2)2-piperazinylene-(CH2)7-, -(CH2)2-piperazinylene-(CH2)8-, -(CH2)3-piperazinylene-CH2-, -(CH2)3-piperazinylene-(CH2)2-, -(CH2)3-piperazinylene-(CH2)3-, -(CH2)3-piperazinylene-(CH2)4-, -(CH2)3-piperazinylene-(CH2)5-, -(CH2)3-piperazinylene-(CH2)6-, -(CH2)3-piperazinylene-(CH2)7-, -(CH2)3-piperazinylene-(CH2)8-, -(CH2)4-piperazinylene-CH2-, -(CH2)4-piperazinylene-(CH2)2-, -(CH2)4-piperazinylene-(CH2)3-, -(CH2)4-piperazinylene-(CH2)4-, -(CH2)4-piperazinylene-(CH2)5-, -(CH2)4-piperazinylene-(CH2)6-, -(CH2)4-piperazinylene-(CH2)7-, -(CH2)4-piperazinylene-(CH2)8-, -(CH2)5-piperazinylene-(CH2)1-,-(CH2)5-piperazinylene-(CH2)2-, -(CH2)5-piperazinylene-(CH2)3-, -(CH2)5-piperazinylene-(CH2)4-, -(CH2)5-piperazinylene-(CH2)5-, -(CH2)5-piperazinylene-(CH2)6-, -(CH2)5-piperazinylene-(CH2)7-, -(CH2)5-piperazinylene-(CH2)8-, -(CH2)6-piperazinylene-(CH2)1-, -(CH2)6-piperazinylene-(CH2)2-, -(CH2)6-piperazinylene-(CH2)3-, -(CH2)6-piperazinylene-(CH2)4-, -(CH2)6-piperazinylene-(CH2)5-, -(CH2)6-piperazinylene-(CH2)6-, -(CH2)6-piperazinylene-(CH2)7-, -(CH2)6-piperazinylene-(CH2)8-, -(CH2)7-piperazinylene-(CH2)1-, -(CH2)7-piperazinylene-(CH2)2-, -(CH2)7-piperazinylene-(CH2)3-, -(CH2)7-piperazinylene-(CH2)4-, -(CH2)8-piperazinylene-CH2-, -(CH2)8-piperazinylene-(CH2)2-, -(CH2)8-piperazinylene-(CH2)3-, -(CH2)8-piperazinylene-(CH2)4-, -(CH2)8-piperazinylene-(CH2)5-, or -(CH2)8-piperazinylene-(CH2)6-;wherein each Ra7 independently represents H or C1-3 alkyl;the phenylene, piperazinylene and piperidinylene are each independently optionally substituted with a substituent selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and any combination thereof.

18. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-17, wherein LIN represents: a bond, C(O), C(O)NH, NHC(O), -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2)10-, -(CH2)11-, -(CH2)12-, -(CH2)13-, -(CH2)14-, -(CH2)15-; -O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)7-, -O-(CH2)8-, -O-(CH2)9-, -O-(CH2)10-, -(CH2)1-O-, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)7-O-, -(CH2)8-O-, -(CH2)9-O-, -(CH2)10-O-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -(CH2)1-O-(CH2)3-, -(CH2)1-O-(CH2)4-, -(CH2)1-O-(CH2)5-, -(CH2)1-O-(CH2)6-, -(CH2)1-O-(CH2)7-, -(CH2)1-O-(CH2)8-, -(CH2)2-O-(CH2)1-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)2-O-(CH2)5-, -(CH2)2-O-(CH2)6-, -(CH2)2-O-(CH2)7-, -(CH2)2-O-(CH2)8-, -(CH2)3-O-(CH2)1-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)3-O-(CH2)4-, -(CH2)3-O-(CH2)5-, -(CH2)3-O-(CH2)6-, -(CH2)3-O-(CH2)7-, -(CH2)4-O-(CH2)1-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-, -(CH2)4-O-(CH2)5-, -(CH2)4-O-(CH2)6-, -(CH2)5-O-(CH2)1-, -(CH2)5-O-(CH2)2-, -(CH2)5-O-(CH2)3-, -(CH2)5-O-(CH2)4-, -(CH2)5-O-(CH2)5-, -(CH2)6-O-(CH2)1-, -(CH2)6-O-(CH2)2-, -(CH2)6-O-(CH2)3-, -(CH2)6-O-(CH2)4-, -(CH2)7-O-(CH2)1-, -(CH2)7-O-(CH2)2-, -(CH2)7-O-(CH2)3-, -(CH2)8-O-(CH2)1-, -(CH2)8-O-(CH2)2-, -CH(CH3)-O-(CH2)1-, -CH(CH3)-O-(CH2)2-, -CH(CH3)-O-(CH2)3-, -CH(CH3)-O-(CH2)4-, -CH(CH3)-O-(CH2)5-,  -CH(CH3)-O-(CH2)6-, -CH(CH3)-O-(CH2)7-, -CH(CH3)-O-(CH2)8-, -(O(CH2)2)2-, -(O(CH2)2)3-, -(O(CH2)2)4-, -(O(CH2)2)5-, -(O(CH2)2)6-, -CH2-(O(CH2)2)2-, -CH2-(O(CH2)2)3-, -CH2-(O(CH2)2)4-, -CH2-(O(CH2)2)5-, -CH2-(O(CH2)2)6-, -CH2-(O(CH2)2)1-OCH2-, -CH2-(O(CH2)2)2-OCH2-, -CH2-(O(CH2)2)3-OCH2-, -CH2-(O(CH2)2)4-OCH2-, -CH2-(O(CH2)2)5-OCH2-, -CH2-(O(CH2)2)6-OCH2-, -(CH2)2-(O(CH2)2)2-, -(CH2)2-(O(CH2)2)3-, -(CH2)2-(O(CH2)2)4-, -(CH2)2-(O(CH2)2)5-,   -(CH2)2-(O(CH2)2)6-, -(CH2)3-(O(CH2)2)2-,   -(CH2)3-(O(CH2)2)3-, -(CH2)3-(O(CH2)2)4-,   -(CH2)3-(O(CH2)2)5-, -(CH2)4-(O(CH2)2)2-,   -(CH2)4-(O(CH2)2)3-, -(CH2)4-(O(CH2)2)4-, -(CH2)4-(O(CH2)2)5-, -CH2-(O(CH2)3)2-, -CH2-(O(CH2)3)3-, -CH2-(O(CH2)3)4-, -(CH2)2-(O(CH2)3)2-, -(CH2)2-(O(CH2)3)3-, -(CH2)2-(O(CH2)3)4-, -(CH2)3-(O(CH2)3)2-, -(CH2)3-(O(CH2)3)3-, -CH2-O-(CH2)2-O-(CH2)3-, -CH2-(O(CH2)2)2-(O(CH2)3)2-, (CH2)2-O-(CH2)2-O-(CH2)3-, -(CH2)2-(O(CH2)2)2-(O(CH2)3)2-, -(CH2)3-O-(CH2)2-O-(CH2)3-, -(CH2)3-(O(CH2)2)2-(O(CH2)3)2-, -CH2-O-(CH2)3-O-(CH2)2-, -CH2-(O(CH2)3)2-(O(CH2)2)2-, (CH2)1-N(Ra7)-(CH2)1-, -(CH2)1-N(Ra7)-(CH2)2-, -(CH2)1-N(Ra7)-(CH2)3-,   -(CH2)1-N(Ra7)-(CH2)4-, -(CH2)1-N(Ra7)-(CH2)5-, -(CH2)1-N(Ra7)-(CH2)6-, -N(Ra7)-(CH2)1-, -N(Ra7)-(CH2)2-, -N(Ra7)-(CH2)3-, -N(Ra7)-(CH2)4-, -N(Ra7)-(CH2)5-, -N(Ra7)-(CH2)6-, -(CH2)2-N(Ra7)-(CH2)1-, -(CH2)2-N(Ra7)-(CH2)2-, -(CH2)2-N(Ra7)-(CH2)3-, -(CH2)2-N(Ra7)-(CH2)4-,   -(CH2)2-N(Ra7)-(CH2)5-, -(CH2)2-N(Ra7)-(CH2)6-, -(CH2)3-N(Ra7)-(CH2)1-, -(CH2)3-N(Ra7)-(CH2)2-, -(CH2)3-N(Ra7)-(CH2)3-, -(CH2)4-N(Ra7)-(CH2)1-, -(CH2)4-N(Ra7)-(CH2)2-, -(CH2)4-N(Ra7)-(CH2)3-, -(CH2)4-N(Ra7)-(CH2)4-,  -(CH2)5-N(Ra7)-(CH2)1-, -(CH2)5-N(Ra7)-(CH2)2-,   -(CH2)5-N(Ra7)-(CH2)3-, -(CH2)5-N(Ra7)-(CH2)4-, -(CH2)5-N(Ra7)-(CH2)5-, -(CH2)6-N(Ra7)-(CH2)1-, -(CH2)6-N(Ra7)-(CH2)2-, -(CH2)6-N(Ra7)-(CH2)3-, -(CH2)7-N(Ra7)-(CH2)1-, -(CH2)7-N(Ra7)-(CH2)2-, -(CH2)7-N(Ra7)-(CH2)3-,  -(CH2)8-N(Ra7)-(CH2)1-, -(CH2)8-N(Ra7)-(CH2)2-, -(CH2)8-N(Ra7)-(CH2)3-, -CH(CH3)-N(Ra7)-(CH2)1-, -CH(CH3)-N(Ra7)-(CH2)2-, -CH(CH3)-N(Ra7)-(CH2)3-, -CH(CH3)-N(Ra7)-(CH2)4-, -CH(CH3)-N(Ra7)-(CH2)5-, -CH(CH3)-N(Ra7)-(CH2)6-, -C(O)NHCH2-, -C(O)NH(CH2)2-,  -C(O)NH(CH2)3-,     -C(O)NH(CH2)4-,     -C(O)NH(CH2)5-,     -CH2C(O)NHCH2-,     -(CH2)2C(O)NH(CH2)2-,       -(CH2)2C(O)NH(CH2)3-,       -(CH2)2C(O)NH(CH2)4-,       -(CH2)2C(O)NH(CH2)5-,       -(CH2)3C(O)NH(CH2)3-,       -(CH2)3C(O)NH(CH2)4-,       -(CH2)4C(O)NH(CH2)4-,    -(CH2)5C(O)NH(CH2)5-,    -(CH2)2C(O)NH(CH2)2-O-(CH2)2-,    -NHC(O)CH2-, -NHC(O)(CH2)2-, -NHC(O)(CH2)3-, -NHC(O)(CH2)4-, -NHC(O)(CH2)5-,  -CH2NHC(O)CH2-, -(CH2)2NHC(O)(CH2)2-, -(CH2)2NHC(O)(CH2)3-, -(CH2)2NHC(O)(CH2)4-, -(CH2)2NHC(O)(CH2)5-,       -(CH2)3NHC(O)(CH2)3-,       -(CH2)3NHC(O)(CH2)4-,       -(CH2)4NHC(O)(CH2)4-,    -(CH2)5NHC(O)(CH2)5-,    -(CH2)2NHC(O)(CH2)2-O-(CH2)2-,    -(CH2)4NHC(O)CH2-, -CH2-phenylene-CH2-, -CH2-phenylene-(CH2)2-, -CH2-phenylene-(CH2)3-, -CH2-phenylene-(CH2)4-, -CH2-phenylene-(CH2)5-, -CH2-phenylene-(CH2)6-, -(CH2)2-phenylene-(CH2)1-, -(CH2)2-phenylene-(CH2)2-, -(CH2)2-phenylene-(CH2)3-, -(CH2)2-phenylene-(CH2)4-, -(CH2)2-phenylene-(CH2)5-, -(CH2)3-phenylene-CH2-, -(CH2)3-phenylene-(CH2)2-, -(CH2)3-phenylene-(CH2)3-, -(CH2)3-phenylene-(CH2)4-, -(CH2)3-phenylene-(CH2)5-, -(CH2)4-phenylene-CH2-, -(CH2)4-phenylene-(CH2)2-, -(CH2)4-phenylene-(CH2)3-, -(CH2)4-phenylene-(CH2)4-, -(CH2)4-phenylene-(CH2)5-, -CH2-piperidinylene-CH2-, -CH2-piperidinylene-(CH2)2-, -CH2-piperidinylene-(CH2)3-, -CH2-piperidinylene-(CH2)4-, -CH2-piperidinylene-(CH2)5-, -CH2-piperidinylene-(CH2)6-, -(CH2)2-piperidinylene-(CH2)1-, -(CH2)2-piperidinylene-(CH2)2-, -(CH2)2-piperidinylene-(CH2)3-, -(CH2)2-piperidinylene-(CH2)4-, -(CH2)2-piperidinylene-(CH2)5-, -(CH2)3-piperidinylene-CH2-, -(CH2)3-piperidinylene-(CH2)2-, -(CH2)3-piperidinylene-(CH2)3-, -(CH2)3-piperidinylene-(CH2)4-, -(CH2)3-piperidinylene-(CH2)5-, -CH2-piperazinylene-CH2-, -CH2-piperazinylene-(CH2)2-, -CH2-piperazinylene-(CH2)3-, -CH2-piperazinylene-(CH2)4-, -CH2-piperazinylene-(CH2)5-, -(CH2)2-piperazinylene-(CH2)1-, -(CH2)2-piperazinylene-(CH2)2-, -(CH2)2-piperazinylene-(CH2)3-, -(CH2)2-piperazinylene-(CH2)4-, -(CH2)2-piperazinylene-(CH2)5-, -(CH2)3-piperazinylene-CH2-, -(CH2)3-piperazinylene-(CH2)2-, -(CH2)3-piperazinylene-(CH2)3-, -(CH2)3-piperazinylene-(CH2)4-, -(CH2)3-piperazinylene-(CH2)5-, -(CH2)4-piperazinylene-CH2-, -(CH2)4-piperazinylene-(CH2)2-, -(CH2)4-piperazinylene-(CH2)3-, -(CH2)4-piperazinylene-(CH2)4-, -(CH2)4-piperazinylene-(CH2)5-, -(CH2)8-piperazinylene-CH2-, -(CH2)8-piperazinylene-(CH2)2-, -(CH2)8-piperazinylene-(CH2)3-, -(CH2)8-piperazinylene-(CH2)4-, or -(CH2)8-piperazinylene-(CH2)5-; orLIN represents:Di-Xycy- i-CXy^OCX h>€X nXO■^a^nC^ c^nSH4yy-NCN^ ~^L / ~NTy^^4^NC^_ 'Kiyo 400 ^n'wherein the 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, carboxyl, C2-6 alkynyl, and C2-6 alkenyl.

19. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-18, whichis also represented by Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I-6), Formula (I-7), or Formula (I-8):(1-2)wherein Z, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Ra6, LIN, Rc, (R1a)p1a, R1b, (R1c)p1b, R1d, ring A, R2a, R2b, (R2c)p2a, (R2d)p2b, (R3a)p3a, R3b, X1, X2, X3, X4, R4a, R4b, (R4c)p4a, (R4d)p4b, ring B, R5a, R5b, (R6a)p6a, (R6b)p6b, Rx1, ring C, ring D, ring E, R8a, R8b, (R8c)p8a, and (R8d)p8b are as defined in claim 3.

20. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 1, which is selected fromthe compounds in Table 1.

21. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof as claimed in any one of claims 1-20, which is hydrohalides (including hydrochlorides, hydrobromides), sulfates, maleates, sulfonates, citrates, lactates, lactobionates, L-tartrates, fumarates, L-malates, L-lactates, a-Ketoglutarates, hippurates, D-glucuronates, D-gluconates, a-D-glucoheptonates, glycolates, mucates, L-ascorbates, orotates, picrates, glycinates, alaninates, argininates, cinnamates, laurates, pamoates, sebacates, benzenesulfonates, methanesulfonates, ethanesulfonates, edisylates, formates, acetates, 2,2-dichloroacetates, trimethylacetates, propionates, valerates, palmitates, triphenylacetates, 2-ethylsuccinates, iodates, niacinates, L-pyroglutamates, L-prolinates, ferulates, 2-hydroxyethanesulfonates, nitrates, gentisates, cholates, salicylates, terephthalates, glutarates, adipates, stearates, oleates, undecenoates, camphorates,320 camphorsulfonates, dodecyl sulfonates, phosphates, thiocyanates, dihydrophosphates, pyrophosphates, metaphosphates, oxalates, carbonates, malonates, benzoates, mandelates, succinates, pyruvates, para-chlorobenzenesulfonates, 1,5-naphthalenedisulfonates, 3-hydroxy-2-naphthoates, 1-hydroxy-2-naphthoates, 2-naphthalenesulfonates, trifluoroacetate, glycolate, or 4-methylbenzenesulfonate of the compound of Formula (I).

22. A compound of Formula (II)(II)or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof,wherein Z represents C(O) or CH2;Ra1, Ra2, Ra3, and Ra4 are identical or different and each independently represents 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, wherein each Ra5 is identical or different and independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, or halogenated C1-6 alkoxy;m represents an integer of 0, 1, 2, or 3;RE represents:RE1—r^Y^J—Ri-^-(Rdl)n1wherein ring Y1 represents heterocyclylene containing at least two nitrogen atoms, and (Rd1)n1 indicates that ring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 0-20; andR1 represents N(Rw), where Rw represents hydrogen or C1-3 alkyl, and RE1 represents hydrogen; orR1 represents a bond, and RE1 represents NH2; orRE represents:(Rd3)n3Re2 ~ N^Y^— Rs1~^wherein ring Y3 represents heterocyclylene containing one nitrogen atom, and (Rd3)n3 indicates that ring Y3 is optionally substituted with n3 Rd3 groups, wherein each Rd3 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n3 represents an integer of 0-20; and* * * *wherein Rsi represents         °-2   , symbol **** indicates the point of attachment toring Y3; and RE2 represents NH2;provided that the following compounds are excluded:3-(1-oxo-5-(piperazin-1-ylamino)isoindolin-2-yl)piperidine-2,6-dione.

23. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 22, wherein the compound of Formula (II) is also represented by Formula (II-1), Formula (II-2), Formula (II-3), or Formula (II-4):wherein Z, Ra1, Ra2, Ra3, Ra4, (Ra5)m, and RE are as defined in claim 21.

24. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 22 or 23, wherein(i) when Z represents CH2, m represents an integer of 0, Rw represents hydrogen, and ring Y1 represents piperazinyl, ring Y1 is substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 1-20; or(ii) ring Y1 represents 4- to 20-membered heterocyclylene containing at least two nitrogen atoms, and (Rd1)n1 indicates that ring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 0-20; or(iii) ring Y3 represents 4- to 20-membered heterocyclylene containing one nitrogen atom, and (Rd3)n3 indicates that ring Y3 is optionally substituted with n3 Rd3 groups, wherein each Rd3independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, andn3 represents an integer of 0-20.

25. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-24, wherein ring Y1 represents 4- to 20-membered heterocyclylene containing 2 to 4 nitrogen atoms, e.g., ring Y1 represents:diazetidinylene, imidazolidylene, pyrazolidylene, piperazinylene, 1,2,3,4-tetrahydropyrazinylene, diazacycloheptanylene,hexahydropyrimidinylene,       hexahydropyridazinylene,diazacyclooctylene,        diazabicyclo[3.1.1]heptanylene,diazabicyclo[2.2.1]heptanylene, diazabicyclo[2.2.2]octanylene, diazaspiro[2.4]heptanylene, diazaspiro[4.4]nonanylene,diazaspiro[2.3]hexylene, diazaspiro[3.4]octanylene, diazaspiro[4.5]decanylene,diazabicyclo[3.2.1]octanylene, diazaspiro[3.3]heptanylene, diazaspiro[3.5]nonanylene, diazaspiro[5.5]undecanylene,octahydropyrrolo[3,4-c]pyrrolylene, or decahydronaphthyridinylene, orJ / N 'V 4~N\f / H' -^r ^4" -^-N^yM-|- 4"^ YN~^ __ / N”^ring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independentlyrepresents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl,deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 0-20.

26. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 22, which is selected from the compounds in Table 2.

27. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof as claimed in any one of claims 22-26, which is hydrohalides (including hydrochlorides, hydrobromides), sulfates, maleates, sulfonates, citrates, lactates, lactobionates, L-tartrates, fumarates, L-malates, L-lactates, a-Ketoglutarates, hippurates, D-glucuronates, D-gluconates, a-D-glucoheptonates, glycolates, mucates, L-ascorbates, orotates, picrates, glycinates, alaninates, argininates, cinnamates, laurates, pamoates, sebacates, benzenesulfonates, methanesulfonates, ethanesulfonates, edisylates, formates, acetates, 2,2-dichloroacetates, trimethylacetates, propionates, valerates, palmitates, triphenylacetates, 2-ethylsuccinates, iodates, niacinates, L-pyroglutamates, L-prolinates, ferulates, 2-hydroxyethanesulfonates, nitrates, gentisates, cholates, salicylates, terephthalates, glutarates, adipates, stearates, oleates, undecenoates, camphorates, camphorsulfonates, dodecyl sulfonates, phosphates, thiocyanates, dihydrophosphates, pyrophosphates, metaphosphates, oxalates, carbonates, malonates, benzoates, mandelates, succinates, pyruvates, para-chlorobenzenesulfonates, 1,5-naphthalenedisulfonates, 3-hydroxy-2-naphthoates, 1-hydroxy-2-naphthoates, 2-naphthalenesulfonates, trifluoroacetate, glycolate, or 4-methylbenzenesulfonate of the compound of Formula (II).

28. A pharmaceutical composition, comprising:the compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-21, and at least one pharmaceutically acceptable carrier; orthe compound of Formula (II) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-27, and at least one pharmaceutically acceptable carrier;and optionally comprising at least one additional therapeutic agent, e.g., an anticancer agent.

29. A medicine kit or reagent kit comprising:the compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-21; orthe compound of Formula (II) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 22-27; orthe pharmaceutical composition as claimed in claim 28.

30. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopicallyenriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-21, for use in the prevention and / or treatment of a disease or disorder selected from the group consisting of: tumors, infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological disorders, respiratory diseases, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, Richter syndrome (RS), acute liver failure, diabetes, Kennedy disease, seborrheic alopecia, hirsutism, skin diseases, dysfunctional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, polycystic ovary syndrome, and thyroid diseases.

31. The compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 30, 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 (AML), chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, B-cell acute lymphoblastic leukemia, T-cell lymphocytic leukemia, T-cell acute 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 large B-cell lymphoma, primary mediastinal 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 large B-cell lymphoma, refractory transformed non-Hodgkin’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; glioma; peripheral neuroepithelioma; 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; 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 1 diabetes mellitus, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis sicca; autoinflammatory diseases, including gout etc.; 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; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplantation rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; multiple organ dysfunction caused by cachexia and septic shock; acute liver failure; dysfunctional uterine bleeding; anemia; pediatric aplastic anemia; endometriosis; polycystic ovary syndrome; thyroid disease; cardiovascular diseases (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); skin diseases (e.g., acne); Kennedy disease; seborrheic alopecia; and hirsutism.

32. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-27, for use in the prevention and / or treatment of a disease or disorder associated with cereblon protein.

33. The compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 32, wherein the disease or disorder associated with cereblon protein is selected from the group consisting of: tumors, cancers, and autoimmune diseases, e.g., 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 (AML), chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, B-cell acute lymphoblastic leukemia, T-cell lymphocytic leukemia, T-cellacute 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 large B-cell lymphoma, primary mediastinal 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 large B-cell lymphoma, refractory transformed non-Hodgkin’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; glioma; peripheral neuroepithelioma; 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; 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); and 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 1 diabetes mellitus, urticaria, and inflammatory bowel disease (including Crohn's disease and ulcerative colitis).

34. Use of the compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-21 for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder selected from the group consisting of: tumors, infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological disorders, respiratory diseases, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, Richter syndrome (RS),acute liver failure, diabetes, Kennedy disease, seborrheic alopecia, hirsutism, skin diseases, dysfunctional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, polycystic ovary syndrome, and thyroid diseases.

35. 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 salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 1-21, wherein the disease or disorder is selected from the group consisting of: tumors, infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological disorders, respiratory diseases, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, Richter syndrome (RS), acute liver failure, diabetes, Kennedy disease, seborrheic alopecia, hirsutism, skin diseases, dysfunctional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, polycystic ovary syndrome, and thyroid diseases.

36. The use as claimed in claim 34, or the method as claimed in claim 35, 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 (AML), chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, B-cell acute lymphoblastic leukemia, T-cell lymphocytic leukemia, T-cell acute 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 large B-cell lymphoma, primary mediastinal 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 large B-cell lymphoma, refractory transformed non-Hodgkin’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; glioma; peripheral neuroepithelioma; ovarian cancer; bronchial cancer; prostatecancer; 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; 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 1 diabetes mellitus, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis sicca; autoinflammatory diseases, including gout etc.; 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; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplantation rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; multiple organ dysfunction caused by cachexia and septic shock; acute liver failure; dysfunctional uterine bleeding; anemia; pediatric aplastic anemia; endometriosis; polycystic ovary syndrome; thyroid disease; cardiovascular diseases (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); skin diseases (e.g., acne); Kennedy disease; seborrheic alopecia; and hirsutism.

37. Use of the compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-27, or 3-(1-oxo-5-(piperazin-1-ylamino)isoindolin-2-yl)piperidine-2,6-dione or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder associated with cereblon protein.

38. 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 thecompound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-27, or the pharmaceutical composition as claimed in claim 30 or 31, 3-(1-oxo-5-(piperazin-1-ylamino)isoindolin-2-yl)piperidine-2,6-dione or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof.

39. The use as claimed in claim 37, or the method as claimed in claim 38, wherein the disease or disorder associated with cereblon protein is selected from the group consisting of: tumors, cancers, and autoimmune diseases.

40. The use as claimed in claim 37, or the method as claimed in claim 38, wherein the disease or disorder associated with cereblon protein 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 (AML), chronic myeloid leukemia (CML), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, leukemia-associated anemia, B-cell acute lymphoblastic leukemia, T-cell lymphocytic leukemia, T-cell acute 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 large B-cell lymphoma, primary mediastinal 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 large B-cell lymphoma, refractory transformed nonHodgkin’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; glioma; peripheral neuroepithelioma; 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; 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); and 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 1 diabetes mellitus, urticaria, and inflammatory bowel disease (including Crohn's disease and ulcerative colitis).

41. Use of the compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-27, or 3-(1-oxo-5-(piperazin-1-ylamino)isoindolin-2-yl)piperidine-2,6-dione or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof for the manufacture of a CRBN binder.

42. Use of the compound of Formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in any one of claims 22-27, or 3-(1-oxo-5-(piperazin-1-ylamino)isoindolin-2-yl)piperidine-2,6-dione or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof for the preparation of the compound of Formula (I) or salts, enantiomers, stereoisomers,solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof as claimed in claim 1.

43. A method for preparing the compound of Formula (I) as claimed in claim 1, comprisingusing a compound of Formula (M1) and a compound of Formula (M2) as starting materials toobtain the compound of Formula (I):wherein PBM, Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z, Rw2, ring A1, ring A2, ring A3, y1, y2, y3, (Ry1)a1, (Ry2)a2, and (Ry3)a3 are as defined in claim 1; andRw3 represents a bond or an optionally substituted linear or branched C1-19 alkylene, wherein any one or more methylene groups in the main carbon chain skeleton of the linear or branchedC1-19 alkylene are optionally replaced by one or more groups selected from: Ra, Rb, and any combination thereof; wherein each Ra is independently selected from the group consisting of: O, C(O), OC(O), S, S(O), S(O)2, S(O)2N(Ra7), N(Ra7)S(O)2, C(O)N(Ra7), N(Ra7)C(O), N(Ra7), and N(Ra7)C(O)N(Ra7), where each Ra7 independently represents H or C1-3 alkyl, and when any two or more methylene in the main carbon chain skeleton of the linear or branched C1-19 alkylene are replaced by two or more Ra groups, the Ra groups are not directly connected to each other; and wherein each Rb is independently selected from the group consisting of: optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, alkynylene, alkenylene, and any combination thereof; and wherein one or more hydrogens of said linear or branched C1-19 alkylene are optionally replaced by a substituent selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, deuterated C3-6 cycloalkyl, 4- to 10membered heterocyclyl, and any combination thereof; andRw4 represents CHO, COOH, or (Rd2)n2, wherein ring Y2 and (Rd2)n2 are as defined in claim 1;wherein (1) when Rw4 represents CHO or COOH,(a1) RL1 represents N(Rw), and RL2 and RL3, together with the nitrogen atomto which they are attached, form (Rdi)m ; or(a2) Rli and Rl2 together form     (Rdi)ni , and Rl3 represents H or C1-3 alkyl;or(a3) RL1 represents NH, RL2 represents a bond, and RL3 represents H; or(a4) RL1 represents0-2   , wherein the symbol **** indicates the(Rd3)n3point of attachment to RL2, RL2### represents, wherein the symbol ###indicates the point of attachment to N, and ring Y3 and (Rd3)n3 are as defined in claim 1, and RL3 represents H or C1-3 alkyl; orwherein (2) when Rw4 represents (Rd2)n2, Rli represents N(Rw), and Rl2 and Rl3, togetherwith the nitrogen atom to which they are attached, form (Rdi)ni ; and wherein each of the above Rw, ring Y1, and (Rd1)n1 is as defined in claim 1.

44. The method as claimed in claim 43, wherein(1) when Rw4 represents CHO, the compound of Formula (M1) and the compound of Formula (M2) are subjected to a reductive amination reaction to give the compound of Formula (I), wherein the moiety 2R«1 Ra6 in the compound of Formula (I) correspondingly represents a structure represented by the following general formula:RL34rw3-CH2-N--RL2—Rli4-      .;(2) when Rw4 represents COOH, the compound of Formula (M1) and the compound ofFormula (M2) are subjected to an amide condensation reaction to give the compound of Formula—I—R __R  (I), wherein the moiety 5 w1 a6 ? in the compound of Formula (I) correspondinglyrepresents a structure represented by the following general formula:Ri 3O |4"rw3—c—N—RL2; or(3) when Rw4 represents (Rd2)n2, the compound of Formula (M1) and the compound ofFormula (M2) are subjected to a urea-forming reaction to give the compound of Formula (I), wherein the moiety ’ w1 a6 * in the compound of Formula (I) correspondingly represents a structure represented by the following general formula:(Rd2)n2 (Rdl)n1*45. A method for preparing the compound of Formula (II) as claimed in claim 22, comprising using a compound of Formula (M3) and a compound of Formula (M4) as starting materials toobtain the compound of Formula (II):M3(Rdl)n1wherein Ra1, Ra2, Ra3, Ra4, (Ra5)m, Z, ring Y1, Rw, and (Rd1)n1 are as defined in claim 22;Y represents F or Br;W1 represents H, and W2 represents an amino protecting group; orW1 represents an amino protecting group, and W2 represents H; andRE represents:Rei—R^(Rdl)n1wherein ring Y1 represents heterocyclylene containing at least two nitrogen atoms, and (Rd1)n1 indicates that ring Y1 is optionally substituted with n1 Rd1 groups, wherein each Rd1 independently represents deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, oxo, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or C1-6 alkoxy, and n1 represents an integer of 0-20; andR1 represents N(Rw), where Rw represents hydrogen or C1-3 alkyl, and RE1 represents hydrogen; orR1 represents a bond, and RE1 represents NH2.

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